Melatonin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

MELATONIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J AMES N. ...

Author: ICON Health Publications

31 downloads 666 Views 5MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

MELATONIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

ii

ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Melatonin: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84032-6 1. Melatonin-Popular works. I. Title.

iii

Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

iv

Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on melatonin. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

v

About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

vi

About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

vii

Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON MELATONIN .............................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Melatonin...................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 57 The National Library of Medicine: PubMed ................................................................................ 59 CHAPTER 2. NUTRITION AND MELATONIN .................................................................................. 105 Overview.................................................................................................................................... 105 Finding Nutrition Studies on Melatonin .................................................................................. 105 Federal Resources on Nutrition ................................................................................................. 115 Additional Web Resources ......................................................................................................... 115 CHAPTER 3. ALTERNATIVE MEDICINE AND MELATONIN............................................................ 117 Overview.................................................................................................................................... 117 The Combined Health Information Database............................................................................. 117 National Center for Complementary and Alternative Medicine................................................ 118 Additional Web Resources ......................................................................................................... 139 General References ..................................................................................................................... 145 CHAPTER 4. DISSERTATIONS ON MELATONIN ............................................................................. 147 Overview.................................................................................................................................... 147 Dissertations on Melatonin ....................................................................................................... 147 Keeping Current ........................................................................................................................ 148 CHAPTER 5. CLINICAL TRIALS AND MELATONIN ........................................................................ 149 Overview.................................................................................................................................... 149 Recent Trials on Melatonin ....................................................................................................... 149 Keeping Current on Clinical Trials ........................................................................................... 151 CHAPTER 6. PATENTS ON MELATONIN ........................................................................................ 153 Overview.................................................................................................................................... 153 Patents on Melatonin................................................................................................................. 153 Patent Applications on Melatonin............................................................................................. 174 Keeping Current ........................................................................................................................ 187 CHAPTER 7. BOOKS ON MELATONIN ............................................................................................ 189 Overview.................................................................................................................................... 189 Book Summaries: Federal Agencies............................................................................................ 189 Book Summaries: Online Booksellers......................................................................................... 190 The National Library of Medicine Book Index ........................................................................... 193 Chapters on Melatonin .............................................................................................................. 193 Directories.................................................................................................................................. 194 CHAPTER 8. MULTIMEDIA ON MELATONIN ................................................................................. 195 Overview.................................................................................................................................... 195 Bibliography: Multimedia on Melatonin ................................................................................... 195 CHAPTER 9. PERIODICALS AND NEWS ON MELATONIN .............................................................. 197 Overview.................................................................................................................................... 197 News Services and Press Releases.............................................................................................. 197 Academic Periodicals covering Melatonin ................................................................................. 202 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 205 Overview.................................................................................................................................... 205 NIH Guidelines.......................................................................................................................... 205 NIH Databases........................................................................................................................... 207 Other Commercial Databases..................................................................................................... 209 The Genome Project and Melatonin........................................................................................... 209

viii Contents

APPENDIX B. PATIENT RESOURCES ............................................................................................... 213 Overview.................................................................................................................................... 213 Patient Guideline Sources.......................................................................................................... 213 Finding Associations.................................................................................................................. 216 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 219 Overview.................................................................................................................................... 219 Preparation................................................................................................................................. 219 Finding a Local Medical Library................................................................................................ 219 Medical Libraries in the U.S. and Canada ................................................................................. 219 ONLINE GLOSSARIES................................................................................................................ 225 Online Dictionary Directories ................................................................................................... 225 MELATONIN DICTIONARY ..................................................................................................... 227 INDEX .............................................................................................................................................. 317

1

FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with melatonin is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about melatonin, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to melatonin, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on melatonin. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to melatonin, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on melatonin. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

3

CHAPTER 1. STUDIES ON MELATONIN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on melatonin.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and melatonin, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “melatonin” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Music Therapy Increases Serum Melatonin Levels in Patients With Alzheimer's Disease Source: Alternative Therapies. 5(6): 49-57. November 1999. Summary: This journal article describes a study of the effects of music therapy on neurotransmitters and neurohormones in patients with Alzheimer's disease (AD). Participants were 20 male patients at the Miami Veterans Administration Medical Center. The researchers took blood tests to determine the concentrations of melatonin, norepinephrine, epinephrine, serotonin, and prolactin in the patients before initiating the therapy, immediately at the end of four weeks of therapy, and at a six week followup after cessation of the therapy sessions. Melatonin concentration increased significantly after therapy and had increased further at the six week follow-up. Norepinephrine and epinephrine levels increased after four weeks of music therapy, but

4

Melatonin

returned to pre-therapy levels at the follow-up. Prolactin and platelet serotonin levels were unchanged. The authors conclude that increased levels of melatonin following the therapy may have contributed to patients' relaxed and calm mood. 2 tables, 86 references. •

Effect of Melatonin in Selected Populations of Sleep-Disturbed Patients Source: Biological Signals and Receptors. 8: 126-131. 1999. Summary: This journal article describes two studies of the effects of melatonin in selected populations of patients with sleep disturbances. In one study, 22 patients patients with sleep disturbances only, 9 with sleep disturbances and signs of depression, and 10 with sleep disturbances and dementia received 3 mg of melatonin by mouth at bedtime for 21 days. After two to three days of treatment, melatonin significantly improved sleep quality and decreased the number of awakening episodes in patients with sleep disturbances alone or associated with depression. Estimates of next-day alertness improved significantly only in patients with primary insomnia. Agitated behavior at night (sundowning) descreased significantly in the patients with dementia. In the second, retrospective study, 14 patients with Alzheimer's disease (AD) received 9 mg of melatonin daily for 22 to 35 months. Sleep quality was significantly improved, although there was no change in neuropsychological performance. The authors conclude that melatonin may be useful for treating sleep disturbances in older insomniacs and AD patients. 1 figure, 2 tables, 18 references.

Federally Funded Research on Melatonin The U.S. Government supports a variety of research studies relating to melatonin. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to melatonin. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore melatonin. The following is typical of the type of information found when searching the CRISP database for melatonin: •

Project Title: A NEW METHOD FOR TREATING SLEEP DISORDERS Principal Investigator & Institution: Nichols, L D.; Biotek, Inc. 21-C Olympia Ave Woburn, Ma 01801 Timing: Fiscal Year 2002; Project Start 19-SEP-2002; Project End 31-JUL-2004

2

Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

Studies

5

Summary: (provided by applicant): BIOTEK has developed a transdermal melatonin formulation capable of producing flux levels high enough to allow a small patch to deliver a night-time melatonin pulse similar to that of healthy young adults. Such delivery should foster drowsiness, restful sleep, and alert waking more effectively than available oral dose forms and would also be more easily administered to impaired or uncooperative subjects. Because transdermal melatonin provides non-invasive delivery of a human hormone at natural levels, it should not lead to tolerance or harmful side effects. Transdermal melatonin may be of value to night shift workers, elderly individuals who lack an endogenous high-amplitude melatonin cycle, long distance air travelers, and those with sleep or seasonal affect disorders. In Phase I GMP patches were made and characterized, stability studies were initiated, a human Clinical Protocol was developed with the Brigham and Women?s Sleep Center in Boston, MA, and a draft IND was prepared. Phase II will conduct a human clinical study aimed at establishing safety and testing efficacy under well-controlled conditions. PROPOSED COMMERCIAL APPLICATION: A melatonin patch should encourage development of transdermal systems for other cyclic hormones, leading to products capable of modifying or restoring other types of hormone-mediated behavior. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A RAPID ASSAY SYSTEM FOR PHOTORECEPTOR GENE FUNCTIONS Principal Investigator & Institution: Hasegawa, Minoru; Biology and Biochemistry; University of Houston 4800 Calhoun Rd Houston, Tx 77004 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The long-term goal of this research project is to understand cellular and molecular mechanisms of the circadian system in vertebrate retinal photoreceptors. Circadian rhythms are observed in a variety of biological processes, and disruption of the circadian rhythm is related to physiological diseases and psychological disorders. Since a number of retinal processes show circadian rhythms, fulfillment of this research project will also contribute to prevention of retinal diseases. Several putative molecular components of the circadian system have been identified recently in vertebrates, and the functional roles of those components are of fundamental interest in circadian research. The specific aim of this proposed research is to develop an experimental system for rapid analysis of photoreceptor gene functions and to apply it to circadian research. The isolated Xenopus retinal photoreceptor layer will be used because this photoreceptor preparation eliminates complex interactions from other cell types. This enables us to investigate effects of experimental treatments and output measurements from a nearly pure population photoreceptor cells. In addition, cellular mechanisms of photic entrainment of the circadian oscillator can be investigated because this system is directly photosensitive. We will investigate whether morpholino antisense oligonucleotide techniques are useful for the study of photoreceptor gene functions. Morpholino oligos have overcome major problems encountered in other antisense techniques developed earlier and have been proven to be a powerful tool to study gene functions in research area such as developmental biology. In addition, a recently developed carrier molecule, ethoxylated polyethylenimine (EPEI), has enabled application of the morpholino technique to several cultured cell lines and primary cultured cells. We will employ western blotting analysis to examine specificities and functional effect of morpholino oligos on translation of a target mRNA and fluorescence confocal microscopy analysis to examine the delivery efficiency of morpholino oligos into photoreceptor cells. We will also examine the strength of the

6

Melatonin

morpholino technique in circadian research by investigating functional roles of CLOCK and CRYPTOCHROMES in the regulation of a photoreceptor circadian rhythm. Since various genome projects have provided tremendous amount of gene sequence data, the next step is identification of functions of those genes. Successful completion of this proposed research will dramatically accelerate functional genomics research in vertebrate photoreceptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADENOVIRUS PHOTORESPONSES

MEDIATED

REGULATION

OF

PINEAL

Principal Investigator & Institution: Max, Marianna; Physiology and Biophysics; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: (applicant's abstract): Endogenous circadian clocks allow organisms to appropriately time their behavioral and physiological responses to environmental cycles such as daily light cycles and seasonal changes in day length. A prominent output of the clock in vertebrates is the pineal hormone melatonin. The rhythm of melatonin synthesis controlled by the circadian clock is reset by the daily light cycle. Melatonin synthesis is regulated independently by the circadian clock and by light. Thus, light regulates melatonin synthesis via two pathways. Pinealocyte cultures provide a useful system to study both these pathways; pinealocytes rhythmically release melatonin for weeks in culture and their rhythms in vitro are entrained by light. Pharmacological methods have been extensively used to study in vitro pineal rhythms; however, no genetic manipulation of this system has been achieved because transgenic or "knock out" methods to alter expression of specific genes have not been possible in chickens to genetically manipulate pinealocyte gene expression. Replication-deficient, recombinant adenoviruses that express sense, mutant, ribosomal or antisense versions of pineal cDNAs will be used to infect pinealocytes. P-opsin, a pineal-specific opsin, will be expressed and "knocked out" in pinealocyte cultures. The pineal-expressed G-protein alpha rod transducin will be knocked out and a GTPase-deficient rod transducin alpha mutant with prolonged activation will be expressed in pinealocytes. The wild type gamma subunit of cGMP PDE and two mutant forms, one that is hyperactive and one that is hypoactive, will be expressed in pinealocytes. The effects of these genetic manipulations on melatonin biosynthesis and rhythmicity and the photosensitivity of the pinealocytes will be assessed by both static and flow through cultures and by radioimmunoassay for melatonin. Specific predictions are made for the effects of these molecular-genetic manipulations on the pineal's response to light based upon the hypothesis that a retina-like phototransduction pathway exists in the chick pinealocyte. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AGING AND NEURONAL 5 LIPOXYGENASE Principal Investigator & Institution: Manev, Hari; Professor; Psychiatry; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2001; Project Start 01-DEC-1998; Project End 30-NOV-2002 Summary: Aging is associated with chronic neurodegenerative diseases and increased brain vulnerability that may lead to a worse outcome from brain insults in elderly than in young subjects. Inflammation is one of the pathophysiological mechanisms of both chronic and acute neurodegeneration. Leukotrienes are inflammatory lipid mediators whose formation from arachidonic acid is initiated by 5-lipoxygenase (5-LO). 5-LO is

Studies

7

also expressed in neurons and can be activated by brain injuries, whereas 5-LO inhibitors can provide neuroprotection. The expression of the 5-LO gene appears to be inhibited by the pineal hormone, melatonin, which also is a potent neuroprotective agent. Melatonin deficiency normally develops with aging. We found that old or pinealectomized, i.e., melatonin-deficient, rats are more susceptible to kainate-triggered excitotoxic limbic brain injury than the corresponding young or sham-pinealectomized controls, and that pinealectomy or aging result in an enhanced expression of 5-LO in limbic structures. We hypothesize that an aging brain is at a higher risk of neurodegeneration via aging-suppressed melatonin secretion and the resultant upregulation of 5-LO expression, and that suppressing the 5-LO expression and/or activity will increase the brain's resistance to injury. These hypotheses will be tested in the following AIMS: (1) Characterize in aging rats (i.e., at 2, 6, 12, and 24 months of age): the neuronal expression of mRNAs and proteins of 5-LO and its activating protein FLAP; the effect of kainate on leukotriene formation and neuronal damage in the hippocampus and the entorhinal cortex; blood and brain melatonin levels (2) Characterize in limbic structures of young and old rats the effects of the nuclear melatonin receptor agonist CGP-52608 or melatonin on 5-L0 expression and kainateinduced leukotriene formation and neuronal damage; (3) Investigate the action of different classes of 5-LO inhibitors on kainate-induced leukotriene formation and neuronal damage; and (4) Investigate whether kainate is less neurotoxic in 5-LOdeficient (i.e., knockout) mice, and whether aging equally affects the vulnerability to kainate of 5-LO-deficient and age-matched wild mice. Techniques to be used include: quantitative reverse transcription/polymerase chain reaction for 5-LO and FLAP mRNAs, 5-LO and FLAP immunocytochemistry/immonobloting, enzyme- or radioimmunoassays, gas chromatography/mass spectrometry, TUNEL/Nissl stainings, and computer-assisted quantitative morphometry. The results are expected to elucidate the role of 5-LO in aging and neurodegeneration and to indicate neuroprotective therapies that would target the 5-LO pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASSESSMENT OF URINARY MELATONIN IN EPIDEMIOLOGIC STUDIES Principal Investigator & Institution: Schoenfeld, Elinor R.; Research Associate Professor; Preventive Medicine; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2001; Project Start 01-AUG-2000; Project End 31-JUL-2003 Summary: Several lines of evidence suggest that the hormone melatonin may inhibit breast cancer. However, to date no epidemiologic studies of breast cancer have included assessment of melatonin levels. The overall objective of this study is to determine how to reliably measure melatonin levels for use in epidemiologic studies. A nocturnal/ morning void urine sample and 4 daytime spot urine samples throughout the day will be obtained from 50 women diagnosed with invasive breast cancer and 50 women with no prior history of breast cancer. In addition, a second set of urine samples will be obtained from a subsample of 20 women (10 cases and 10 controls) approximately one month after the first collection in order to assess intra- individual variation. Cases will be enrolled after completion of treatment. Levels of 6-sulfatoxymelatonin (6-SMT), the major metabolite of melatonin in urine, will be determined by a highly sensitive and reliable radio-immunoassay, and creatinine will be assayed. Questionnaire data will also be collected on factors thought to influence melatonin levels and on breast cancer risk factors. A number of parameters will be used to characterize melatonin excretion patterns, including the proportion of women with a peak during the nocturnal hours,

8

Melatonin

mean nocturnal level, and the amplitude (maximum - minimum 6-SMT). The specific aims are: l) to estimate the proportion with a nocturnal peak, the mean nocturnal level, and the mean amplitude among cases and controls and to determine whether these parameters differ between the two groups; 2) to assess intra-individual variation in 6SMT levels by resampling a subsample of women; 3) to identify predictors of 6-SMT parameters (including sleep hours, alcohol intake, body mass index, and other variables); and 4) to assess the prediction of peak nocturnal levels from a daytime spot urine sample. This project will provide valuable information for the design of epidemiologic studies investigating the relationship of melatonin to breast and other cancers. If a significant proportion of women have their peak outside the nocturnal period, this would argue for the necessity of collecting additional urine samples throughout the day. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASTHMA INTERACTIONS

CHRONOBIOLOGY:

CENTRAL

AND

LUNG

Principal Investigator & Institution: Martin, Richard J.; Department of Medicine; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: The long term objective of this project is to understand the chronobiology of asthma so as to improve asthma treatment in general thereby decreasing asthma morbidity and mortality. The nocturnal worsening of asthma is associated with the three major asthma characteristics: reversible airway obstruction, bronchial hyperresponsiveness, and inflammation. These characteristics occur on a circadian (24 hour) basis and thus must be controlled by other endogenous circadian events. The specific aims will evaluate how these factors are controlled as well as why the nocturnal asthma patient does not readily awake so as to treat decreases in lung function as would occur more readily during the daytime hours. To these ends, the specific aims will determine: (1) if clock gene(s) expression in blood and lungs exhibit a circadian pattern and its relationship to certain other outcome factors as lung function, melatonin, and inflammatory markers; (2) if melatonin produces a state of enhanced inflammation that results in decreased steroid sensitivity; (3) if there is a dysregulation of corticotropin releasing hormone production in response to enhanced inflammation at night; and (4) the effects of melatonin on physiologic and arousal responses during sleep. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BASIC MECHANISMS OF DELAYED SLEEP PHASE SYNDROME Principal Investigator & Institution: Wyatt, James K.; Assistant Professor; RushPresbyterian-St Lukes Medical Ctr Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Delayed Sleep Phase Syndrome (DSPS) describes patients who cannot fall asleep until several hours past their preferred bedtime and have extreme difficulty arising in the morning in order to attend to normal activities (e.g., school, work). This differs from traditional sleep-onset insomnia in that DSPS patients can fall asleep quickly and obtain a normal 8-hr sleep episode, but only at a much-delayed clock hour (e.g., 3 am to 11 pm). Prevalence estimates range from 0.13 percent to 7 percent. Peak onset is in the second and third decades. Possible consequences of this disorders include increased risk for accidents, impaired learning, higher use of alertness-enhancing substances, and lower productivity. The specific aims

Studies

9

are: 1. To confirm the hypothesis that the circadian phase, as assessed from core body temperature and salivary melatonin, will be delayed, with week-to-week stability, in patients with Delayed Sleep Phase Syndrome (DSPS) relative to normal-sleeping, ageand gender-matched control subjects. 2. To test the hypothesis that DSPS patients will display the same internal phase relationships between their habitual bedtimes and wake-times, and the circadian phase markers of the minimum of core body temperature, the dim-light melatonin onset, and the fitted maximum of melatonin, but will have a larger amplitude of core body temperature and melatonin rhythms. 3. To test the hypothesis that with a sufficient increase in sleep homeostatic drive, given by the sleep loss incurred during a constant routine protocol, patients with DSPS syndrome will be able to obtain a normal sleep episode at a clock time 3 hours earlier than their habitual, delayed schedule. However, unlike normal control subjects, patients with DSPS return to their baseline pattern of inability to fall asleep at this earlier hour, on a second recovery night of sleep following the constant routine. The proposed investigations fulfill the criteria for the R21 mechanism by offering innovation (e.g., first measurement of temporal stability of phase delay, first measurement of full circadian and sleep parameters), bringing approaches new to an area (e.g., constant routine protocol), and initiating the first step in programmatic research for this investigator (basic mechanisms, diagnostic protocols, and evidence-based treatments for circadian phase disorders, beginning with DSPS). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOCHEMICAL ANALYSIS OF NEUROTRANSMITTERS Principal Investigator & Institution: Johnson, Dianna A.; Professor; Ophthalmology; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2002; Project Start 01-MAR-1983; Project End 31-MAR-2003 Summary: Developing neurons assemble their functional circuitry in response to intrinsic genetic instructions and complex external clues in the local environment. Some of these environmental dues may come from classical neurotransmitters, such as GABA, produced by early maturing, pioneer neurons. The overall goal of this project is to provide a developmental analysis of GABA, glutamate and melatonin systems in retina. Specifically, we will examine how developmental events regulate the expression of transmitter phenotype and in return, how neurotransmitters influence developmental events. Since these are highly complex problems, we have chosen to study a preparation with relatively simplistic circuitry involving only two major cell types, cone photoreceptors and type A horizontal cells. We have been able to analyze the development of these synapses which are presumably reciprocal between GABAergic horizontal cells and glutamatergic cones, in relative isolation from other maturing cell types during the initial stages of synaptogenesis in the outer plexiform layer of rabbit retina. One of our most important findings has been that blockage of GABA A receptors by picrotoxin at birth either in vivo or in vitro, blocks cone synaptogenesis and leads to disruption of the cone mosaic. This data suggests that GABA produced from pioneering horizontal cells, may be necessary for maintaining the position of cones within a normal mosaic array. These studies will be pursued using a highly multidisciplinary approach which involves previously established microscopy techniques and neurochemical analyses, as well as procedures new to the P.I. such as tissue culture and single cell injections of Lucifer Yellow. 1) We will establish the most suitable preparation using isolated retinas or retinal cultures for the subsequent examination of the cellular and molecular mechanisms involved in the picrotoxin effect. II) If the effect of picrotoxin is linked to its antagonism of endogenous GABA interaction with postsynaptic receptors,

10

Melatonin

then GABA receptors should be present in the outer retina at birth and horizontal cells should release sufficient GABA to activate them. We will test these assumptions first, by localizing GABA receptors with antibodies and second, by measuring endogenous GABA and glutamate release with GCMS under basal conditions and after stimulation with GABA and glutamate analogues. III) A more complete understanding of neurochemical mechanisms will require a detailed appreciation of the anatomical substrate upon these interactions are carried out. Various staining techniques including intracellular injections of Lucifer Yellow, will be used to map the distribution of cone and horizontal cells and to detail the synaptic convergence of these cell types in the outer plexiform layer. IV) In the final set of experiments, we will examine whether or not the melatonin system found in adult photoreceptor cell terminals, is present early in postnatal retina coincident with expression of the glutamate immunoreactivity. If so, additional studies will examine how melatonin might interact with GABA and/or glutamate in influencing retinal development. The results of these experiments should enhance our understanding of 1) synaptogenesis in retinal cell types which are pivotal in establishing the overall visual mosaic; 2) the role of GABA in development and 3) basic aspects of synaptogenesis and neuronal development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BLUE LED LIGHT PANEL FOR TREATMENT OF WINTER DEPRESSION Principal Investigator & Institution: Savage, Henry C.; Apollo Light Systems, Inc. 352 West 1060 South Orem, Ut 84058 Timing: Fiscal Year 2002; Project Start 25-SEP-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Multiple studies have established that bright light therapy is effective in alleviating symptoms of winter depression (seasonal affective disorder, or SAD). Light units used for treating SAD in the past have generally emitted polychromatic white light of highly variable spectral properties. Although several studies have attempted to test the effectiveness of specific wavelengths of red, blue and green light for treatment of SAD, the devices used in those studies employed relatively broad bandwidths of light. With the technological advancements in light emitting diodes (LEDs), the production of new light treatment equipment with much narrower bandwidths of light is possible. A recently completed action spectrum demonstrated that 446-477 nm is the most potent wavelength range for regulating melatonin secretion. These results suggest that a novel opsin photopigment, separate from the four classical visual opsins, mediates the effects of light on melatonin and raises the possibility that light treatment for SAD may share a common photoreceptor system and therefore, a similar spectral sensitivity. The specific aims of this proposed study are to: 1) produce an LED panel light box which emits narrow band light stimuli with a 470 nm peak (30 nm half-peak bandwidth) for light treatment of SAD; 2) confirm safety of this device through a hazard analysis based on accepted federal and industrial guidelines, and 3) use this device to test the hypothesis that light stimuli concentrated in the 470 nm range is therapeutically effective in treating SAD. Therapeutic efficacy will be tested in a double-blind, randomized cross-over study design comparing a narrow band LED light source with a spectral peak at 470 nm (30 nm half-peak bandwidth) to a narrow band dim red light placebo control with peak emission at 700 nm. Demonstration of efficacy of relatively narrow bandwidth blue light will pave the way for future studies in which this spectral range may be further tested for SAD treatment and circadian rhythm dysfunctions in order to maximize therapeutic benefits with lower light intensities and therefore, fewer side effects.

Studies

11

Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR ELECTROPHYSIOLOGY OF THE SUPRACHIASMATIC NUCLEI Principal Investigator & Institution: Allen, Charles; Assistant Staff Scientist; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 30-NOV-2003 Summary: Mammalian circadian rhythms are generated by a molecular clock located within individual neurons of the suprachiasmatic nucleus (SCN). The molecular clock drives the activity of SCN neurons which fire action potentials at a higher frequency during the day than during the night. The mechanisms underlying this activity are unknown, but must involve circadian regulation of ion channels involved in the generation of action potentials. Our hypothesis is that neurotransmitters which alter SCN neuronal activity and phase shift circadian rhythms also modulate the activity of ion channels which are necessary for the rhythmic firing of SCN neurons. In the SCN these questions are complicated by the heterogeneity of neuronal phenotypes and differences in signal transduction coupling at different times of the circadian day. Electrophysiological and morphological techniques will be used to investigate neurotransmitter signal transduction in SCN neurons. The specific aims of the proposal are to: 1) Examine the mechanisms coupling neurotransmitter receptors to ion channels which are important for action potential generation in SCN neurons. 2) Determine the role of circadian time in the coupling of neurotransmitter receptors to ion channels. 3) Investigate how melatonin receptors modulate the activity of other neurotransmitter receptors in the SCN. 4) Catalogue the morphological cell types which respond to specific neurotransmitters. Identification of unique ion conductances and signal transduction pathways in the SCN will provide new targets for clinical treatment of sleep and circadian disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CELLULAR MECHANISMS OF CIRCADIAN RHYTHMICITY Principal Investigator & Institution: Cahill, Gregory M.; Associate Professor; Biology and Biochemistry; University of Houston 4800 Calhoun Rd Houston, Tx 77004 Timing: Fiscal Year 2001; Project Start 30-SEP-1992; Project End 30-JUN-2003 Summary: (Adapted from the applicant's abstract): The long-term goal of this project is understand basic mechanisms of circadian rhythmicity in vertebrate retina. Many aspects of retinal physiology and metabolism are regulated by circadian clocks. These clocks are set by daily cycles of environmental and physiological stimuli, resulting in appropriately timed daily rhythms of visual system function. Rhythmic retinal activities include the expression of photoreceptor genes, the turnover of photoreceptive membrane, changes in synaptic structure and function, rod-cone dominance, and the synthesis and release of retinal neuromodulators. The ubiquity of circadian rhythmicity in the retina indicates a critical role for the circadian system in maintenance of retinal health and optimal visual function. Previous studies demonstrated that a fully functional circadian clock is located within the retinal photoreceptor layer, and suggested that individual photoreceptor cells are capable of circadian rhythm generation. This clock regulates melatonin synthesis within the photoreceptor cells. The photoreceptor clock can be entrained by cycles of either light or a neuromodulator, dopamine. The circadian clock, the melatonin synthetic and regulatory mechanisms, and the transduction pathways for entrainment of the clock by light and dopamine are

12

Melatonin

all preserved in a cultured photoreceptor layer preparation from the retina of Xenopus laevis. This preparation makes it possible to test hypotheses about photoreceptor clock mechanisms without the complications of interactions with other cell types. The melatonin release rhythm of photoreceptor layers will be used in the proposed experiments as a measure of circadian clock responses to experimental manipulations. The specific goal of this project is to define transduction mechanisms by which light and dopamine entrain the photoreceptor circadian clock. Previous studies showed that light and dopamine have nearly identical ultimate effects on the timing of the clock. However, recent data indicate that the transduction pathways for these signal are distinct at the second messenger level, and suggest specific hypotheses about how components of these pathways interact to entrain retinal rhythms. The experiments proposed here will determine: (1) the characteristics and identities of the dopamine receptors and photopigments that mediate entrainment; (2) the roles of membrane potential and Ca2+ fluxes in the entrainment pathways; and (3) the role of a novel protein kinase mechanism in the entrainment pathways. The results of these studies will define basic mechanisms of retinal circadian rhythmicity, and will provide important information about how therapeutic interventions may affect the retinal circadian clock. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERIZATION OF ADVANCED SLEEP PHASE SYNDROME Principal Investigator & Institution: Ptacek, Louis J.; Associate Investigator; Human Molecular Biology/Genet; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-JUL-2006 Summary: Biological circadian clocks are ubiquitous and provide important adaptational advantages to life on our planet. The advanced sleep-phase syndrome (ASPS) of aging and the delayed sleep-phase syndrome )DSPS) of adolescence are common human sleep disorders that have significant adverse health consequences. Shift work, jet lag, and free-running rhythms of the blind are also important circadian dysrhythmias. Despite a rapid increase in molecular-genetic understanding of circadian pacemakers in Drosophila and rodents over the past decade, very little is known about the workings of the human clock, largely because no naturally occurring mutations are available to give us clues about how the human clock can malfunction. We recently reported the first Mendelian human circadian rhythm disorder (familial ASPS) a short period circadian rhythm variant manifest by a 4 hour phase advance of the temperature, melatonin and sleep-wake rhythms. We have mapped and identified the causative gene (hPer2) in one large ASPS family. We have also identified the hPER2 region where casein kinase 1epsilon (CK1epsilon) binds and demonstrated that hPER2 is a substrate for phosphorylation by CK1epsilon; the functional consequence of the mutation of hypophosphorylation of hPER2. The combination of clinical and physiological characterization, genetics, and in vitro biochemical analysis has begun to shed light on first model of circadian rhythm variation in humans. We have also identified over 20 additional ASPS probands, many of whom have family histories of ASPS, and shown that several of these do not map to the first ASPS locus; these families will allow us to identify additional ASPS genes and mutations. Our ongoing studies will continue to use clinical, genetic, and biochemical tools to work toward an understanding of how the human clock functions. Identification of genetic alterations causing circadian rhythm variation and characterization of variant proteins encoded by such genes will help extend animal models of circadian clocks to human and eventually may lead to improved diagnosis and treatment of human circadian disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

13

Project Title: CHARACTERIZING THE NIGHT EATING SYNDROME Principal Investigator & Institution: Stunkard, Albert J.; Professor Emeritus of Psychiatry; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: Description (adapted from the investigator's abstract): The present application is designed to delineate the behavioral and biological characteristics of a newly proposed eating disorder-the night eating syndrome-and to explore the neuroendocrine mechanisms underlying its clinical characteristics. It was recently shown that persons selected on the basis of reports of morning anorexia, evening hyperphagia and insomnia manifest a distinct clinical entity, characterized by greatly increased food intake late in the day and evening, a lowered mood that falls during the afternoon and evening and frequent nighttime awakenings during which small, high carbohydrate snacks are consumed. Study of a different group of night eaters showed elevated cortisol levels throughout the 24 hours and attenuation in the nighttime rise in melatonin and leptin. This application is designed to more clearly delineate the syndrome by replicating and extending a previous study, this time using the same subjects for the behavioral and neuroendocrine measurements. The study will involve two phases. Phase I will consist of a 1-week outpatient study to determine the distinctive behavioral features of the night eating syndrome by comparing 30 night eaters with 30 persons suffering from binge eating and 30 persons without an eating disorder. During the week subjects will keep careful records of all food and fluid intake, and will wear sensitive motion sensors which record all nighttime awakenings. Phase II will consist of a 3-day hospitalization in the Clinical Research Center of the Hospital of the University of Pennsylvania comparing 15 night eaters with 15 non-eating-disordered controls. Polysomnography will determine the sleep architecture of the three groups, particularly the sleep stage during which arousals occur in the night eaters. Levels of melatonin, leptin and cortisol will be determined every 30 minutes, allowing far greater precision in determining circadian rhythms, than was possible with the 2-hour interval in our previous study. Statistical analyses will compare the results of the behavioral, sleep and neuro-endocrine studies with a goal to have the most complete characterization of an eating disorder yet undertaken. Exploratory analyses will include correlation among the behavioral variables (food intake, mood, and nighttime awakenings) and the neuroendocrine variables to explore determinants of the clinical picture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CIRCADIAN OSCILLATORS IN CULTURED MAMMALIAN RETINA Principal Investigator & Institution: Menaker, Michael; Commonwealth Professor; Biology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2001; Project Start 01-JAN-1997; Project End 31-DEC-2001 Summary: Our long-term goals are 1) to understand the mechanism that generates circadian rhythmicity in the retina and 2) to elucidate the role played by rhythmic synthesis of melatonin in retinal function. We will begin by defining optimal culture conditions for studying circadian rhythms of melatonin synthesis in in vitro preparations of isolated neural retinas from rats and mice. We will then measure the activity of the enzymes involved in melatonin synthesis and the breakdown products produced by its catabolism in order to define the proximate source of the circadian rhythmicity. We will determine whether dopamine is also produced rhythmically by cultured retinas. Using mice and rats with genetic defects that affect specific cell types in

14

Melatonin

the retina we will ask which cell types are essential for synthesis and degradation of melatonin (and dopamine) and which are essential for circadian oscillation. We will define the response of the retinal circadian oscillators to light pulses and explore the light input pathway using pharmacological agents that block or mimic the resetting effects of light. Finally we will ask whether melatonin is causally involved in synchronized rhythmic outer segment disc shedding by comparing disc shedding in C3H mice, whose retinas synthesize melatonin rhythmically, with disc shedding in C57 mice whose retinas, like their pineal glands, make no melatonin at all. What we learn about rhythmicity in mammalian retinas in culture is likely to be applicable to pathologies of retinal function in humans, particularly since so many aspects of retinal physiology have been shown to be rhythmic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COUPLED ENZYME PROCESS FOR TRYPTAMINE SYNTHESIS Principal Investigator & Institution: Kilgore, James L.; Biocatalytics, Inc. 129 N Hill Ave, Ste 103 Pasadena, Ca 911051955 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 31-JAN-2004 Summary: (provided by applicant): Neuroactive tryptamine derivatives can be prepared by a new coupled-enzyme process developed in Phase 1 by combining tryptophansynthetic and -decarboxylating enzymes. This comprises the first reported single-pot aminoethylation process. The tryptamine products can thereby be conveniently produced from readily-available indole precursors. Expression systems which provide higher enzyme yields will be utilized in order to permit scaleup to preparative reaction systems. The gene encoding Camptothectin accuminata tryptophan decarboxylase 1 (TDC 1) will be redesigned to optimize expression in E. coli. Stepwise binding of tryptophan synthase subunits and mutation of specific sites on the enzyme surface in order to improve enzyme activity following immobilization. Directed evolution will be explored in an effort to broaden the substrate ranges of two enzymes. New substrates will be tested he process will be utilized in the preparation of the migraine drugs rizatriptan, and sumatriptan, as well as melatonin and a series of melatonin receptor active compounds. PROPOSED COMMERCIAL APPLICATION: The coupled aminoethylation process will be used to make intermediates for neuropharmaceuticals, including both currently-approved and developmental neuroactive drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CRYPTOCHROME PHOTORECEPTION

FUNCTION

IN

NON-VISUAL

Principal Investigator & Institution: Van Gelder, Russell N.; Assistant Professor; Ophthalmology and Visual Sci; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Recent experiments have demonstrated that mice with complete outer retinal degeneration still retain the ability to synchronize their circadian rhythms to exogenous light-dark cycles, constrict their pupils in response to light, and suppress important hormonal signals (such as melatonin) with light. A subset of retinal ganglion cells have recently been shown to be directly photoresponsive. The photopigment(s) underlying these responses are presently unknown. The cryptochromes are a family of flavin-based proteins related to photolyase that are potential photopigments in the inner retina. Retinal degenerate mice lacking

Studies

15

cryptochrome function show markedly decreased sensitivity to light for behavioral rhythmicity and pupillary responsiveness. Using a combination of genetic and physiologic approaches, the investigators propose testing the hypothesis that cryptochromes function as photopigments in the inner retina of retinal degenerate mice. Four specific aims are proposed: 1.) Determine the action spectrum, kinetics, and bleaching properties of the photopigment(s) for pupillary responsive-ness in retinal degenerate (rd/rd) mice with and without cryptochrome function; 2.) Compare inner retinal physiology and direct ganglion cell photoresponsive-ness between mice with and without cryptochrome function; 3.) Establish genetic rescue paradigms for the eyespecific expression of mammalian cryptochromes in genetically null backgrounds and perform systematic mutagenesis to delineate essential domains of cryptochrome function in the mouse eye; and 4.) Utilize the yeast two-hybrid system to characterize the light-dependent interaction of mammalian cryptochrome with potential downstream signaling molecules. The long-term objective of this work is to understand the mechanisms of non-visual ocular phototransduction, from photopigment to neural signal transduction. The full range of physiology subserved by this irradiance detection pathway is unknown but likely includes synchronization of the master circadian pacemaker to the external light-dark cycle, seasonal hormone fluctuations, and lightmodulation of the sleep-wakefulness cycle. Subsets of patients with ophthalmologic disease are known to be at high risk for sleep disorders arising from circadian desynchronization; understanding the precise mechanisms by which the eye communicates with the subcortical brain centers responsible for these behaviors will greatly enhance understanding of the pathophysiology of these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT OF MAMMALIAN CIRCADIAN RHYTHMS Principal Investigator & Institution: Davis, Frederick C.; Professor; Biology; Northeastern University 360 Huntington Ave Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-APR-1984; Project End 30-JUN-2003 Summary: ( applicant's abstract): The disruption of sleep is a widespread problem among children and is one of the most common concerns parents have about their children's behavior. Sleep problems early in life tend to persist into older ages, and sleep disorders can be severe in children with neurological or psychiatric pathologies. Sleep is controlled by two processes, a homeostatic process and a circadian pacemaker. Entrainment of the circadian pacemaker is responsible for the appropriate timing of sleep and wakefulness relative to the environment. The development of a normal sleep/wake cycle requires the development and entrainment of the circadian pacemaker. Previous work of this project has shown in hamsters that the pacemaker begins before birth and is entrained by rhythmicity of the mother. Similar timing in humans would mean that the fetal pacemaker is functioning and is influenced by maternal rhythms throughout most of gestation. The goal of the proposed project is to better understand the physiology of the fetal pacemaker and understand how it is influenced by maternal rhythms, including the long-term consequences of abnormal entrainment. By measuring recently discovered molecular components of the pacemaker, we will test hypotheses about the similarities and differences between the developing and mature pacemaker and about the regulation of these molecules during development. We will specifically examine the physiological significance of maternal melatonin and the long-term effects of maternal entrainment. The project will better our understanding of fetal pacemaker regulation and the importance of the environment under which it develops.

16

Melatonin

Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT OF MELATONIN RECEPTOR LIGANDS Principal Investigator & Institution: Li, Pui-Kai; Associate Professor; Veterinary Biosciences; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 1999; Project Start 05-AUG-1999; Project End 31-DEC-2003 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: DIFFERENTIAL GENE EXPRESSION IN CILIARY EPITHELIUM Principal Investigator & Institution: Coca-Prados, Miguel; Professor; Ophthalmology and Visual Sci; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-JUL-1984; Project End 30-NOV-2005 Summary: (provided by applicant): Lowering intraocular pressure in Primary Open Angle Glaucoma, the most prevalent form of glaucoma, is a major objective in the treatment to prevent the progression of this ocular disease. Our long-term goal is the understanding at the cell and molecular level of the mechanisms involved in the regulation of intraocular pressure. A great body of evidence emerging, for the most part, from studies on molecular biology has supported that the human ciliary epithelium is neuroendocrine and expresses a functional peptidergic system. Many of the peptides identified are vasoactive and they are involved in the regulation of blood pressure in the cardiovascular system. The existence of a peptidergic system in the ciliary epithelium provides suggestive evidence for its involvement in the regulation of eye pressure at a "local" level by autocrine/paracrine mechanisms. In this application, we propose a 5year study to examine the hypothesis that intraocular pressure is a neuroendocrine function of the ciliary epithelium, mediated by the expression of regulatory peptides and hormones entrained in a circadian rhythm by a non-visual light-sensing mechanism. The plan comprises three main aims. Aim 1, biochemical characterization, by HPLC and mass spectrometry, of neuroendocnne regulatory peptides with hypertensive/hypotensive activities expressed in the ciliary epithelium, including neuropeptide Y and natriuretic peptide-C. To study their signaling pathway upon activation of their cognate receptors by measuring second messengers including cAMP, cGMP and Ca2+. Aim 2, to examine the circadian variations of neuropeptides in experimental animals and cultured cell models of the ciliary epithelium entrained to light/dark cycles. To identify the components of the endogenous "circadian oscillator" that underlie the circadian gene expression in the ciliary epithelium, including melatonin-rhythm-generating enzymes and clock genes. Aim 3, to establish the molecular nature of the non-visual phototransduction cascade in the ciliary epithelium, by focusing on the expression of rhodopsin and other opsin-like molecules, and components of the activation and deactivation of rhodopsin, including rhodopsin kinase, recoverin and arrestin. To determine any light-sensing responses in intact and cultured ciliary epithelial cells, by studying the cGMP-gated channel under light and dark conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: DISK RENEWAL IN RETINAL VISUAL CELLS Principal Investigator & Institution: Besharse, Joseph C.; Assistant Professor; Cell Biol, Neurobiol/Anatomy; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801

Studies

17

Timing: Fiscal Year 2001; Project Start 01-JUL-1989; Project End 31-MAR-2005 Summary: (provided by applicant): Our goal is to understand the role of light-dark cycles and a photoreceptor circadian clock in the control of overt rhythmic physiology in the retina. This application capitalizes on the recent discovery that Period genes are critical to circadian rhythmicity and to light responses of the circadian clock. We will study the role of a light- and dopamine-responsive period gene (xPer2) in rhythmic retinal physiology. The model underlying the application is that xPer2 plays an important role in coordinating the effects of light-dark cycles with an endogenous clock. We will study (1) light- and dopamine-induced up-regulation of xPer2 in relationship to expression of other clock genes, (2) the consequences of over-expression of xPer2 in the photoreceptor-RPE complex using Xenopus transgenesis, and (3) transcriptional regulation of the xPer2 gene using nuclear run-on assays. A central hypothesis is that the protein product of the xPer2 gene interacts with other cycling components of the retinal circadian clock to mediate the phase resetting effects of light and dopamine. Disruption of these interactions in constant light is proposed to account for disruption of circadian rhythms and for known alterations in photoreceptor membrane turnover. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISRUPTED SLEEP IN THE ELDERLY--CIRCADIAN ETIOLOGY Principal Investigator & Institution: Duffy, Jeanne F.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-JUL-1985; Project End 31-MAR-2003 Summary: (adapted from investigator's abstract): More than one-quarter of older people complain that they wake up frequently during the latter part of the night, with 15 percent reporting that they cannot sleep past 5 AM. Prior results show that early morning awakening also occurs in most healthy older people who have no sleep complaint, who are not depressed and who do not exhibit any evidence of age-related shortening of intrinsic circadian period. Studies funded by the current grant suggest that this age-related increase in sleep interruptions during the latter part of the night cannot be explained by an age-related change in circadian photic resetting sensitivity. Based on recent analyses, the investigators have found: 1) an age-related narrowing of the circadian phase interval over which the latter part of sleep can remain consolidated, leading to a marked age-related increase in the susceptibility of sleep to misalignment of circadian phase; and 2) an age-related increase in the variability of entrained circadian phase. It is hypothesized that these age-related circadian changes may account for a substantial component of the high prevalence of disrupted sleep and early morning awakening observed among older people. This implies that in older people, achieving and maintaining a precise (and narrow) relationship between circadian phase and the timing of sleep is crucial to attain sleep consolidation. The investigators' findings on the effect of light on human rhythms suggest that the optimum phase relationship between sleep and endogenous circadian rhythms in older people can be achieved by appropriately timed exposure to a novel light exposure pattern of brief, intermittent bright light pulses. Four testable hypotheses are proposed: (I) the phase of the melatonin and temperature rhythms and wake-time will occur at an earlier hour for older than for young adults living on self-selected sleep-wake schedules at home; (II) under base-line conditions on those self-selected schedules, wakefulness in the final third of the night will be higher for older subjects; (III) four brief exposures to evening bright light each day will be sufficient to establish and maintain entrainment of the sleep-wake cycle at an optimal circadian phase, resulting in reduced wakefulness in the

18

Melatonin

final third of the night and enhanced daytime alertness; and (IV) a similar pattern of bright light exposure in the morning will not improve circadian phase misalignment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF AGING AND CALORIC RESTRICTION ON CIRCADIAN PH* Principal Investigator & Institution: Urbanski, Henryk F.; Associate Professor; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): Human physiology shows strong rhythmic components with peaks and nadirs occurring regularly at specific times of the day. Accumulating evidence suggests that perturbation of the circadian neuroendocrine circuitry may play an important role in several aging-related disorders and may have a major influence on life span. Furthermore, there is growing support for the view that neuroendocrine aging may be caused by oxidative injury, stemming from a progressive overload of a cell's antioxidant capacity. The proposed research will use male rhesus monkeys to examine the mechanism by which caloric restriction can prevent agingrelated deterioration of key neuroendocrine circadian rhythms, including DHEAS, cortisol, melatonin and testosterone. We will perform experiments to examine the aging-related progression of circadian dysfunction in ad libitum-fed and age-matched calorie-restricted animals in vivo. This will involve repeated serial blood collections via a catheter-swivel-tether set up, together with concomitant body temperature recordings and actography. In addition, changes in body composition and brain morphology will be assessed non-invasively using DEXA and MRI respectively. Ultimately, the brains of these animals will be examined postmortem to test the hypothesis that caloric restriction protects the aging primate hypothalamus from oxidative injury. Using electron microscopy, we will examine the synaptology of key hypothalamic nuclei involved in mediating circadian neuroendocrine function and use in situ hybridization histochemistry to assess changes in gene expression. We will also use immunohistochemistry to examine loss of specific axonal projections and the associated increase in gliosis. We expect to show that caloric restriction helps to protect hypothalamic nuclei from oxidative injury and, more importantly, that it helps to maintain the integrity of the neural pathway that links the suprachiasmatic nucleus (the central biological clock) to the paraventricular nucleus (the hypothalamic regulator of the adrenal axis). A deeper understanding of aging-related changes in central neuroendocrine circadian circuits of primates and the protective influence of caloric restriction should help to elucidate the mechanism of human aging and help with the development of effective therapies for a wide range of disorders in the elderly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: EFFECTS OF SHORT AND LONG NIGHTS ON THE CIRCADIAN CLOCK Principal Investigator & Institution: Eastman, Charmane I.; Professor of Psychology; Rush-Presbyterian-St Lukes Medical Ctr Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 30-JUN-2007 Summary: (provided by applicant): It is widely recognized that humans in modern society do not get the sleep they need. This chronic sleep debt significantly degrades productivity, increases accident rates and has been linked to poor health and increased risk of death. Humans are exposed to a light dark (LD) cycle created by natural and

Studies

19

artificial light alternating with sleep. Sleep duration determines the length of dark in the daily LD cycle. However, the effects of repeated short dark periods (short nights) on the human circadian system remain unknown. It has been proposed that mammals have a complex circadian pacemaker, consisting of an evening oscillator, that regulates the onset of melatonin secretion, and a morning oscillator, that regulates the offset of melatonin secretion. In short summer nights (longer photoperiods), the phase relationship between the evening and morning oscillators is decreased, which shortens the duration of the nocturnal melatonin profile, in turn regulating appropriate seasonal changes. Other animal work shows that the range and amplitude of the light phase response curve is decreased in short nights. We propose to investigate the effects of short and long nights on the human circadian system, by keeping subjects in bed, in the dark, for either 6 or 9 hours per night. We will determine if the duration of the melatonin rhythm in dim light compresses after a history of short nights, and expands after a history of long nights, thus revealing that the circadian pacemaker has a memory of the previous night length. We will also determine if a history of short nights reduces the phase shifting response to light. Our goal is to determine the extent to which the chronic sleep debt in modern society is altering the functioning of the human circadian system. This work has important implications for the sleep deprived general population and for jet travelers and night shift workers who must phase shift their circadian rhythms in order to adjust to phase shifts in their light/dark cycle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOGENOUS REGULATION OF INTRAOCULAR PRESSURE Principal Investigator & Institution: Liu, John H.; Professor; Ophthalmology; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-NOV-1991; Project End 30-NOV-2002 Summary: (adapted from the applicant's abstract): Primary open- angle glaucoma is associated with an elevated intraocular pressure (IOP). Although lowering IOP has been the only therapeutic means, how IOP is regulated endogenously is largely unclear. Clinical observations indicate that IOP is regulated to some extent by the central nervous system (CNS). How CNS signals affect ocular tissues in vivo, especially inside the target cells, has not been established. The circadian rhythm of IOP in rabbits has been used as an experimental model to study the endogenous regulation of IOP. Rabbit's IOP is high in the dark phase due to the activation of ocular sympathetic nerves. Using this nocturnal IOP elevation as the basic model, in vivo intracellular signal transduction in the ciliary processes will be studied (Aim 1). Levels of second messengers will be probed using laser irradiation. The activation of protein kinases and the inhibition of protein phosphatases will be assayed. Changes in the activity of Na+K+ ATPase will be determined. These intracellular events will be verified using various pharmacological and physiological techniques. Since the synchronization of the circadian IOP rhythm in rabbits is probably mediated through the sensation of shortwavelength light by the blue cones, the afferent neural pathway affecting the nocturnal IOP elevation will be studied (Aim 2). The circadian IOP rhythm in rabbits without functional blue cones will also be characterized. Recently there have been several human studies showing an unexpected IOP elevation in the dark/sleep phase. Under a strictly controlled environment, the circadian IOP pattern in young healthy adults will be critically examined (Aim 3). Its relationship with the light-dark cycle and the sleep patterns will be studied. Its mechanism via the change of outflow resistance will be clarified. The spectral effects on the nocturnal IOP will be examined. The circadian IOP rhythm in older healthy adults will be characterized as well. The common goal of these

20

Melatonin

diversified approaches is to define the endogenous mechanisms involved in the regulation of IOP. This information should be useful for the development of antiglaucoma medicines. The human studies may lead to further studies in glaucoma patients and possibly a refinement of glaucoma therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENVIRONMENTAL DEVELOPMENT

LIGHT

AND

RETINAL

MEMBRANE

Principal Investigator & Institution: Organisciak, Daniel T.; Professor & Chair; Biochem and Molecular Biology; Wright State University Colonel Glenn Hwy Dayton, Oh 45435 Timing: Fiscal Year 2001; Project Start 01-APR-1977; Project End 31-MAR-2004 Summary: (Adapted from applicant's abstract): This study seeks to determine the mechanisms of intense light-mediated photoreceptor cell degeneration. The hypotheses to be tested are: (1) that there is a sensitive period within the circadian cycle which results in enhanced susceptibility to retinal light damage and which is mediated by the expression of intrinsic factors in the retina (aim 1) and (2) that susceptibility to light damage is affected by genetic inheritance, which can enhance the rate of photoreceptor cell loss from environmental insult in the form of dim cyclic light exposure or acute intense light treatment (aim 2). This proposal will focus on identifying the circadian expression of intrinsic factors in the retina that enhance or prevent light-induced cell damage leading to apoptotic cell death. The investigator will study the interactions of light-and dark rearing conditions and the timing of intense light treatments in vivo that produce synchronous photoreceptor cell damage in normal albino rats and in transgenic rats with mutations in the rhodopsin primary amino acid sequence. Photoreceptor cell loss will be assayed using rhodopsin and photoreceptor DNA measurements, electrophoretic analysis of DNA fragmentation, and light and electron microscopy of light-damaged retinas. The circadian expression of melatonin and dopamine will be measured and Western and Northern analysis will be used to identify potential modulators of retinal damage. These measurements will be complimented by 2D gel electrophoresis of retinal proteins and ordered differential display of mRNA from retinas at different times of the day and night. The synthetic antioxidant dimethylthiourea will be used as a probe to uncover early events in the mechanism of cell death, including mitochondrial involvement and the potential for oxidative stress to induce apoptosis. In addition, the time course of the appearance of cytoplasmic cytochrome C and the activation of cellular caspases will be determined by antibodybased techniques, immunocytochemistry and enzymatic analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPROVING NEURAL GRAFT FUNCTION IN PARKINSONIAN MONKEYS. Principal Investigator & Institution: Redmond, D Eugene.; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: The benefits of fetal neural transplantation in primate Parkinson's models have been partially confirmed by studies in patients, but transplantation may have significant problems which should be addressed. Functional improvement appears variable, less effective in older patients, and incomplete in spite of some apparent increases in dopamine production. The hypotheses are that transplantation's limitations result from inadequate grafts, due to poor survival of implanted cells, lack of critical

Studies

21

growth factors, or nonphysiological graft placements and distribution. This program proposes to test these hypotheses with strategies which may improve functional benefits--the primary outcome measure of all studies in MPTP parkinsonian monkeys. Project One targets early cell death after grafting, with strategies to reduce oxidant stress, hypoxia/ischemia, and apoptosis using cell adhesion factors, the lazaroid tirilizad mesylate, melatonin, vascular endothelial growth factor, and cAMP. Project Two focuses on growth factors produced by fetal striatum enriched in astrocyte progenitor cells, or the growth factor, GDNF, delivered from encapsulated cells. An optimized method will be tested to determine benefits of combined methods in young adult and aged monkeys. Project Three aims to restore the relevant dopamine pathways by implantation of substantia nigra (SN) precursor tissue into SN and directing its outgrowth to the target areas, using co-grafted fetal striatal cells, or GDNF delivery. Duration of and stability of behavioral improvement, possible dyskinesias, or other toxic effects will be evaluated for three years and compared with striatal grafts. Quantitative behavioral effects will be correlated with biochemical and morphological measurements post-mortem. These studies may contribute to improving graft survival, reinnervation, and physiological restoration of the defective dopamine circuits and normalizing function. Although considerable preliminary work has been done in rodents, and because definitive controlled experiments with verifiable outcomes cannot be accomplished in humans, hypotheses and safety should be tested in the MPTP model in monkeys. The projects will be undertaken jointly by the program investigators, applying the resources of a unique primate transplantation laboratory (Core A) and shared outcome methodologies, all coordinated by a program support unit (Core B). Understanding of fetal precursor cell survival and outgrowth may also lead to improved understanding of the plasticity and function of other potential replacement cells, such as stem cells, and be relevant to other human neurodegenerative or traumatic conditions in addition to Parkinson's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIGHT VISOR FOR TREATING JET LAG: CONTROLLED FIELD TRIAL Principal Investigator & Institution: Boulos, Ziad; Research Scientist; Bio-Brite, Inc. 4340 East West Hiwy, Ste 401 Bethesda, Md 20814 Timing: Fiscal Year 2003; Project Start 30-SEP-2000; Project End 31-JUL-2005 Summary: (provided by applicant): Jet lag is a syndrome of behavioral, cognitive, and physical symptoms that result when travelers are exposed to a sudden shift of the daynight cycle. These symptoms impact on alertness and performance of airline and military personnel and the safety of the traveling public. They may also exacerbate medical and psychiatric illness, and frequent flyers may face increased risk of disease. The long-term objective of this project is to develop a practical and effective treatment for jet lag using the Bio-Brite Light Visor to phase-shift circadian rhythms. Phase 1 demonstrated that the visor was effective in phase-shifting human circadian rhythms and accelerating circadian reentrainment following a westward flight across 6 time zones, but the effect on reentrainment rate was not sufficient to improve sleep, performance, or subjective measures of jet lag. Phase 2 is designed to improve the efficacy of the light treatment by implementing changes to the visor itself and to the light treatment schedule. These changes will be tested first in laboratory experiments, and then in a field study with both eastward and westward flights across 6 time zones (New York-Zurich-New York). Bright light (3000 lux) or dim red light (control) treatment will be scheduled for 3 h on the three mornings immediately preceding the

22

Melatonin

eastward flight, and on the three evenings immediately following the westward flight. Subjects will also be required to avoid exposure to bright light at specific times after the eastward flight. Circadian reentrainment rates will be examined, using salivary dim light melatonin onset (DLMO) as phase reference. Other jet lag indices will include sleep quality and duration, determined from wrist actigraphic recordings and from scores on a subjective sleep quality questionnaire, performance on a psychomotor vigilance task, and subjective assessments of mood, daytime sleepiness, and other jet lag symptoms. Phase 2 will also include a data analysis component aimed at generating light exposure and avoidance schedules keyed to individual chronotype and to travel origin and destination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIGHT, CIRCADIAN DISRUPTION, AND BREAST CANCER Principal Investigator & Institution: Stevens, Richard G.; Associate Professor of Basis Sciences; Community Med and Health Care; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-MAR-2005 Summary: (provided by applicant): Breast cancer incidence and mortality are much higher in industrialized societies than in developing societies, and the reasons for these differences are not well understood. The search for aspects of modern life that increase risk has been intense but of limited success. "Circadian Disruption" may play a role. The overall goal is to develop an interdisciplinary scientific team and program of research on the topic of circadian disruption, primarily from alterations in lighting, as it might influence risk of breast cancer. Integral to this effort is targeted utilization of the Environmental Genome to find candidate genes which may modify human physiological response to "circadian disruptors" such as altered lighting. This effort will begin with investigation of CLOCK genes and genes affecting circadian phototransduction. The researchers intend to establish a multidisciplinary collaboration among molecular, developmental, and circadian biologists; statisticians and epidemiologists to develop a better understanding of the impact of light on breast cancer induction and the role that genetic polymorphisms may play in this. In order to initiate this collaboration, a 3-day retreat will be conducted early in the first year of the project period. From this, priorities will be discussed and focused pilot projects planned. The principal investigator will ensure regular communication among study collaborators as the project progresses. There will also be a meeting in each of years 2 and 3 of the project. In addition, the investigators will translate the insight gained above into markers for use in epidemiological studies of light and breast cancer that are relevant to the biological mechanisms involved and at the same time efficient for use in the large numbers of women necessary to provide meaningful data. Results of theoretical work among combinations of the participants, and of the experiments conducted, will be published. A final summary document will be prepared by the end of the third year with input from all collaborators. Most of the researchers in this proposal participated in a conference at NIH in March, 2000 entitled "Circadian Disruption as Endocrine Disruption in Breast Cancer." This conference was covered in a NEWS article in the May 3, 2000 issue of journal of the National Cancer Institute which is archived on the web at: http://jnci.oupjoumals.org/cgi/content/full/92/9/686. It represents the investigators' initial efforts at crossdiscipline collaboration on the emerging topic of lighting, circadian disruption, and breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

23

Project Title: LIGHTION THERAPY FOR SEASONAL AFFECTIVE DISOR Principal Investigator & Institution: Terman, Michael; Professor; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 01-AUG-1987; Project End 30-SEP-2003 Summary: Light therapy for winter depression (Seasonal Affective Disorder, SAD), offers the promise of major alleviation of symptoms of fatigue, hyperphagia, hypersomnia, dysphoria, and anxiety that - according to recent surveys - are experienced by millions of people living in the middle-to- northern latitudes of the U. S., as well as a larger number of subsyndromal sufferers. Although early studies ha e consistently demonstrated rapid improvement in outpatient populations, individual protocols have been compromised by factors such as inadequate sample size, ambiguous controls, inconsistent level of severity at entry points into treatment and evaluation of relapse upon withdrawal, and application of lenient measures of symptom reduction. And although previous morning-evening comparisons of light scheduling have led to an impression of morning-light superiority, our preliminary data suggest that both are equally effective when presented as initial treatment. Evening light, however, becomes ineffective following morning treatment, with total lack of response observed thus far. Such evening-light decrement is also seen in reanalysis of cross-center data. This sequential dependency provides a procedural framework for distinguishing among alternate mechanisms that may subserve the specific action of light therapy. Our proposed experiments build upon a rigorously controlled protocol in which SAD patients receive successive, randomized tests of bright artificial light in morning and evening hours, including parallel-group controls designed to elucidate the morninglight carryover effect. We raise the new hypotheses, that (1) clinical response to light is effective at any time of day except when it induces circadian phase delay (as measured by nocturnal onset of melatonin secretion), and (2) light treatment serves to stimulate retinal photoreceptor metabolism, potentiating visual input signals to the central nervous system. We propose to test an interactive model of phase delay and retinal response through melatonin measurements and dark-adaptometry at selected points within the clinical protocol. Further, we plan to challenge these physiological explanations of light effect by addition of an inert placebo control. At issue is whether initial evening light response is nonspecific, and whether lack of response is induced by prior exposure to the putative active agent, morning light. Patients will also receive detailed ophthalmological evaluations pre-and posttreatment, and in long- term followup, in an ongoing effort to document ocular safety of bright light treatment, and to probe for the presence of any retinal effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: PERIODICITY

MATERNAL

INFLUENCE

ON

DEVELOPING

24-HOUR

Principal Investigator & Institution: Reppert, Steven M.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-APR-1981; Project End 30-JUN-2001 Summary: During fetal life, a biological clock located in the hypothalamic suprachasmatic nuclei (SCN) is oscillating. The mother coordinates (entrains) the timing of the fetal biological clock to ambient light-dark conditions. The experiments proposed in this application use physiological, and newly developed cellular and molecular approaches to probe the biology of the fetal SCN. Our long-term goal is to better understand the basic mechanisms underlying biological clock function. First , the signals

24

Melatonin

communicating circadian phase information to the fetal SCN will be examined. Periodic feeding or pharmacological doses of the pineal hormone, melatonin, can entrain the fetuses of SCN-lesioned pregnant rodents. Experiments will investigate which aspect of periodic food presentation entrains the rat fetus. It will also be determined whether a physiological pattern of melatonin administration entrains the fetus. Potential fetal entraining agents will be examined in vitro by monitoring the electrical activity rhythm in brains slices containing fetal SCN. Second, a dopamine system within the fetal SCN will be defined. The expression of c-fos in the fetal SCN can be activated through a Dldopamine receptor suggesting that a functional dopamine system exists within the fetal SCN. Experiments will characterize the components of a dopamine system in the fetal hypothalamus, assess the functional significance of this dopamine system, and investigate the potential role of other transmitter systems in the fetal SCN. Third, the functional properties of migrating SCN neurons will be elucidated. Dopamine Dlreceptor mRNA will be used to identify SCN neurons during migration. This will permit investigation of the circadian properties of migrating SCN neurons. Fourth, the oscillatory properties of the developing SCN will be investigated, utilizing multimicroelectrode plates to record electrical activity from cultured neurons. The ability of fetal SCN cells to form a functional circadian clock following dissociation will be used to examine the functional interactions among SCN cells which develop to form, a circadian clock in vitro. This system will also be used to determine whether single SCN cells express circadian oscillations in firing rate in vitro. Circadian variations affect virtually all aspects of human physiology and can contribute to pathophysiological states. Thus, increased understanding of the basic mechanisms of biological clock function may facilitate the development of better treatment strategies for a wide range of disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEDIATORS OF OXIDATIVE DAMAGE IN OLIGODENDROCYTES Principal Investigator & Institution: Gard, Anthony L.; Professor; Structural/Cellular Biology; University of South Alabama Mobile, Al 366880002 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: This project tests the central hypothesis that increased oligodendroglial oxidative stress promotes dysmyelination of the aging CNS through specific mediators of membrane lipid peroxidation (MLP) that are subject to environmental regulation. The studies will employ an in vitro approach to identify mechanisms of oxidative injury and glioprotection in the oligodendrocyte (OC)-myelin unit, modeled with myelinogenic OCs grown to maturity in isolation from other cell types. Experiments in Aim 1 will determine the identity of proteins of the myelin membrane and associated microtubule cyrtoskeleton adducted by 4- hydroxynonenal (HNE), a highly reactive cytotoxic effector of MLP- mediated injury implicated in neurodegenerative diseases of aging. They will further examine the peturbing effect of HNE on the amount and integrity of myelin-like membrane biogenesis, microtubule assembly and microtubule-dependent translocation of myelin basic protein mRNA to the myelin compartment in living cells. Experiments in Aim 2 will identify the capacity of specific environmental signals instrumental to differentiation and/or maintenance of the OC-myelin unit to regulate anti-oxidant defenses in myelinogenic OCs. They will identify specific diffusible factors and non-diffusible homotypic and heterotypic cell-cell interactions that suppress the generation of reactive oxygen species and cellular injury, using a menadione model for oxyradical production, and determine whether regulation occurs to stimulate glutathione biosynthesis and/or oxyradical-detoxifying enzyme activities. Experiments

Studies

25

in Aim 3 will determine the capacity of estrogens and melatonin, both recognized as natural neuroprotectants with antioxidant activity, and non-pschycotropic cannabinoid to protect myelinogenic OCs against HNE and reactive oxygen species evoked by oxyradical generators and pro-oxidants of neuropathologic significance to aging (glutamate, beta-amyloid peptide. Successful completion of these aims will indicate biochemical loci where therapeutic intervention may suppress acute and chronic forms of oxidative stress in OCs and reduce morbidity consequent to dysmelination in normal and pathologic aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELATONIN ANALOG FOR SLEEP DISORDERS Principal Investigator & Institution: Mulchahey, James J.; Assistant Professor; Phase 2 Discovery, Inc. 3130 Highland Ave, 3Rd Fl Cincinnati, Oh 45219 Timing: Fiscal Year 2002; Project Start 12-SEP-2002; Project End 31-DEC-2002 Summary: (PROVIDED BY APPLICANT): Phase 2 Discovery is developing a synthetic melatonin analog (PD6735) for the treatment of sleep disorders. PD6735 is being developed as a safe and effective treatment for sleep disorders that lacks the side effects of current first-line sleep medications. Initial clinical studies indicate that PD6735 is safe and well tolerated in humans through the maximal dose tested, 20 mg. PD6735 produced a dose-response improvement in sleep latency in subjects with sleep onset insomnia (double-blind, placebo controlled, crossover study, N=1 9). The PD6735 effect on sleep latency was more pronounced at 20 mg than at 5 mg. The goal of the present Fast Track application is to determine whether the dose-response effect of PD6735 on sleep latency will be more pronounced at higher PD6735 doses. Phase 1 of this proposal will establish the safety and tolerability of PD6735 at 20 to 100 mg doses. Phase 2 will determine the effect of the 20 to 100 mg doses (or the maximum safe P 06735 dose identified in Phase I) on sleep latency in subjects with sleep-onset insomnia. The Specific Aims of the Phase 1 portion of this proposal are: Aim I: Evaluate the safety and tolerability of PD6735 at doses up to 100 mg. Oral doses of 20, 35, 50 and 100 mg will be employed. Aim 2: Determine the pharmacokinetics of PD6735 at doses up to 100 mg. Aim 3: Determine the pharmacodynamics of PD6735 at doses up to 100 mg. PD6735 effects on body temperature and subjective sleepiness will be evaluated. PROPOSED COMMERCIAL APPLICATIONS: Sleep disorders affect over 60 million Americans who spend more than $1.4 billion on sleep medications would have a competitive advantage over current first line therapies by virtue of possessing fewer side effects. As such, the melatonin analog should capture a substantial portion of this market. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MELATONIN ENTRAINMENT OF ELDERLY BLIND FREE-RUNNERS Principal Investigator & Institution: Lewy, Alfred J.; Professor; Psychiatry; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): In our just completed project, we have shown that nightly oral administration of 10 mg melatonin can entrain (synchronize) free-running circadian rhythms in eight of nine younger blind people to the 24.0-hour day, resulting in improved nighttime sleep and daytime alertness. The one person who did not entrain had the longest pre-treatment free-running period (24.9 h). In addition, we have shown that 10 mg of melatonin has a direct soporific action when given to blind subjects when their free-running circadian rhythms are inverted. Most recently, we have found that the

26

Melatonin

dose can be "stepped down" to 0.5 mg in three out of three of these people. We have further found that they could also be entrained to a de novo 0.5 mg dose (their longest free-running period was 24.4 h). The pre-treatment period appears to predict the likelihood of entrainment to melatonin and the steady-state phase of entrainment, which is consistent with several important principles established in animal studies. Therefore, our projects are of both clinical and scientific importance. There are approximately 200,000 totally blind people in the U.S. About 50 percent of these people have free-running circadian rhythms. Many of these people are elderly. The goal of this project will be to determine the efficacy of melatonin treatment at three doses (0.5 mg, 10 mg and 20 mg), with the prediction that the 0.5 mg dose will work only in people with relatively short periods (<24.5 h). In treatment failures with the 0.5 mg dose, we will test the efficacy of higher doses. Blind subjects who successfully entrain with melatonin will be followed for one year to assess the long-term benefits and risks of melatonin administration. It is particularly important to study the elderly blind, because - compared to younger blind people - they may be more susceptible to side effects of melatonin and they may respond differently to melatonin treatment. Among the many basic science questions that we will be addressing is the effect of age on circadian period. The study of blind people provides an opportunity to understand the physiology of the circadian system in humans unperturbed by the light/dark cycle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELATONIN REGULATION OF MT2 MELATONIN RECEPTORS Principal Investigator & Institution: Gerdin, Matthew J.; Mol Pharm & Biol Chemistry; Northwestern University Office of Sponsored Programs Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 16-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): This proposal aims to investigate the mechanisms by which melatonin (MET) regulates MT2 melatonin receptors and assess the physiological significance of these events. The specific aims include: 1) to investigate the mechanisms by which melatonin desensitizes the MT2 melatonin receptor 2) assess the role of endogenous melatonin in regulating MT2 melatonin receptor-mediated phase shifts of circadian rhythms in the suprachiasmatic nucleus (SCN). It is hypothesized that a potential mechanism mediating the decreases in specific 2-[125 I]-iodomelatonin binding is MLTmediated desensitization of the MT2 receptor through receptor internalization. Desensitization of CHO-MT2 receptors will be addressed using cAMP functional and receptor phosphorylation assays. Using dominant negatives of G protein receptor kinases (GRK), arrestins, and dynamin, confocal microscopic and cell surface biotinylation experiments will examine the process of CHO-MT2 receptor internalization. The physiological significance of this proposed MT2 receptor desensitization will be assessed by recording the neuronal firing of suprachiasmatic nucleus (SCN) neurons in an in vitro rat brain slice. Melatonin can phase shift the peak of neuronal firing in the SCN through activation of endogenous MT2 receptors at CT10 and CT23. Desensitization of the MT2 receptor will be determined following treatment of the SCN with MLT for 8h prior to CT23 and assessing whether MLT can still phase shift the peak of neuronal firing at CT23. Internalization as a mechanism of desensitization in the SCN will be investigated in immortalized SCN cells using GFPtagged MT2 receptors in confocal microscopic experiments. The knowledge gained from this research will advance our understanding of the involvement of MLT and the melatonin receptors in modulating circadian rhythms, whose alteration has been noted in depressive and sleep disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

27

Project Title: MELATONIN, BEHAVIOR AND NEURONAL ACTIVITY IN ZEBRAFISH Principal Investigator & Institution: Zhdanova, Irina V.; Research Associate Professor; Anatomy and Neurobiology; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): The long-term goal of our studies is to identify the mechanisms mediating the physiological effects of melatonin on human sleep and circadian rhythms, and to apply this knowledge to designing new therapeutic strategies for insomnia. Our recent studies have established that rest state in diurnal genetically well-characterized lower vertebrate, zebrafish, has critical behavioral similarities with sleep and that melatonin can promote a sleep-like state in zebrafish via specific melatonin receptors. The goals of the proposed project are to determine the contribution of overnight melatonin receptor activation by endogenous melatonin to quantitative parameters of nighttime sleep-like state and the circadian rhythm of activity in zebrafish, to identify melatonin receptor subtypes responsible for sleep and circadian modulation, and to identify the reticulospinal neurons mediating locomotor effects of melatonin treatment. The effects of melatonin on sleep-like state and circadian rhythm parameters will be assessed in wild-type and melatonin receptor knockdown larval zebrafish using: i) high throughput automatic image analysis system for locomotor activity recordings; ii) melatonin receptor ligands with different affinity to melatonin receptor subtypes and inhibition of melatonin synthesis; iii) knockdown of melatonin receptor subtypes with antisense morpholino oligonucleotides; iv) in vivo confocal calcium imaging for monitoring spontaneous and evoked activity of individual neurons during high-speed recordings of larval locomotor behavior; v) laser ablation of candidate neurons under confocal microscope, followed by behavioral evaluation. These studies would clarify the role of endogenous melatonin in sleep regulation in the diurnal vertebrate, characterize functional specificity of melatonin receptors and role of reticulospinal neurons in locomotor effects of melatonin. They would also constitute a background for the identification of neuronal networks and intracellular signaling pathways mediating the effects of melatonin on sleep-like state and circadian rhythmicity. Furthermore, a continuation of these studies on the physiological regulation of the sleep-like state in zebrafish, in conjunction with the availability of multiple zebrafish mutants and a complete sequence of zebrafish genome soon to be available, could potentially lead to a better understanding of the genetic basis of sleep regulation and sleep function in vertebrates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MELATONIN'S ROLE IN TECTAL PHYSIOLOGY AND PLASTICITY Principal Investigator & Institution: Udin, Susan B.; Associate Professor; Physiology and Biophysics; State University of New York at Buffalo Suite 211 Ub Commons Amherst, Ny 14228 Timing: Fiscal Year 2001; Project Start 02-FEB-2001; Project End 31-JAN-2004 Summary: (Adapted from Applicant's abstract): The hormone melatonin is a molecule secreted by the brain on a circadian basis. Thee is evidence that it plays a role in governing sleep cycles and, in some species, reproductive readiness, but it also has been purported to influence everything from aging to cancer. It is consumed by many people, but our knowledge of what melatonin really does and where it exerts it effects is still quite incomplete. The tectum of Xenopus laevis frogs is an appropriate system in which

28

Melatonin

to study melatonin's effects, since the tectum is richly endowed with melatonin receptors; in addition, visual input plays a dramatic role in the Xenopus tectum in the formation of orderly binocular projections (plasticity and preliminary data indicate that chronic melatonin prolongs the critical period during which visual input can alter axonal projections. The experiments proposed here focus on exploring the role of melatonin on tectal function in normal Xenopus and on testing further whether chronic melatonin treatment prolongs the critical period of development of binocular maps in the tectum. Levels of melatonin, melatonin receptors, and melatonin receptor mRNA will be assessed at different times of day, and under different conditions of plasticity in order to determine whether any of those parameters change in correlation with plasticity. The anatomical consequences of chronic melatonin treatment on axonal morphology will be assessed using horseradish-peroxidase filling of isthmotectal axons in order to determine where the axons' development and responses to visual input are altered by chronic melatonin. To assess whether melatonin alters neuronal transmission in the tectum, fluorescent indicators will be used to assess melatonin's effects on calcium levels in axons and cells; also patch-clamp recording from tectal cells will be used to test whether melatonin changes presynaptic transmitter release and/or postsynaptic responses to glutamate or acetylcholine. The results of these studies will provide new information on both the acute and chronic effects of melatonin in the developing and mature nervous system. These data will be relevant to our understanding of how normal patterns of melatonin secretion affect the brain and will serve to alter us to possible consequences of long-term ingestion of melatonin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELATONIN

METABOLIC

CHANGES

DURING

AGING:

A

ROLE

FOR

Principal Investigator & Institution: Rasmussen, Dennis D.; Research Associate Professor; Psychiatry and Behavioral Scis; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2004 Summary: (provided by applicant) Adiposity, especially intra-abdominal adiposity, commonly increases by middle age in humans, non-human primates and rats, as do plasma insulin and leptin. These aging-associated increases in adiposity, insulin and leptin levels are associated with detrimental metabolic consequences, such as glucose intolerance, insulin resistance, diabetes, dyslipidemia, hypertension and cardiovascular disease. This spectrum of disorders, commonly grouped together as the "metabolic syndrome," is responsible for considerable aging-associated progressive pathology. Conversely, nocturnal pineal melatonin secretion decreases with aging in humans, other primates and rats. The proposed investigation evolves from our ongoing work demonstrating that chronic daily nocturnal administration of melatonin to middle-aged and older rats to produce youthful plasma melatonin levels and restore full amplitude circadian rhythmicity of plasma melatonin exposure also restored intra-abdominal adiposity, plasma insulin and plasma leptin to youthful levels. Administration of melatonin to young rats did not alter any of these parameters, suggesting that these responses were dependent upon the aging-associated decline in endogenous melatonin secretion. If melatonin supplementation to primates exerts these same effects, appropriate melatonin treatment could potentially provide effective prophylaxis or therapy for significant progressive pathologies associated with aging. Although indirect evidence suggests that melatonin may indeed play a role in regulating metabolism, body weight and adiposity in primates, a cause-effect relationship remains to be demonstrated. Testing this hypothesized relationship in middle-aged rhesus monkeys is

Studies

29

the sole specific aim of the proposed investigation. A single study will be conducted, utilizing daily nocturnal intravenous melatonin vs. control infusions in unanesthetized and freely-moving middle-aged rhesus monkeys bearing indwelling vascular catheters protected by tethers. If chronic daily nocturnal melatonin treatment does decrease the monkeys' body weight, abdominal adiposity, plasma insulin, and/or insulin sensitivity to more youthful levels, the results of this investigation will justify and facilitate subsequent investigations to resolve mechanisms and clinical utility of these responses. Development of a therapy or preventive treatment that would attenuate or reverse the detrimental changes in carbohydrate and lipid metabolism which are commonly first expressed at middle age would reduce the progressive aging-associated morbidity which is the consequence of these conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHOXYINDOLES IN RETINA--FUNCTION AND REGULATION Principal Investigator & Institution: Iuvone, P. Michael.; Professor; Pharmacology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 01-JUL-1983; Project End 30-JUN-2003 Summary: (Adapted from the applicant's abstract): Melatonin is a methoxyindole synthesized in the retina and pineal gland under the influence of circadian clocks. In retina, melatonin synthesis occurs in photoreceptor cells. Retinal melatonin is involved in the regulation of the cellular function of photoreceptors, retinal pigment epithelial (RPE) cells, and dopamine neurons. Together with dopamine, melatonin appears to play a pivotal role in the modulation by photoperiod and circadian clocks of visual sensitivity and metabolism in the photoreceptor-pigment epithelial complex. A retinal circadian clock regulates two enzymes in the melatonin biosynthetic pathway: tryptophan hydroxylase (TPH) and serotonin N-acetyltransferase (NAT). In addition, NAT is regulated by light and a signaling cascade that links photoreceptor membrane potential to cAMP-dependent phosphorylation. The long-term goal of the study is to characterize the melatonin system of retina and related aspects of visual cell physiology. To this end, cellular and molecular mechanisms in the regulation of melatonin biosynthesis will be explored. Specifically, experiments will be conducted to investigate: (1) the signal transduction cascade that regulates the effects of light and darkness on NAT activity in photoreceptor cells; (2) the molecular basis for the effects of light and cAMP on NAT mRNA and protein levels; (3) the molecular mechanisms for coupling the circadian clock to NAT and TPH gene expression; and (4) the localization of NAT in the retina and brain. These studies will be conducted using an integrated research approach involving biochemical, pharmacological, and cell and molecular biological methodologies. The research is significant because it characterizes cellular and biochemical systems that play an important role in the regulation of retinal physiology and photoreceptor cell function. It is anticipated that characterization of these systems will contribute to the understanding of visual cell physiology and some of the pathological processes that underlie photoreceptor degeneration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MODULATORY ROLE OF MELATONIN IN CNS FUNCTION Principal Investigator & Institution: Dubocovich, Margarita L.; Professor; Mol Pharm & Biol Chemistry; Northwestern University Office of Sponsored Programs Chicago, Il 60611 Timing: Fiscal Year 2001; Project Start 01-JUL-1987; Project End 30-JUN-2004

30

Melatonin

Summary: Our long term goal is to understand the role of the hormone melatonin and its receptors in coordinating behavioral and physiological responses to daily and seasonal changes in the environment. Here, we propose to use functional, immunohistochemical and molecular tools, in order: I) To determine the subtype and location of neuronal putative melatonin receptor subtype (ML1) in the central nervous system. The retina and brain visual system will be used as models to determine the location and subtype of melatonin receptor(s) using a) functional responses (i.e., modulation of the dopamine release from retina and glutamate from optic tectum and ectostriatum, b) immunohistochemical localization of melatonin receptor subtype immunoreactivity in the retina and brain, and colocalization with D1 dopamine receptors in single retinal ganglion cells, and c) molecular approaches to amplify melatonin receptor subtypes in the tectofugal pathway by RT-PCR and coexpression of melatonin and D1 dopamine receptors in single retinal ganglion cells; II) To determine the effect of physiological activation of human recombinant ML1A and ML1B melatonin receptors on signalling and gene expression. This hypothesis will be tested in CHO cells expressing human recombinant ML1A and ML1B melatonin receptors and in neuronal cultures of embryonic retinas. Cells will be exposed to physiological concentrations of melatonin for a length of time that mimic either long (16/8 L/D) or short (8/16 L/D) photoperiods. At different times after melatonin withdrawal we will measure a) expression of melatonin receptor protein and mRNA, b) supersensitization of cAMPmediated signalling (i.e., foreskolin stimulated cAMP formation, protein kinase A activity, phosphorylation of the cAMP response element binding protein), and c) regulation of CRE-mediated gene expression using the luciferase reporter gene system; III) To determine the role of light in regulating melatonin receptor expression we will measure receptor density by quantitative autoradiography with 2-[125I]- iodomelatonin, and mRNA expression by in situ hybridization histochemistry in brain visual pathways that are exposed to various light intensities, and in animals with unilateral eye patches. We will also examine modulation of melatonin receptor protein and mRNA expression in tectofugal pathways by light and activation of retinal D1-dopamine receptors. These studies will enhance our understanding on how environmental light and endogenous melatonin regulate melatonin receptor density and the expression of genes involved in circadian rhythms and visual function. Furthermore our studies are aimed to discover subtype selective melatonin receptor agonists and antagonists which may lead to new therapies for the treatment of visual function and circadian rhythms disturbances of sleep and mood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR DISSECTION OF MELATONIN SYNTHESIS IN VIVO Principal Investigator & Institution: Borjigin, Jimo; Carnegie Institution of Washington, Dc 1530 P St Nw Washington, Dc 20005 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (provided by applicant) Melatonin is a nocturnal hormone rhythmically synthesized and released from the pineal gland due to the actions of four enzymes: tryptophan hydroxylase (TPFI), aromatic amino acid decarboxylase (AAADC), serotonin N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT). Although current evidence suggests that in rats cAMP signaling mediates both transcriptional and post-transcriptional control of melatonin formation, little is known about the in vivo targets of cAMP in the pineal. We hypothesize that cAMP regulates melatonin synthesis principally by PKA activation, which phosphorylates key proteins involved in the biosynthesis of melatonin; phosphorylation of these proteins results in a

Studies

31

combination of increased transcription and decreased degradation of these biosynthetic enzymes. We plan to investigate the role of the cAMP signaling pathway in pineal circadian rhythms in the intact animal by using an integrated molecular and physiological approach. Aim 1 will establish the importance of the cAMP-dependent protein kinase (PKA) and CREB in transcriptional activation of NAT and melatonin formation in vivo. We will determine the effects of pharmacological inhibitors and activators of PKA catalysis in vivo by microdialysis and examine their influence on NAT transcriptional activation and repression during the day and night. We will also deliver recombinant adenoviral vectors expressing A-CREB or constitutively active PKA into the intact pineals to examine their effects on NAT mRNA and melatonin production. Aim 2 will evaluate the role of FKA in NAT protein stability in vivo. We will utilize a phospho-NAT specific antibody to study the functional significance of PKA-mediated NAT phosphorylation; we will characterize NAT from a mutant strain of rat we discovered that has lower NAT protein level due to a point mutation in a PKA phosphorylation site; lastly, we will use in vivo viral vector delivery and in vivo on-line microdialysis to study the stability and function of NAT mutants. Aim 3 will characterize the role of cAMP in the generation of our newly discovered tri-phasic circadian serotonin release in the pineal in vivo by again utilizing pharmacologic and molecular manipulations of cAMP signaling combined with in vivo physiological measurements of serotonin rhythms. These experiments will further our understanding of the in vivo signal transduction mechanisms that control transcriptional and posttranscriptional activation of melatonin and serotonin formation, which may play a role in the pathogenesis of sleep, psychiatric, and neurological disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR ROLE OF RIGUI IN MAMMALIAN CIRCADIAN PATHWAY Principal Investigator & Institution: Lee, Cheng C.; Assistant Professor; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 15-JUL-1998; Project End 31-MAY-2003 Summary: The molecular components of mammalian circadian clocks are elusive. The applicant has isolated a human gene termed RIGUI that encodes a bHLH/PAS protein 44 percent homologous to the period gene in Drosophila. The highly conserved mouse homolog (m-rigui) is expressed in a circadian pattern in the suprachiasmatic nucleus (SCN), the master regulator of circadian clocks in mammals. Circadian expression in the SCN continues in constant darkness, and a shift in the light/dark cycle evokes a proportional shift of m-rigui expression in the SCN. m-rigui transcripts also appear in a periodic pattern in Purkinje neurons, pars tuberalis, and retina, but with a timing of oscillation different from that seen in the SCN. Given the observation that the RIGUI gene has all the properties known about a core circadian component the principal investigator would like to define better its exact role in the circadian pathway. The specific aims of this study are to: a) Identify specific brain and peripheral tissue where the various circadian oscillators reside; b) Determine whether melatonin plays a role in the expression of m-rigui in the hypophyseal pars-tuberalis; c) Investigate the response of m-rigui expression in the retina and suprachiasmatic nucleus to environmental light cues; d) Make the targeted disruption of the m-rigui locus by gene knock-out methodology and determine the effect of its loss on the circadian behavior of the animals; e) Identify genes encoding proteins that interact with RIGUI using the twohybrid system; f) Determine the genomic structure of the human RIGUI locus and delineate its promoter and cis-acting elements. Understanding genetics and molecular

32

Melatonin

basis of RIGUI function could lead to new paradigms on how genes control mammalian behavior. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR/GENETIC ANALYSIS OF BIOLOGICAL CLOCKS Principal Investigator & Institution: Johnson, Carl H.; Associate Professor; Biology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2001; Project Start 10-JUL-1994; Project End 30-JUN-2004 Summary: This research concerns daily biological clocks, which are an important component of the physiology of humans and other organisms. For example, medical and psychiatric studies have shown that these biological clocks are involved in some forms of depressive illness, "jet lag," drug tolerance/efficacy, memory, and insomnia. Therefore, understanding the biochemical mechanism of these clocks may lead to procedures which will be useful in the diagnosis and treatment of disorders which are relevant to sleep, mental health, and pharmacology. Despite the importance of clocked phenomena, however, the nature of the underlying biochemical mechanism is unknown. The research strategy is to study the molecular and genetic nature of biological clocks in two model organisms: one prokaryotic, and the other eukaryotic. The immediate aims of his research are (I) to manipulate genetically the model organisms so that they express rhythms which can be easily screened, (2) to identify and clone genes which are involved in the timing mechanism, (3) to characterize the input pathway (light) by which this clock is synchronized to environmental time, and (4) to track the output pathways of the clock "upstream" to discover the clock mechanism itself. The long-term research goal is to understand the mechanism of this fascinating clockwork. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: MULTICENTER, PLACEBO CONTROLLED TRIAL OF MELATONIN FOR SLEEP DISTURBANCE Principal Investigator & Institution: Cummings, Jeffrey L.; Director; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-DEC-1999; Project End 30-NOV-2000 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NEURAL DEVELOPMENT

AND

HORMONAL

PATHWAYS

IN

OCULAR

Principal Investigator & Institution: Howland, Howard C.; Professor; Neurobiology and Behavior; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2001; Project Start 01-JUL-1979; Project End 31-MAY-2004 Summary: (Adapted from Applicant's Abstract): This grant addresses aspects of the general question: how do neural and hormonal pathways work together to establish regulation of refraction and growth of both eyes during early postnatal development? These pathways are important in coordinating development of eye movements, eye size, refraction and emmetropization. As such, their investigation is of singular importance in understanding the genesis of refractive error, strabismus, and amblyopia in humans. This study is particularly focused on the regulation of growth of the anterior segment of the eye. Using the chick model we will 1a) determine if the signal responsible for

Studies

33

protection from constant light effects (flattened cornea, shallow anterior chamber & hyperopia) is a periodic increase in melatonin concentration, and investigate the causal chain linking illumination and melatonin concentrations; 1b) determine whether the elongation of the vitreous chamber in constant light results from emmetropization growth, induced by the hyperopia that is caused by the flattening of the cornea; 1c) investigate the role of autonomic effects on the growth of the anterior segment; 2) investigate the light-dependent growth influences of one eye on another by various manipulations including optic nerve section, selective retinal cell destruction by drugs, and the generation of unilaterally micro-ophthalmic chicks. 3) investigate the mode of coupling of the light dark cycle to the circadian melatonin rhythm with the aid of mathematical models. Behavioral, surgical, biochemical, histological, and mathematical methods will be employed to answer these questions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROENDOCRINE CONTROL OF SEASONALITY Principal Investigator & Institution: Goodman, Robert M.; Professor; Physiology and Pharmacology; West Virginia University P. O. Box 6845 Morgantown, Wv 265066845 Timing: Fiscal Year 2002; Project Start 01-SEP-1983; Project End 30-JUN-2007 Summary: (provided by applicant) The long-term goal of this research is to understand the structural and functional changes in the hypothalamus that are responsible for the reversible suppression of ovarian function, such as occurs prior to puberty. It has been recognized for over 40 years that increases in response to estradiol (E2) negative feedback play a major role in producing these periods of infertility (e.g., the gonadostat theory of puberty), but the underlying changes in hypothalamo-pituitary function remain largely unknown. Using seasonal breeding as a model, we have identified a neural circuit (the vmPOA-RCh system) that plays a key role in alterations in E2 negative feedback in the ewe. This circuitry mediates E2 inhibition of gonadotropinreleasing hormone (GnRH) pulse frequency and is activated during periods of anovulation (anestrus) and inactivated during periods of fertility (breeding season). The first specific aim will better characterize this circuit by determining the phenotype of estrogen-responsive elements in the vmPOA and RCh and evaluating the role of ER in mediating the actions of E2. The second specific aim will test three alternate explanations for the activation of this system in anestrus: an increase in estrogen receptors, an increase in key neurotransmitter levels, or an increase in synaptic contacts within the circuit. The third specific aim will begin to determine the mechanisms by which external factors control the activity of this circuit. There is now evidence that another hypothalamic area, the premammillary region (PMR) controls changes in responsiveness to E2 negative feedback. The experiments in Specific Aim 3, we will examine the anatomical and functional connections between this area and the vmPOARCh system and test the hypothesis that it is critical for changes in response to E2 negative feedback. These questions will be addressed using a combination of anatomical, molecular and physiological approaches that include immunocytochemical analysis (at the light and electron microscopic levels), in situ hybridization, tract-tracing, local administration of drugs and hormones to different hypothalamic areas, and the production of small hypothalamic lesions. The results of these studies will provide fundamental information on the control of reproductive function and on neural plasticity in the adult brain that may be relevant to both physiological and pathological suppression of ovarian function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

34

Melatonin

•

Project Title: NEUROENDOCRINE DYSFUNCTION IN PATIENTS WITH CLOSED HEAD INJURY Principal Investigator & Institution: Urban, Randall J.; Professor; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: This study will test the hypothesis that dysfunction of neuroendocrine regulatory structures (hypothalamus, pituitary gland, pineal gland) occurs in a subset of patients with closed-head injury. Because partial dysfunction of these structures presents with subtle clinical features, these features may be overlooked acutely but may contribute to non-specific symptoms, diminished quality of life during the recovery and rehabilitation of closed-head injury patients. We propose to investigate the frequency of neuroendocrine deficiencies in individuals recovering from closed head injuries by endocrine testing. This two year study will consist of two phases. In Phase I, recovering (at least 3 months post-injury) closed-head injury patients will be screened for the presence of neuroendocrine dysfunction with tests routinely used in clinical endocrinology. This will include assessment of adrenal, thyroid, and gonadal function, and prolactin and growth hormone secretion by the pituitary. In addition, melatonin secretion by the pineal galnd will be assessed via measurement of its principal urinary metabolite. One hundred subjects will be enrolled in Phase I. Any patient with an abnormal test result will undergo Phase II testing, in which dynamic tests of neuroendocrine function will be used. Results from this study could lead to standard neuroendocrine function testing of patients with closed-head injury in clinical practice. Subsequent hormone replacement would improve function and well-being in this group of patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NEUROENDOCRINE INFLUENCES ON MAMMARY CANCER Principal Investigator & Institution: Hill, Steven M.; Associate Professor; Anatomy; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 30-APR-2007 Summary: (provided by applicant): Our laboratory has shown that melatonin significantly inhibits the proliferation of ER+, but not ER- human breast cancer cells, and modulates the expression and transcriptional activity of the ERa. We have also demonstrated that melatonin can cross-talk with the retinoic acid (RA) signaling pathway, such that, when treated with a regimen of melatonin followed by RA at physiologic doses, breast cancer cells undergo apoptosis. In vivo, the combination of melatonin and 9-cis-RA was shown to be significantly more effective than RA alone at inhibiting the development and inducing the regression of carcinogen-induced rat mammary tumors. Furthermore, we have developed new data showing that melatonin's effects in tumor cells are mediated via the Mella/mt1 G protein-coupled receptor, and that overexpression of this receptor can enhance the response of ER+ breast tumor cells to the growth inhibitory effects of melatonin. These data led to our current hypothesis that the growth-inhibitory actions of melatonin are mediated, at least in part, through the Mella/mt1 melatonin receptor via modulation of the transcriptional activity of steroid/thyroid hormone receptor signaling pathways (ERa and RAR/RXR), and that overexpression of the Mella/mt1 receptor can generate a melatonin supersensitive phenotype in ER+ breast cancer cells. To test this hypothesis, we have developed the following Specific Aims: (1) To elucidate the importance of the Mella/mt1 receptor in the development and progression of breast cancer, and the signaling pathway(s) utilized

Studies

35

by the Mel la/mt1 receptor to suppress MCF-7 cell proliferation; (2) To define the importance of the Mella/mt1 receptor in controlling breast cancer cell growth using Mel I a/mt1 gene ablation and transgenic overexpression techniques; (3) To determine if MCF-7 cells overexpressing the Mella/mtl receptor exhibit an enhanced response to the timed regimen of melatonin and RA, and to delineate further the interaction/cross-talk between melatonin and RA signaling pathways in regulating MCF-7 cell proliferation and apoptosis; and (4) To determine the optimal retinoid, dosage, and time period for the regimen of melatonin and RA which induces maximal regression of Nnitrosomethylurea (NMU)-induced rat mammary tumors. The characterization of the pathways by which melatonin inhibits the development and growth of breast tumors, and cross-talks with other hormone response pathways, such as the estrogen and retinoid pathways, is essential for the development of future endocrine strategies in the treatment and prevention of breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELATONIN

NEUROENDOCRINE/IMMUNE

INTERACTIONS:

ROLE

OF

Principal Investigator & Institution: Yellon, Steven M.; Professor; Center for Perinatal Biology; Loma Linda University Loma Linda, Ca 92350 Timing: Fiscal Year 2001; Project Start 20-JAN-2000; Project End 30-NOV-2002 Summary: (applicant's abstract): Physiological adaptations anticipate and coincide with changes in season. Failures to adapt are associated with increased incidence of disease, mortality and mental dysfunctions that include seasonal affective disorders and depression. Day length is the primary environmental cue that regulates a variety of physiological adaptations that anticipate seasonal challenges. Preliminary studies indicate that day length selectively regulates immune functions in the Siberian hamster, a seasonal breeding species in which the mechanism that controls physiological adaptations to day length has been extensively studied. Hamsters in short days (analogous to winter) had increased numbers of leukocytes, T helper cells and eosinophils; natural killer cell cytolytic activity and spontaneous lymphoblastogenesis were also enhanced. In contrast, other indices of immune cell functions were reduced, including T cell-dependent antibody production, as well as phagocytosis and oxidative burst activities by granulocytes and monocytes. Since the neuroendocrine system that mediates the influence of day length on seasonal reproductive physiology involves the circadian pineal melatonin rhythm, the major focus of the proposal is to test the hypothesis that the pineal melatonin rhythm mediates photoperiod control of innate and adaptive immune system functions. An integrative approach to this hypothesis is based upon assessment of the magnitude and tempo of immune responses to changes in day length. The possibility that daily rhythms in immune cell functions are driven by changes in specific immunophenotypes will be addressed. To determine whether photoperiod effects on immune functions depend on the melatonin rhythm, hamsters will be pinealectomized and administered timed treatments to replace specific aspects of the melatonin rhythm. Measures were developed for this seasonal animal model to assess multiple immune system indices by highly sensitive and sophisticated flow cytometry methods for phenotyping, cell-mediated cytolysis, antibody isotype switching and phagocytic cell function. Regulation of specific immune system parameters by photoperiod may potentiate disease resistance, promote adaptations to seasonal challenges in the environment, and provide the foundation to address the therapeutic value of such treatments to selectively modulate immune function in other species. Fundamental knowledge of circadian time keeping and neuroimmune

36

Melatonin

interactions may lead to development of novel approaches to maximize immune responsiveness or slow the deterioration of immune system function that is associated with immunodeficiency, autoimmunity, sleep disturbances, aging and seasonality in behavioral disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURONAL PLASTICITY IN THE RETINA Principal Investigator & Institution: Mangel, Stuart C.; Associate Professor; Neurobiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 01-MAR-1984; Project End 30-JUN-2003 Summary: (Adapted from applicant's abstract): This project seeks to understand how neuronal circuits in the rabbit retina change or adapt due to a circadian oscillator. A circadian clock or oscillator has a rhythmicity of approximately 24 hours in the absence of external timing cues. Cyclic environmental stimuli such as light can entrain the circadian clock. This project will determine whether a circadian clock regulates conehorizontal cells that exhibit a diurnal rhythm. The dominant photoreceptor input to dark-adapted, cone horizontal cells exhibits a diurnal rhythm; cone inputs predominate during the day and rod inputs predominate during the night. A combination of electrophysiological, neurochemical and anatomical techniques will be utilized to determine whether a circadian clock is involved in horizontal cell and ganglion cell light responsiveness, as well as horizontal cell gap junctional coupling. It will be determined whether a circadian clock controls the levels of dopamine, melatonin and adenosine, as well as extracellular pH. It will then be determined whether the circadian clock uses any of these signaling mechanisms to regulate the light responses of horizontal and ganglion cells. Measurements will be made in constant darkness (absence of timing cues) in a superfused, retinal eyecup preparation. Disruption of the circadian clock may result in retinal photoreceptor degeneration. Thus, increased understanding of the circadian clock processes will aid in the understanding of human retinal processes and dysfunction. These studies may also provide the basis for drug therapy for retinal disorders thought to be linked to the disruption of circadian processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NEUROSCIENCE Principal Investigator & Institution: Chiaki, Fukuhara; Morehouse School of Medicine Atlanta, Ga 30310 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: Our long-term research objective is to understand the molecular mechanisms that initiate circadian gene expression following external stimulation. We will use the pineal gland to study signaling pathways because it has been extensively used to study signaling cascades and so provides an extensive knowledgebase for our studies. Our research proposal has two goals: (1) to understand the mechanisms by which norepinepherine (NE) controls Period1 expression and (2) to investigate the regulation of circadian "Clock" genes' expressions following external stimulation. First, since NE increases intra-cellular cyclic AMP (cAMP) and cyclic GMP (cGMP) levels, we will investigate the mechanisms by which cAMP and cGMP signaling pathways induce Period 1 mRNA levels. Since Period 1 is thought to be involved in the resetting of circadian rhythms, we will focus on the regulation of Period 1 expression in specific aims I and I1. Secondly, we will investigate whether or not other circadian "Clock"

37

Studies

mRNA levels are induced by NE, cAMP, cGMP, or cAMP and cGMP co-stimulation. Besides its biological importance and interest, the use of pineal gland as a model, has promise for providing information that may be applicable to the prevention of neurodegenerative diseases, such as Alzheimer's disease, since it has been suggested that melatonin may play a role in neuroprotection. In addition, our studies have the pete" tial to address problems associated with jet lag, circadian-based sleep disorders, some neuropsychiatric illnesses, and shift work. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROSCIENCES ANTIOXIDANTS

TECHNOLOGY

DEVELOPMENT

FOR

Principal Investigator & Institution: Kumar, Dinender; Director; Brain Research Laboratories, Inc. (Brl) 115 Mill St Belmont, Ma 02478 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: adapted from applicant's abstract): There is growing evidence that ROS may be implicated in aging and a variety of age-related human degenerative disorders. In this context, exogenous antioxidants are beginning to assume an unprecedented importance in the arsenal of therapeutic agents that are continuously being developed in order to combat age related diseases and the phenomenon of aging itself. These antioxidants are supposed to supplement and reinforce the natural defenses of the body and to protect it when the endogenous antioxidant levels are diminished as a result of disease or aging. The current problems in the in vitro assay of antioxidants are many and varied: (a) different laboratories use different species of ROS and different target molecules under different experimental conditions in formulating their assay systems; (b) there are no comparative studies to evaluate the reliability of one method over an other, (c) many have been mainly employed for investigating the mechanisms of action of specific oxygen free radicals and are not particularly relevant as procedures for the assay of antioxidants; (d) since many of the methods are not specifically designed for antioxidant assay, they have not been optimized taking into consideration the prooxidant or antioxidant properties of certain substances under different conditions; and (e) they often require expensive instrumentation and highly sophisticated technical skill to perform the analysis and to interpret the resulting data. In the first step in this project, our goal will be to develop in vitro assay systems for the measurement of individual biological activities of coenzyme Q, lipoic acid and melatonin, using pure commercial preparations of these compounds, taking into consideration the properties of both the ROS and the antioxidants involved. In the second step, we will develop an in vivo method using for determining antioxidant activity using intact cells and intracellular macromolecules as targets. The results of the two systems will be analyzed to yield an approach which can be employed for the determination of biological activities of known or unknown mixtures of antioxidants using a minimum number of simple assay procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NIGHT SHIFT WORKERS AND HORMONE LEVELS IN WOMEN Principal Investigator & Institution: Davis, Scott; Professor of Epidemiology; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 11-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): The primary objective of the proposed study is to determine whether working at night is associated with decreased levels of the nocturnal

38

Melatonin

urinary concentration of 6-sulphatoxymelatonin, and increased levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol in a sample of healthy women of reproductive age. Secondarily, this study is designed to investigate whether urinary levels of melatonin are lower and levels of reproductive hormones are higher during daytime sleep relative to nighttime sleep among women who work at night. Approximately 200 nurses who work the night shift exclusively and 150 nurses who work the day shift exclusively will be recruited as volunteers in the Seattle metropolitan area. Eligible participants must be between the ages of 20 and 40, employed for at least 20 hours/week, resident of King or Snohomish County, do not take oral contraceptives or other hormone preparations, and have no personal history of breast cancer. In addition, the night shift nurses must normally sleep at night during off days. This study will employ a design which allows for both between-subject comparisons of night shift v. day shift workers, and within-subject comparisons during day sleep v. night sleep among the night shift workers. Participation will span two months. In the first month the study will evaluate menstrual cycle regularity, determine the day of ovulation using a commercial kit, conduct a personal interview regarding employment and reproductive history, assess the participant's ability to adjust to shift work, and collect a blood sample. In the second month urine sample collections will be scheduled during both work and sleep periods, and will take place in the early to mid-luteal phase of each participant's cycle. Sleep patterns will be measured via actigraphy during the sleep periods corresponding to urine collection. Oral temperature data will be collected during waketime in the night shift workers to determine temperature amplitude. Information will be collected on factors which may be related to the hormones under study, such as alcohol consumption, medication use, and hours of daylight during sample collection. Urine samples will be assayed for the primary urinary metabolite of melatonin, 6sulphatoxymelatonin, and levels of LH, FSH, and estradiol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL NON-PEPTIDE ANTAGONIST OF THE MCH RECEPTOR Principal Investigator & Institution: Clark, Melody E.; Neurocrine Biosciences, Inc. 10555 Science Center Dr San Diego, Ca 921211100 Timing: Fiscal Year 2001; Project Start 01-JAN-2001; Project End 30-JUN-2001 Summary: (Scanned from the applicant's description) The prevalence of obesity has risen dramatically among all segments of the U.S. population in the last two decades. Recent studies have established a role for melanin-concentrating hormone (MCH) in the control of feeding behavior and body weight. For example, direct central administration of the MCH peptide in rats increases feeding. Also, mice that lack the MCH gene eat significantly less than control mice and have a 25-30 percent reduction in body weight. These observations provide a compelling basis for the development of MCH antagonists as novel drug treatments for obesity and diabetes. In preliminary experiments, we have identified a number of compounds with low micromolar affinity for the MCH receptor, including compounds that have affinities below the micromolar range. In Phase I, we propose a high throughput parallel synthesis approach to generate small molecule libraries in order to develop multiple leads with high affinity. We will also investigate the functional effects of these compounds and determine their specificity for the MCH receptor compared to related receptors. Finally, we will examine selected compounds in a rat MCH-induced feeding model for their ability to block MCH in vivo. The specific aims proposed in Phase I are designed to generate potent small molecule MCH receptor antagonists, together with the data necessary to support the development of these antagonists into valid clinical candidates in Phase II. PROPOSED COMMERCIAL

Studies

39

APPLICATION: This research, if successful, will result in small molecule antagonists of the melanin- concentrating hormone receptor that selectively inhibits the feeding response. Orally active forms of a small molecule MCH receptor antagonist would provide a novel therapeutic strategy for indications such as obesity and diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OCULAR CONTROL OF MELATONIN REGULATION: ACTION SPECTRUM Principal Investigator & Institution: Brainard, George C.; Professor; Neurology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2001; Project Start 01-APR-1997; Project End 30-JUN-2005 Summary: (provided by applicant): Studies have shown light therapy to be effective in treating selected sleep disorders and re-entraining circadian physiology relative to the challenges of shift work or intercontinental air travel. A Congressional report estimates that the population of 20 million shift workers in the U.S. suffers from increased health problems including reduced sleep, reduced neurobehavioral performance, and higher risk of cardiovascular and gastrointestinal disease. The long term goal of this work is to identify the circadian photoreceptor(s) responsible for the clinical benefits of light therapy in humans. Currently, it is not known which photopigments transduce light stimuli for the circadian and therapeutic effects of light. The present work is aimed toward identifying the photopigment(s) responsible for light regulation of melatonin by investigating the spectral characteristics of light involved in acute melatonin suppression and phase shifting of the circadian melatonin rhythm in humans. The primary technique to accomplish this aim will be action spectrum analysis. An action spectrum: 1) defines the relative effectiveness of wavelengths for eliciting a biological response, and 2) helps to identify the photoreceptor involved in that response. Over the past four years, an 8 wavelength action spectrum for light-induced melatonin suppression in healthy volunteers has been developed which fits a vitamin A1 opsin photopigment nomogram with a spectral maximum (lambda max) at 464 nm. The specific aims of this proposal are to: 1) Test the hypothesis that fluence-response data from melatonin suppression with monochromatic wavelengths at 400 and 420 nm in volunteers with normal color vision will fit the 464 nm vitamin A1 opsin nomogram. 2) Test the hypothesis that the photoreceptor for melatonin regulation is independent of the photoreceptors for photopic vision by comparing action spectra for acute lightinduced melatonin suppression in subjects with normal color vision and subjects who have the cone system deficiencies of deuteranopia and protanopia. 3) Test the hypothesis that both acute melatonin suppression and phase-shifting of the melatonin rhythm are similar in wavelength sensitivity by testing phase-shifts of the melatonin circadian rhythm following exposure to equal photon densities of monochromatic light at 464 nm and 555 nm in normal subjects. Ultimately, this research will lead to the identification of photoreceptors implicated in the use of light as a therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: PHASE SHIFT TOLERANCE IN OLDER PEOPLE Principal Investigator & Institution: Monk, Timothy H.; Professor; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 10-FEB-1996; Project End 31-JAN-2006

40

Melatonin

Summary: The sleep problems of older men and women often have timing difficulties as a significant part of their etiology. A misalignment of the circadian system ("biological clock") of older people by only a few hours can lead to significant sleep impairment. Thus, an examination of the effects of shifts in the timing of sleep may lead to therapeutic strategies which could alleviate the sleep disorders of older people without resorting to hypnotic medications. In our previous work we have studied the tolerance of elderly people to phase shifts of 6h. We now propose to investigate rather smaller (2h) phase shifts. We shall compare three groups: older men, older women, and young controls, in their response to both phase delays and phase advances, with all subjects doing control, advance and delay conditions. We also plan to investigate the relationship between circadian rhythms and sleep by indexing the bedtime (control or shifted) to its phase difference from the phase of the endogenous circadian pacemaker. We shall use two well accepted circadian phase markers: 1) the time of minimum [Tmin] of the rectal temperature rhythm as fitted by 24h and 12h sinusoids, and 2) the timing of Dim Light Melatonin Onset (DLMO) as measured by half-hourly evening salivary samples. Each subject will experience three conditions in three separate 120h runs. In each run, after two baseline days and nights (48h) at the subject's habitual routine, subjects will live for 3 days and nights under ad-lib sleep length (time in bed) conditions, but with the timing of bedtime specified. First, in the control condition, the bedtime will always be at habitual bedtime, so that baseline levels of sleep and daytime performance can be obtained and the phase difference between Tmin and bedtime, and between DLMO and bedtime later calculated from the entire 5-day run. In the advance condition the bedtime on nights 3-5 will be two hours earlier than habitual bedtime. In the delay condition bedtime on nights 3-5 will be two hours later than habitual bedtime. In all cases, sleeps will be polysomnographically recorded, rectal temperatures monitored continuously, and daytime alertness, mood and performance assessed using our usual battery of tests. We propose to study 10 older (70y+) women, 10 older (70y+) men and 10 young (20y - 35y) controls (5m, 5f), with order of presentation of the advance and delay conditions counterbalanced. Hypotheses will be tested relating both to the effect of phase shift on nocturnal sleep and daytime alertness and performance variables, and also to the effect on these variables of individual daily variations in observed circadian phase angle between Tmin and bedtime, and between DLMO and bedtime. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MELATONIN.

PHOTIC

AND

CIRCADIAN

REGULATION

OF

RETINAL

Principal Investigator & Institution: Tosini, Gianluca; Anatomy; Morehouse School of Medicine Atlanta, Ga 30310 Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2006 Summary: (provided by applicant): The presence of melatonin rhythmicity in the retina of mammals has been demonstrated by several in vivo and in vitro studies, but many aspects of its synthesis and regulation in this tissue are still obscure. The goals of the present research proposal are to identify the cell type(s) that synthesizes melatonin and to elucidate the role of environmental light and of the circadian clock in regulating melatonin synthesis in the retina of mammals. The first specific aim will test the hypothesis that cone photoreceptors contain the melatonin synthesizing machinery as well as the circadian clock components to regulate it. The second aim will test the hypothesis that rod photoreceptors and/or inner retinal neurons contain the circadian clock(s) that drives retinal melatonin biosynthesis in cones. Finally, the third aim will

Studies

41

test the hypothesis that cone photopigments mediate the suppression of retinal melatonin that follows exposure nocturnal exposure to light. In our research we will use a wide array of new and technologically advanced techniques such as dual in situ hybridization, quantitative real time PCR and Laser Capture Dissecting Microscopy. Retinal melatonin is involved in the modulation of several aspects of retinal physiology; thus the understanding of how this hormone (neuromodulator) is regulated will likely improve our understanding of retinal physiology and pathologies. Modem life style has tremendously changed our daily exposure to light and darkness and thus it is important to understand the effect that such exposure may have on the organism and, in particular, retinal function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHOTOPERIOD, MELATONIN, AND SICKNESS BEHAVIORS Principal Investigator & Institution: Nelson, Randy J.; Professor; Psychology; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Infection results in the rapid onset of adaptive sickness responses, termed the acute phase response, and includes physiological changes such as fever, increased sleep, as well as behavioral changes such as reduced food and water intake, activity, exploration, and social interactions. These so-called "sickness behaviors" are organized, adaptive strategies that are often crucial for host survival, rather than nonspecific manifestations of illness. Mounting an immune response is energetically costly. For many animals living in non-tropical habitats, a predictable annual energy shortage occurs each winter. During the short days of winter, low food availability often coincides with high thermoregulatory demands in low temperatures. Specific adaptations to conserve energy, such as inhibiting reproduction and growth, have evolved among animals to enhance winter survival. Immune function and responses to infection are also constrained by available energy, and may be altered by changes in the external environment. The proposed experiments are designed to investigate whether sickness behaviors or immune cell trafficking may be influenced by available energy or other factors signaled by melatonin. The specific aims of the proposed research are: (1) To determine if early immune activation evokes long-term reproductive costs. (2) To determine if short-day alterations in sickness responses are mediated by melatonin. (3) To discover if melatonin acts directly on lymphocytes to alter cytokine production. (4) To determine if short days and melatonin reduce the duration of fever by affecting brain levels of cyclooxygenase (COX) and interleukin(IL)1a. (5) To determine if photoperiod and melatonin affect immune cell populations and leukocyte trafficking. (6) To determine if photoperiod influences the extent to which stress compromises immune function. Taken together, these studies may reveal novel therapeutic uses of melatonin on fever and anorexia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: PHOTOPERIODIC CONTROL OF OBESITY Principal Investigator & Institution: Bartness, Timothy J.; Professor; Biology; Georgia State University University Plaza Atlanta, Ga 30303 Timing: Fiscal Year 2001; Project Start 01-SEP-1984; Project End 31-JUL-2004 Summary: (applicant's abstract): Obesity is a disease of literally and figuratively enormous proportions. A model of naturally occurring obesity, photoperiod-induced seasonal obesity in Siberian hamsters, was chosen for study. Siberian hamsters are

42

Melatonin

naturally obese when housed in long "summer-like" days. This obesity gradually develops and is expressed fully when the animals are adults. When Siberian hamsters are exposed to short days, as in fall/winter, they lose body fat. With subsequent increasing day lengths, as occurs in spring/summer, they regain their body fat; thus, the obesity is reversible, unlike most of the animal models of human obesity. It seems that a better understanding of the fundamental processes involved in the development and reversal of obesity might result from studying this natural cycle of body fat because, in these animals, it is seasonally advantageous for them to be obese at one time of year and lean at another time of the year. Two aspects of the control of fatness are the focus of this grant proposal: 1) the connections of the brain to body fat by the sympathetic nervous system, and 2) the regulation of total body fat as revealed by the compensatory increases in fat that are triggered after surgically-produced decreases in fatness (lipectomy). Attempts will be made to identify a brain controller of the number of fat cells in the body, including the chemical means by which the brain communicates with fat depots to increase or decrease fat cell number. Further attempts will be made to identify how the brain "knows" when body fat is decreased after we remove some of it experimentally (lipectomy). Tests will be done directly to one brain area, the paraventricular nucleus, to determine whether it is involved in the control of the short-day-induced decreases in fatness, as seems to be suggested by the neural circuitry connecting this brain area to body fat. Finally, a new strategy/tactic will be used to identify the chemicals in the brain that are part of the neural circuit connecting the brain to fat and that may be involved in the reversal from obese to the lean state. This multidisciplinary approach should provide new information about the importance of the control of body fat by the brain. In addition, these findings should provide insight into the fundamental processes involved in the development, maintenance, and especially the reversal of obesity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHOTOPERIODIC CONTROL OF REPRODUCTION: EFFECTS OF AGE Principal Investigator & Institution: Turek, Fred W.; Professor; Northwestern University Office of Sponsored Programs Chicago, Il 60611

Neurology;

Timing: Fiscal Year 2001; Project Start 30-JUN-1976; Project End 31-DEC-2001 Summary: (from applicant's abstract): The annual change in day length is the major environmental factor regulating the timing of reproduction in many seasonally breeding mammals. Both the circadian clock located in the hypothalamic suprachiasmatic nucleus and the pineal melatonin rhythm play a central role in relaying information about length of the day to the neuroendocrine-gonadal axis. Despite the fact that a variety of age-related changes in the circadian clock system have now been well documented in mammals, including changes in the response to the entraining effects of the light dark cycle and dampening of the pineal melatonin rhythm, very little is known about how age-related changes in circadian function may impact on the response of seasonally breeding animals to changes in day length. In the proposed studies, golden and Siberian hamsters will be utilized to test various hypotheses regarding 1) the effects of age on the photoperiodic control of neuroendocrine-gonadal activity and the circadian clock system, 2) how aging alters the interactions between the various components of the photoperiodic time measuring system and 3) how day length influences the effects of age on circadian rhythmicity. For all studies the rhythm of locomotor activity will be used as a marker for the state of the circadian clock system. Serum LH, FSH and testosterone levels, as well as testicular size, will be monitored to assay the state of the reproductive system, and in some studies serum melatonin levels will be determined.

Studies

43

Various studies are proposed to determine how aging may effect 1) the critical day length for the photoperiodic response and the entrainment to different light-dark cycles, 2) the pattern of melatonin secretion, 3) the response of the neuroendocrine-gonadal axis to melatonin, 4) the sensitivity of the neuroendocrine-gonadal axis to light intensity and 5) feedback relationships in the circadian clock system and in the neuroendocrinegonadal axis. Other studies will determine if age-related changes in the photoperiodic response can be blocked by stimuli that alter the circadian temporal organization. Taken together, the proposed studies are expected to yield new information about the physiological mechanisms that underlie age related changes in the photoperiodic response. Age related changes in the way hamsters respond to changes in the length of the day offer new avenues for elucidating the physiological and cellular mechanisms that underlie the generation of circadian rhythms as well as the photic control of the hypothalamic-pituitary-gonadal axis. In view of recent demonstrations that the pattern of human endocrine rhythms is also influenced by the length of the day, the results of the proposed studies are expected to increase our understanding of how age-related changes in the human neuroendocrine system may be affected by the seasonal change in day length; such information may also lead to new treatments of mood disorders that have been associated with seasonal rhythms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PINEAL CELL BIOLOGY GORDON CONFERENCE Principal Investigator & Institution: Green, Carla B.; Associate Professor; Gordon Research Conferences Box 984, 512 Liberty Ln West Kingston, Ri 02892 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2003 Summary: (provided by applicant): The Pineal Cell Biology Gordon Conference will be held in Ventura, California from February 10-15, 2002. The chair of this conference is Carla B. Green from the Department of Biology and the NSF Center for Biological Timing at the University of Virginia. The co-chair is Elizabeth Maywood from the Department of Anatomy, Cambridge University, U.K. This conference will explore topics related to pineal cell biology on a broad scale. Although the major focus of this meeting is on cellular and molecular aspects of pineal function, these topics will be augmented by sessions that investigate systems-level studies of pineal function and melatonin action in both animals and humans. This broad range of topics is indicative of this field, which is by its nature very multi-disciplinary. The program includes the following sessions: regulation of melatonin synthesis, signal transduction in the pineal and retina, non-visual photoreceptive mechanisms, regulation of gene expression in the pineal, molecular mechanisms of circadian clocks, regulation of photoperiodic responses, melatonin pharmacology, and human responses to melatonin including clinical applications. The speakers and discussion leaders for this conference have been chosen so that many areas will be well represented, including academic researchers (including those from minority institutions), government scientists, and industrial researchers. In addition, we have a large representation of women (including the chair and vice-chair) and have made an effort to invite scientists from Europe and Asia, in addition to those from the US. This meeting is held every two years and this next meeting will be the fifth time it has been held. The previous meetings have been quite successful, and attendance of this conference has steadily increased such that the last meeting was well over-subscribed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

44

Melatonin

•

Project Title: PINEAL OPIOID RECEPTORS & ANALGESIC ACTION OF MELATONIN Principal Investigator & Institution: Ebadi, Manuchair; Professor; Pharm/Toxicology/Therapeutics; University of North Dakota 264 Centennial Drive Grand Forks, Nd 58202 Timing: Fiscal Year 2001; Project Start 15-AUG-1999; Project End 31-JUL-2003 Summary: (Verbatim from the Applicant's Abstract) Present treatment for acute and/or chronic pain rely on non-steroidal anti-inflammatory agents and narcotic analgesics. However, there are various persistent painful conditions such as neurodegenerative diseases that respond poorly to existing analgesics and hence await novel therapeutic avenues. Physicians have noted since antiquity that their patients complained of less pain and required fewer analgesics at night times. In human, the circulating levels of melatonin, a pineal substance with analgesic and hypnotic properties, exhibit a pronounced circadian rhythm, with serum levels being high at night and very low during day times. Moreover, melatonin exhibits maximal analgesic effects at nights, pinealectomy abolishes the analgesia effects of melatonin, and opioid receptor antagonists disrupt the day-night rhythm of nociception. Since delta opioid receptors modulate the release of substance P, the first specific aim of this proposal is to search for and characterize delta one and two opioid receptor subtypes in bovine pinealocytes, using [D-Ala2-,N-MePhe4,Gly-ol5]enkephalin and [D-Pen2,5]enkephalin. Since crosstolerance exists between mu opioid and alpha-2 adrenergic receptors, but not between mu and delta receptors, the second specific aim of this proposal is to characterize the specific nature of the mu and delta receptors, differentially coupled to G protein subtypes in pineal membranes. Since addition to narcotic alters the kinetic parameters of D1 and D2 dopaminergic receptors in the brain, the third specific aim of this proposal are to determine the nature of dopamine transporters in bovine pineal gland by using [3H]GBB-12935 and autoradiography and to delineate the expression of D1 and D2 dopamine receptor mRNA by employing in situ hybridization histochemistry. Since melatonin may behave as a mixed opioid receptor agonist-antagonism, it is doubtful that physician simply could potentiate the analgesic efficacy of narcotics such as morphine by co-administering melatonin. Therefore, future research must synthesize highly efficacious melatonin analogues capable of providing maximum analgesia and hopefully being devoid of addiction liability now associated with currently available narcotics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: TREATMENT

POLYSOMNOGRAPHIC

ASSESSMENT

OF

ALTERNATIVE

Principal Investigator & Institution: Bliwise, Donald L.; Professor of Neurology; Neurology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 30-JUN-2005 Summary: Patients with Parkinson's Disease have exceptionally poor sleep. Even relative to other neurodegenerative diseases such as Alzheimer's Disease, the sleep of the PD patient is fragmented and disturbed. Most notably, sleep in PD is characterized by excessive activity in surface electomyographic (EMG) recordings from many different muscle groups. Despite the sleep disturbance, approximately 50 percent of PD patients note that, on nights when they are able to achieve sleep, they experience a transient (1 to 3 hour) reduction in waking motor symptoms upon arising in the morning. This effect has been termed Sleep Benefit. To date there are no double-blind placebo-controlled

Studies

45

studies treating sleep disturbance using PD using any (conventional or alternative) medical treatments. In this randomized, double- blind, parallel-groups, placebocontrolled polysomnographic clinical trial we will compare two alternative medical treatments (valerian, melatonin) and two conventional medical treatments (diphenhydramine, zolpidem) for the disturbed sleep of PD patients. Compelling basic science and clinical rationales exist for use of each of these substances (including valerian and melatonin) for treatment of sleep disturbance in PD. The proposed study will be conducted for six consecutive nights (3 Baseline, 3 Drug) using state-of the-art digitized ambulatory polysomnography in each patient's home. Outcomes will include both measures of nocturnal sleep and waking motor function. Polysomnographic measurements will include customary variables such as total sleep time, sleep efficiency and sleep latency, as well as EMG measures of periodic and isolated muscle activity during sleep. Assessments of motor function will be made the morning immediately, following the third Baseline night and third Drug night in order to test for improvement related to improved sleep. Data will be analyzed with Analysis of Covariance examining Condition (Baseline, Drug), (valerian, melatonin, diphenhydramine, zolpidem, placebo), and characteristic Sleep Benefit (positive, negative) main effects, as well as their interactions, after adjusting for Baseline values. The results would represent the first data applying rigorous clinical trial methodology to the study of disturbance sleep in PD patients and would critically examine the efficacy of two substances currently seeing widespread use as over-the counter hypnotics for which little polysomnographic data currently exist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROBING PREMENSTRUAL DYSPHORIC DISORDER WITH LIGHT Principal Investigator & Institution: Parry, Barbara L.; Professor; Psychiatry; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2002; Project Start 19-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Depression is a major health problem, on a par with heart disease in its annual cost of $43.7 billion. Women, compared with men, have a 2 to 1 incidence of major depression and are prone to develop episodes at times of reproductive hormonal change. The focus of this revised application is premenstrual dysphoric disorder (PMDD), a depressive disorder in the DSM-1V. In a pilot study, we observed in PMDD, but not in normal control (NC) subjects, an abnormal direction and a decreased magnitude of phase-shift responses in melatonin offset time alter a morning bright light pulse. The abnormality occurred in the symptomatic luteal, but not the asymptomatic follicular, menstrual cycle phase. In this proposal, we aim to replicate and extend these findings to determine whether abnormal phase-shifts to light occur in PMDD at other times of day. We will test the hypothesis that abnormal phase-shift responses to light also occur in the late subjective evening (during a delay portion of the phase-response curve, PRC), and during the early subjective morning (during an advance portion of the PRC). To assess phase-shift responses, we will measure the effects of bright (about 6,000 lux), 3-hour (h) light pulses on the critical circadian parameters of rhythmic plasma melatonin secretion, sleep electroencephalogram (EEG), and core body temperature. Responses to light at 2 different times of day will be compared between the follicular and luteal phases in women with PMDD and in normal control subjects. Altered phase-shift responses may contribute to disturbances in internal temporal order, and thereby result in mood disorders in predisposed individuals. These investigations will provide further insight into the pathophysiology

46

Melatonin

of PMDD and other depressive disorders in women, and serve as a basis for refining light treatment interventions in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROGESTERONE /MELATONIN AS NEUROPROTECTANTS IN NERVE INJ Principal Investigator & Institution: Yu, Wan-Hua A.; City College of New York 138Th St and Convent Ave New York, Ny 10031 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: Motor neurons of adult animals, despite resistance to axotomy-induced cell death, undergo apoptotic cell death after nerve injury with removal of axon associated Schwann cells, indicating that neurotrophic factors from central glial cells may not be adequate to support the survival of injured neurons. This proposal aims to test the hypothesis that glial synthesis of neurotrophic factors can be up-regulated by steroid hormones, and that death of injured neurons is preventable by agents which scavenge free radicals and remove reactive oxygen species. Adult rat hypoglossal nerve innervating the tongue muscles will be lesioned on one side by crush (for reversible injury), ligation (to permanently disconnect neurons from target muscles but retain the proximal nerve segment), and avulsion (to deprive neurons of Schwann cell-derived neurotrophic factors). The vagus nerve will be crushed or transected to include parasympathetic motor neurons for comparison. Since progesterone (PG) and melatonin (MT) possess antioxidant activities; and in cerebral ischemia and truamatic injuries, reduce tissue damage, attenuate brain edema and cell loss, and facilitate functional recovery; and glial cells have PG receptors, nerve lesioned rats will receive PG injection daily via s.c. route, MT by osmotic pump infusion, combined treatment of the two agents, PG antagonist RU486 to block endogenous PG activities, and no treatment as control. Specific questions to be addressed are: (1) Will PG increase the synthesis of brain-derived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF)? (2) Will PG and MT prevent the loss of neurons after nerve avulsion? (3) What is the status of PG receptors in motor neurons before and after axotomy? Will PG affect the expression of PG receptors ininjured neurons? (4) Will a "death receptor" FAS be induced in neurons after nerve avulsion? Will PG and MT block the induction or reduce the expression of FAS and p75 in injured neurons? To answer these questions, tissue sections will be prepared for neuronal cell counting, and for immunostaining of BDNF, GDNF, PG receptors, FAS and p75, and quantify their levels by computerized image analysis. These studies will provide insight into the cellular and molecular events responsible for the initiation and activation of apoptotic pathways in injured neurons, and offer therapeutic potential for treating traumatic injuries and other neuropathological conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: REGULATION OF ADRENAL FUNCTION IN FIBROMYALGIA Principal Investigator & Institution: Adler, Gail K.; Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 25-SEP-1994; Project End 31-JUL-2003 Summary: (Adapted From Applicant's Abstract) This competitive renewal project proposes to extend studies of the hypothalamic-pituitary-adrenal axis in fibromyalgia syndrome previously undertaken by the PI. Her initial data suggested reduced adrenocorticotropin (ACTH) and epinephrine responses to graded hypoglycemic

Studies

47

challenge, and blunting of the normal diurnal cortisol rhythm in patients with fibromyalgia when compared to normal controls. The PI postulates that the decreased ACTH response to hypoglycemic challenge is the result of impaired CRH release, this also results in decreased sympathoadrenal response to hypoglycemia. The PI further proposes that the diurnal cortisol rhythm in patients with fibromyalgia is abnormal due to a shift in the circadian phase. In Specific Aim 1, the PI and her colleagues propose to assess hypothalamic CRH-pituitary ACTH activity at baseline and in response to three stimuli: hypoglycemia, metapyrone-induced glucocorticoid administration, and an immune stimulus with tetanus toxoid vaccine. In Specific Aim 2, sypathoadrenal responses to hypoglycemia, the cold pressor test, metapyrone vs. placebo will be compared in patients with fibromyalgia and controls. In Specific Aim 3, the circadian phase (measured by core body temperature and melatonin levels) will be compared in women with fibromyalgia and healthy controls. Additional studies of the relationship between disrupted sleep pattern and night-time secretion of ACTH and cortisol and cytokines are planned if the circadian phase is not shifted. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION BIOSYNTHESIS

OF

PINEAL

AND

RETINA

MELATONIN

Principal Investigator & Institution: Storm, Daniel R.; Professor; Pharmacology; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JUN-1998; Project End 31-AUG-2002 Summary: (from the applicant's abstract) The circadian organization of behavior determines how complex organisms respond to light/dark cues on a daily and seasonal basis. Disruption of the circadian rhythm in humans can lead to sleep disorders, mental fatigue, and depression, particularly with aging patients. The daily cycle of melatonin synthesis in the pineal is controlled by the circadian clock in the suprachiasmatic nucleus (SCN). Melatonin may stabilize the sleep cycle by maintaining steady-state entrainment of circadian pacemakers. Melatonin biosynthesis in the pineal and retina is regulated by cAMP which stimulates transcription of genes encoding enzymes important for circadian expression of melatonin. Nocturnal release of norepinephrine at the pineal increases cAMP by activation of beta- and alpha-1-adrenergic receptors. Calcium stimulated adenylyl cyclases (AC1 and AC8) may play a major role in regulating melatonin biosynthesis because of their unique regulatory properties. The applicants hypothesize that costimulation of AC1 by Ca++ and beta-adrenergic receptors may generate cAMP signals of sufficient strength and duration to regulate the transcription of specific genes important for melatonin synthesis. They hypothesize that the diurnal variation in expression of AC1 and its stimulation by nocturnal NE regulates the synthesis of melatonin. Furthermore, they hypothesize that cAMP may also play an important role in circadian time keeping in the SCN by regulating gene transcription through the cAMP response element (CRE). The overall goals of this project are to define the role of the Ca++-stimulated adenylyl cyclases and CRE-mediated transcription in the regulation of melatonin synthesis and in circadian rhythm. This proposal uses two unique tools developed in this laboratory; mutant mice lacking Ca++sensitive adenylyl cyclases and a CRE-lacZ transgenic mouse strain that is used to monitor CRE-mediated transcription in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

48

Melatonin

•

Project Title: RETINAL CIRCADIAN SIGNALING IN A TRANSGENIC FROG MODEL Principal Investigator & Institution: Wiechmann, Allan F.; Associate Professor; Cell Biology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 07-FEB-2002; Project End 31-JAN-2005 Summary: (Applicant's Abstract) The neurohormone, melatonin, is a primary output signal of the circadian clock in retinal photoreceptors. In the retina, melatonin acts as a paracrine signal of darkness by activating specific receptors that ultimately leads to increased sensitivity to light. It facilitates dark adaptation and likely coordinates other diumal events that occur in the retina such as photoreceptor outer segment disc shedding. In addition, melatonin increases the degree of light-induced photoreceptor cell death. The cellular location of the melatonin receptor subtypes and the physiological responses to melatonin receptor binding are important factors that determine the influence of melatonin on the normal health and function of the retina. The long-term goal of this research is to understand the molecular mechanisms of action and the function of melatonin in the retina and the role of circadian sitnals in photoreceptor physiology and disease. The retina of the frog Xenopus laevis has been an exceptional in vitro model system to study retinal melatonin synthesis and function, and RNA encoding three melatonin receptor subtypes is expressed both in the neural retina, including the photoreceptors, and retinal pigment epithelium (RPE) of Xenopus retina. Also, recent advancements in transgenic Xenopus technology have greatly enhanced the utility of this frog model in the study of cell-specific gene expression. The goals of this proposal are to 1) direct rod photoreceptor-specific over-expression of each of the three melatonin receptor subtypes in transgenic Xenopus, and to compare the cellular responses to applied melatonin, and 2) direct Melic melatonin receptor subtype cell-specific over-expression in transgenic Xenopus, and identify all retinal cells that express the transgene by reporter gene fluorescence combined with immunocytochemistry of known retinal proteins. Disruption of circadian rhythms may contribute significantly to the photoreceptor cell death in some degenerative retinal diseases, and melatonin may play a pivotal role in coordinating retinal circadian events. Discovering the molecular mechanisms of melatonin action may therefore provide a greater understanding of the role of circadian signals in environmentally- and genetically- induced photoreceptor degenerations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: RF EXPOSURE AND MELATONIN LEVELS IN HEAT-SEALER WORKERS Principal Investigator & Institution: Yost, Michael G.; Environmental Health; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2002 Summary: We propose to conduct a comprehensive study of electromagnetic field (EMF) exposures in a large population of radiofrequency (RF) heat sealer operators and monitor changes in melatonin, a proposed biomarker of response to EMF. The working hypothesis of this study is that melatonin levels will decrease in the subjects exposed to RF fields, in a pattern that mimics the dose-dependent decrease in melatonin we have observed previously in utility workers. This study will be the most detailed exposure survey of RF heat sealer workers to date. This study will be the first to use state-of-theart full-shift personal monitoring to document the diverse exposures to RF and power-

Studies

49

frequency EMFs in this worker population. This also will be the first study to examine biomarkers in response to RF fields. This study will make a strong contribution to improving RF exposure assessment using personal dosimetry. We will use task-based exposure assessment with time-activity information to identify tasks that contribute most to exposures. This will help identify important exposure scenarios for possible engineering changes or other controls. We propose to use two novel instruments, one that will characterize the induced foot currents in the operators and the second to measure the electric and magnetic field components. The application of induced body currents for free ranging subjects is a novel approach to RF dosimetry that can extend beyond the present application. Many other RF exposed occupational populations exist that would benefit from improvements in RF exposure assessment, and emerging technologies that use the RF spectrum will increase the potential for worker exposures. Understanding the benefits and limitations of improved personal monitoring methods for RF in a working population will provide new tools for worker exposure assessment in these emerging technologies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF MELATONIN IN SECONDARY INSOMNIA IN THE ELDERLY Principal Investigator & Institution: Gooneratne, Nalaka S.; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: Chronic insomnia affects up to 30% of the elderly and significantly impairs quality of life and daytime functioning. It is often secondary to other medical conditions, such as pain from osteoarthritis. Recent work has suggested that melatonin, a neurohormone produced by the pineal gland and regulated by the suprachiasmatic nucleus, the primary circadian pacemaker, is decreased in elderly insomniacs. However, treatment trials in primary insomniacs have been equivocal. This has raised many questions regarding the function of melatonin such as its role in sleep-wake regulation and whether it has nocturnal sleep-promoting effects. Interestingly, pain and nonsteroidal anti-inflammatory drugs blunt melatonin rhythms. Thus, I believe that melatonin secretion is impaired in the elderly with chronic pain and that this contributes to their insomnia. To address the hypothesis, the applicant proposes the following aims: 1) A case-control study to test the hypothesis that melatonin deficiency is a risk factor for insomnia in the elderly with osteoarthritis pain and identify a threshold level to distinguish melatonin deficient patients; 2) A randomized, doubleblind, placebo controlled trial of melatonin replacement therapy in elderly insomniacs with osteoarthritis pain to test the hypothesis that melatonin deficiency is a causal factor for their development of insomnia. Analysis will include univariable and multivariable models, and receiver operator curve analysis for Aim 1, and comparison of melatonin vs. placebo treatment arms on l objective parameters for Aim 2. This protocol may provide new insights into the neurohormonal risk factors for the development of insomnia, test the model that melatonin deficiency is a causal factor for insomnia, provide a mechanistic basis for targeted melatonin replacement therapy, and provide the training necessary to conduct rigorous, independently-funded, patient-oriented research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

50

Melatonin

•

Project Title: SEROTONIN N ACETYLTRANSFERASE MECHANISM AND INHIBITION Principal Investigator & Institution: Cole, Philip A.; Professor/Chair; Pharmacol & Molecular Sciences; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: From applicant's abstract): This application is a response to the request for application (RFP) 'Earth-based Research Relevant to the Space Environment' (PA-00088). It concerns the enzyme serotonin N-acetyltransferase, responsible for the daily rhythmic production of melatonin. Melatonin is an animal and human hormone thought to be involved in the regulation of circadian rhythm, reproductive physiology, and mood. Peak melatonin levels appear to fall off with increasing age. Produced in the pineal gland, melatonin levels vary up to 100-fold over a 24 h day, primarily in response to external light, posture, and changes in magnetic fields, and this response is mediated by serotonin N-acetyltransferase. Despite the importance of serotonin Nacetyltransferase, there is currently a poor understanding of its enzyme mechanism. No specific inhibitors of serotonin N-acetyltransferase that are active in vivo have been reported. The main goals of this application are to develop specific and potent inhibitors of serotonin N-acetyltransferase. Employing substrate analogs, mutagenesis, X-ray crystallography, and kinetic studies, insights into the transition state of the catalytic mechanism will be obtained which will be applied to the design of selective enzyme inhibitors. The design and synthesis of inhibitors will be in part based on mechanistic studies as well as a systematic analysis of functional group substitutions. Potent inhibitors will be analyzed in vitro to define their specificity and mechanism of action and promising compounds will be tested in vivo cell culture assays. Specific inhibitors of serotonin N-acetyltransferase will help clarify the role of melatonin in circadian rhythm biology in humans on the ground and during space travel and will be potentially useful as therapeutic agents for a variety of clinical conditions that can affect civilians as well as astronauts, including sleep and psychiatric disorders. Furthermore, such inhibitors could contribute to an understanding of the physiologic and pathophysiologic effects of melatonin changes in the elderly by mimicking in animal models the alterations in melatonin production that occur with aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: SLEEP AND CHRONOBIOLOGY OF LATE-LIFE DEPRESSION Principal Investigator & Institution: Szuba, Martin P.; Assistant Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 15-SEP-1998; Project End 30-JUN-2002 Summary: This application proposes Martin P. Szuba, M.D. for a Mentored Clinical Scientist Development Award at the University of Pennsylvania. The aims of this program include: 1) to support his development into an independent research scientist 2) to support and enhance the applicant's development as an investigator in sleep and chronobiology in the elderly; 3) to develop him for a faculty leadership role in mood disorders at Penn; and 4) to enhance the study of late-life mood disorders at Penn, using a chronobiologic approach. These aims will be structured around a four-part plan: 1) A program of formal academic courses and tutorials aimed at enhancing his research skills. 2) Research training, supervised by Drs. David Dinges and Ira Katz. This training will include supervised participation in three ongoing studies of the Center for Sleep and Respiratory Neurobiology and the Clinical Research Center (CRC) in Depression in the Aged: Medical- Psychiatric Co-Morbidity (I. Katz, PI). 3) Performance of a separate

Studies

51

research project: The first systematic randomized, double-blind, placebo-controlled treatment trial of the effects of exogenous melatonin administration on sleep, mood, and circadian rhythms in depressed elderly subjects. The specific aims of the study include a thorough evaluation in elderly depressed subjects with insomnia of subjective, behavioral, and physiological indices of sleep, in the laboratory and at home, as well as recording of circadian physiology during an unmasking protocol (constant routine), prior to and following treatment with melatonin or placebo. 4)Preparation, as Principal Investigator, of an independent research grant application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SLEEP AND CIRCADIAN RHYTHMS AFTER PINEAL RESECTION Principal Investigator & Institution: Macchi, Mariana M.; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-DEC-2002; Project End 30-NOV-2004 Summary: The hormone melatonin, produced by the pineal gland, is thought to be involved in the regulation of human sleep, body temperature and circadian rhythms, but its mechanisms of action in these areas have not been fully clarified, while its clinical significance remains controversial. The proposed research will examine these issues from a novel perspective, by systematically assessing sleep parameters, core body temperature, cortisol secretion and residual melatonin levels in individuals who have undergone pineal resection. In addition to 24 days of rest-activity recordings through an actigraphy device, the study will consist of two sets of consecutive overnight sessions for the assessment of polysomnographic (PSG) sleep parameters and circadian rhythm parameters of core body temperature, plasma cortisol and melatonin, the latter as a measure of residual pineal functionality. A healthy sex- and age-matched control group will undergo the same procedures. The specific aims of this preliminary study are: (1) to characterize PSG sleep patterns and microstructure in subjects with impaired melatonin production relative to healthy controls; (2) to elucidate the relationship between sleep, melatonin and body temperature in the absence of normal pineal functionality; specifically, we propose to assess (a) whether very low or absent levels of melatonin are accompanied by a dampening of core body temperature rhythm; b) whether insomnia following pineal resection is accompanied by changes in cortisol secretion; (3) to assess the feasibility of the experimental protocol and to obtain data for calculating statistical power of key comparisons, with the future aim of performing larger scale, hypothesisdriven research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: SLEEP DISTURBANCE IN MARIJUANA WITHDRAWAL Principal Investigator & Institution: Bolla, Karen I.; Associate Professor; Neurology and Neurosurgery; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 10-SEP-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Marijuana is the most widely used illicit drug in the United States. Heavy marijuana users who attempt to stop using marijuana frequently report sleep disturbance, restlessness, nervousness/anxiety, increased aggression, and appetite changes. We believe that sleep disturbance may pose an enormous hindrance to successful cessation of heavy marijuana use. Surprisingly, despite several subjective reports of sleep disturbance in newly abstinent heavy marijuana users, there have been no studies using objective polysomnographic (PSG) measures validating these subjective reports. Therefore, this study is highly significant and very innovative because in

52

Melatonin

addition to collecting subjective measures of withdrawal symptoms, we will obtain repeated objective measures of sleep architecture using standard PSG procedures. We will determine if there are objective polysomnographic findings of sleep disturbance in marijuana users (N=16) abstaining from drug use for 14 days in an inpatient setting at NIDA-IRP. Sixteen non-drug using controls, will be included for comparison and matched to the marijuana group on age, gender, and sleep-wake pattern. The control group will reside on our GCRC for 3 days. Baseline sleep-wake patterns will be estimated in both groups with actigraphy and sleep log recordings for 5 days prior to withdrawal/admission. The marijuana users will be transferred from NIDA-IRP to the GCRC core sleep lab for PSG recording. We will obtain PSG sleep measures of sleep onset, sleep maintenance, and restlessness at three separate times over 14 days of withdrawal and compare these to PSG measures obtained from the comparison group. Moreover, changes over time will be determined in the marijuana users. We will also determine if marijuana users have delayed sleep phase syndrome, a possible cause of sleep onset difficulty, by measuring dim light melatonin. The long-term goal of this research is to determine if heavy marijuana use is associated with objective sleep abnormalities as measured by polysomnographic procedures. Such findings could lead to new treatments for alleviating the unpleasant symptoms of marijuana withdrawal. For example, delayed sleep phase syndrome, one cause of insomnia, could be treated with light therapy, the same treatment used successfully for treating seasonal affective disorder. New treatments for alleviating the unpleasant symptoms of marijuana withdrawal would likely increase the number of heavy marijuana users who successfully complete treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NIMODIPINE

SLEEP/WAKE

RHYTHMS

IN

AGING--TREATMENT

WITH

Principal Investigator & Institution: Benloucif, Susan J.; Mol Pharm & Biol Chemistry; Northwestern University Office of Sponsored Programs Chicago, Il 60611 Timing: Fiscal Year 2001; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: The purpose of this project is to gain a basic understanding of the causes of chronic sleep disturbances in older adults and to develop effective therapies for these problems. Altering the age-related changes in the endogenous circadian pacemaker and reducing exposure to bright light can improve the sleep performance in elderly persons. However, age-related changes in synaptic plasticity arising from impaired calcium regulation may decrease the responsiveness of the aging clock to light. Recent findings indicate that treatment with the L-type calcium channel antagonist, nimodipine, can improve light-induced phase shifts of circadian activity rhythms in old mice. This indicates that nimodipine may also improve the response of the clock to light. The goals of this project are to test the hypothesis that responsiveness to light is decreased in the clock of older humans, and that enhancing the responsiveness of the clock to light with nimodipine will normalize disrupted sleep/wake rhythms in an animal model of aging. The specific aims of the project are to 1) assess the conditions under which nimodipine reverse age-related deficits in responsiveness of the clock to light in mice by testing the effects of different treatment regimens on three measures of circadian responsiveness to light in young, middle aged, and old mice; 2) test the hypothesis that nimodipine will restore normal entrainment patterns to a light/dark cycle in aged C3H/HeN mice by measuring the amplitude of the diurnal activity rhythm and the phase angle of entrainment; 3) test the hypothesis that older humans exhibit a decrease in the responsiveness of the clock to light by assessing the light-induced suppression of

Studies

53

nocturnal melatonin levels and phase shifts of circadian rhythms in young and old subjects; and 4) determine the light intensity required to improve sleep and daytime performance in elderly subjects by assessing the effect of daily administration of three different intensities of light on neuropsychological performance and sleep in older adults. The results of the animal and human experiments are designed to determine if nimodipine can enhance the effectiveness of light therapy for sleep/wake disorders in elderly humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TEMPORAL INTEGRATION OF PHOTOPERIODIC SIGNALS IN MAMMALS Principal Investigator & Institution: Gorman, Michael R.; Psychology; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: This project investigates the neuroendocrine mechanisms by which mammals generate seasonal variations in physiological and behavioral traits in synchrony with changing environmental conditions. Prior studies have examined responses of Siberian, Phodopus sungorus, and Syrian hamsters, Mesocricetus auratus, to static long and short day lengths of early summer and winter, respectively. Proposed experiments characterize how these responses differ as a function of prior day length exposure. Accumulating evidence establishes that the normal functioning of photoperiodic systems can only be accurately assessed by incorporating the incrementally and continuously changing pattern of day lengths under which photoperiodic time measurement systems evolved. Accordingly, the proposed experiments make extensive use of naturalistic progressions of day lengths and assess changes in body weight and gonadal condition. Additional experiments simulate directly the melatonin patterns associated with intermediate and gradually changing day lengths in animals with neurological lesions and other manipulations of circadian systems. Specific experiments address 1) whether the gradual decrease in body weight in autumn reflects graded responses to progressively decreasing day lengths or the output of an internally timed mechanism triggered by a single critical day length; 2) how the speed at which the endogenous interval timer runs is influenced by the day lengths experienced early in development; 3) how past melatonin exposures, reproductive status and entrainment state of the circadian system contribute to the interpretation of current melatonin signals; 4) whether prior day lengths influence production of future melatonin signals or responses to them; and 5) whether circadian systems are involved in discriminating inhibitory from stimulatory melatonin signals. The proposed experiments are relevant to an understanding of human seasonal rhythms in cardiovascular disease, neurodevelopmental disorders, immune function, sleep duration, body weight, depression and non-psychiatric mood states. This basic research will add to a body of literature contributing to the development and testing of rational therapies for mood and sleep disorders, jet lag, and shift work. Finally, these studies provide basic information about how seasonal mechanisms may respond to unnatural changes in melatonin signals such as may occur in humans self-administering oral dosages of melatonin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: TRAINING SCHEDULE EFFECTS ON SIMULATOR PERFORMANCE Principal Investigator & Institution: Cronin, John W.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115

54

Melatonin

Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2005 Summary: (provided by the applicant): Daily variations in physiologic and cognitive functions in human beings are driven by an endogenous circadian pacemaker. Human performance is further governed by the relative amounts of both chronic and acute sleep deprivation. Medical trainees, providing a significant amount of primary medical care in the U.S., are vulnerable to impaired performance and learning by virtue of schedules that demand long work hours. Surgical trainees, who are exposed to perhaps the greatest sleep deprivation and who are asked to perform critical tasks at adverse circadian phases, are a particularly important group. While much public policy debate has led to the mandate of reduced work hours, insufficient work has been done to determine the optimal work hours necessary to preserve top performance on critical tasks while preserving the educational opportunities for trainees. In June, 2003, ACGME work hour limitations loosely limit work hours to less than 80 hours a week and to no more than 24 hours of direct patient care. This proposal will attempt to work within that framework by testing surgical trainees on the following three schedules: 8-10 hour shift; 12-16 hour shift; and an on-call shift of 24-30 hours. Sleep will be characterized by actigraphy, diary self report, salivary cortisol assays and EEG recordings. Performance under these conditions will be measured using the MIST-VR laproscopic surgical simulator. Six critical tasks will be assessed for errors, efficiency and time on task and compared across the three schedules. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TREATMENT STRATEGIES IN A RAT MODEL OF CARDIAC ARREST Principal Investigator & Institution: Lamanna, Joseph Charles.; Professor; Anatomy; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): A significant number of individuals die soon after a successful cardiopulmonary resuscitation form cardiac arrest, and of those that survive a significant fraction have residual neurological deficit. Most of the morbidity and mortality after initially successful resuscitation from cardiac arrest can be assigned to the immediate and delayed effects of reperfusion injury in the central nervous system. With aging, there is an increased incidence of cardiac arrest and subsequent death or residual neurological deficit secondary to reperfusion injury. This outcome is probably due to an increase in free radical production and decrease in defense mechanisms that exacerbates reperfusion injury in the aging. Nevertheless, the poor ability of the brain to recover from such reversible ischemic events remains, in all ages, unpromising and is most likely due to free radical damage and unstabilized energy metabolism. This project represents a new collaboration between investigators specializing in the area of reperfusion injury. We propose to investigate new treatment strategies aimed at using alternate energy substrates such as, pyruvate and ketones in combination with antioxidant type drugs, such as, melatonin, N-t-Butyl-a-Phenyl-nitrone, adenosine and methylisobutyl amiloride, as therapies for improving recovery from cardiac arrest. Novel esters will also be tested for their neuroprotective properties in brain against reperfusion injury. These compounds are unique in that they are metabolized to physiological substrates, such as, pyruvate, glycerol and N-acetylcyteine, and have shown to decrease the effects of reperfusion injury in other organ systems. An animal model of cardiac arrest and resuscitation, adult (3 mos) and aged (18 mos) rats will be used to test the efficacy of these new treatment strategies. One set of experimental protocols measures delayed loss of hippocampal CA1 neurons 4 and 30 days after

Studies

55

cardiac arrest and resuscitation and survival rates. Another set of experimental protocols will elucidate specific mechanism(s) by which the selected energy substrates and agents and are effective. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VARIABILITY PHOTORESPONSIVENESS

IN

BRAIN

REGULATION

OF

Principal Investigator & Institution: Heideman, Paul D.; Biology; College of William and Mary Williamsburg, Va 23187 Timing: Fiscal Year 2001; Project Start 19-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): There is a tremendous amount of variation in brain structure and function. This natural variation has important health consequences. Individual variation contributes to adverse drug reactions, dangerous variation in response to general anesthetics, and inappropriate and ineffective drug dosages. We know almost nothing about the underlying neuroendocrine and genetic bases of variation in brain pathways, nor do we have anything more than an empirical sense of how to deal with brain variation as a public health issue. This proposal investigates variation in a neuroendocrine pathway. The research will be conducted on a neuroendocrine pathway that is both intensively studied and known to contain high levels of genetically based individual variation, the pathway through which the short photoperiods cause changes in alter [sic] reproduction, body weight, the immune system, and behavior as adjustments to winter. In humans, elements of this neuroendocrine pathway are thought to play a role both in reproduction and in some types of depression. Preliminary work has identified photoperiod-dependent differences in reproduction, food intake, and body weight among the F344, BN and Harlan Sprague Dawley strains of rats. In addition, preliminary results indicate that the most commonly studied inbred rat strain (F344) and perhaps another strain that is extremely important in biomedical research (BN) undergo hitherto unknown physiological changes in commonly-used laboratory photoperiods, and that these effects could cause spurious results in many research studies. The specific aims of this project are to test how differences in the brain and its chemical messengers cause these changes in fertility and body weight. The project will test whether differences in circadian rhythms (the biological clock) and/or the way in which rats secrete or respond to the hormone melatonin cause these differences in fertility and body weight. These studies will allow us to link variation in phenotype to an underlying neuroendocrine cause. They will begin to uncover the basis for this variation in the brain, and they will provide us with information on the kind of variation we can expect to find in brain pathways. Finally, this work will help us develop ways to understanding the extent and significance of individual variation in the brain in mammalian populations, including human populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFLUENCES

VASCULAR

REACTIVITY--GENDER

AND

HORMONAL

Principal Investigator & Institution: Duckles, Sue P.; Professor; Pharmacology; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2001; Project Start 01-JUL-1994; Project End 30-JUN-2002 Summary: (Adapted from the application) Actions of estrogen on function of endothelial NOS may account for cerebrovascular protection. Thus, the first hypothesis is: 1)

56

Melatonin

cerebrovascular responses involving NOS are affected by estrogen. Rat middle cerebral arteries in vitro will be used to test the influence of sex and gonadal steroids, comparing males and cycling females, control or gonadectomized and steroid-replaced. The investigator will compare myogenic tone in arteries from males and females and test whether NOS inhibition abolishes gender or estrous cycle differences. Possible K+ channel involvement will be investigated. Since shear stress stimulates the activity of NOS, the PI will test whether flow induced vasodilation is influenced by estrogen status and investigate modulation by gender and gonadal steroids. As a control, effects of gender and gonadal steroids on vasodilator responses to increased extracellular K+, which does not involve NOS will be investigated. The second hypothesis is: 2) estrogen acts by regulating levels of eNOS protein. Responses to endothelial dependent vasodilators, levels of NOS protein by Western blot and NOS activity will be measured, and NOSIII-deficient mice will be studied. For the third specific aim, the PI will test whether: 3) estrogen modulates effects of melatonin by a selective action on MT2 receptor mediated vasodilation. Circadian variation in cardiovascular disease onset has been shown and estrogen regulates vascular sensitivity to melatonin. The PI will determine whether melatonin causes constriction of cerebral arteries through MT1 and dilation via MT2 receptors. Influence of sex, transmural pressure, artery size and endothelial factors will be investigated. The PI will also test whether dilator responses via MT2 receptors are preferentially enhanced by estrogen exposure and using RT-PCR whether gonadal hormones alter expression of melatonin receptor subtypes. The final hypothesis is: 4) effects of estrogen are mediated by the classical estrogen receptor Estrogen receptor antagonists and estrogen receptor knockout mice will be used to test whether this receptor accounts for effects on cerebrovascular reactivity. Given the enormous impact of hormone replacement therapy, knowledge of the effects of gonadal steroids and melatonin on the cerebral circulation is essential. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VERIFICATION OF CIRCADIAN ABNORMALITIES IN AGING Principal Investigator & Institution: Kripke, Daniel F.; Professor of Psychiatry; Psychiatry; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-SEP-1998; Project End 31-AUG-2003 Summary: (adapted from investigator's abstract): The investigator's laboratory has recently observed extraordinary malsynchronization of circadian rhythm phases in two samples of aging volunteers. Of subjects averaging about age 70, almost half had 6sulphatoxymelatonin excretion phases wholly outside the normal range for healthy young adults. Moreover, the observed phase abnormalities were well-correlated with objective sleep disruption. The disturbances of circadian rhythm timing observed were so severe as to be comparable to effects of graveyard shiftwork or jet lag after arrival from Nepal. Such appalling circadian malsynchronization, if verified, could provide the main causal explanation for the insomnia and depressive symptoms so highly prevalent among aging Americans. To verify the derangement of circadian rhythms among aging volunteers, this project will measure circadian rhythms in salivary and blood melatonin as well as the urinary 6-sulphatoxy metabolite of melatonin, supplemented by measures of urinary cortisol and temperature, in a sample of 70 volunteers ages 60 years plus. A 3day ultra-short sleep-wake cycle will be used for round-the-clock circadian phase measurement, followed by elevation of the possible synchronization resistance as indicated by impaired melatonin suppression by bright light. Test-retest stability will be examined with repeat observations of 30 aging volunteers in the laboratory and in the

Studies

57

hospital CRC. Twenty healthy controls (ages 20-40) will be assessed to establish with the same methods the normal ranges for circadian phase. If it is verified that circadian phase malsynchronization associated with aging is commonly sufficient to cause insomnia and depression, correcting these phase abnormalities might be an important approach to relieve the distress which so many aging Americans suffer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “melatonin” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for melatonin in the PubMed Central database: •

Effect of Inducing Nocturnal Serum Melatonin Concentrations in Daytime on Sleep, Mood, Body Temperature, and Performance. by Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH.; 1994 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43256

•

Expression Cloning of a High-Affinity Melatonin Receptor from Xenopus Dermal Melanophores. by Ebisawa T, Karne S, Lerner MR, Reppert SM.; 1994 Jun 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=44152

•

Expression of Melatonin Receptors in Arteries Involved in Thermoregulation. by Viswanathan M, Laitinen JT, Saavedra JM.; 1990 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54500

•

Gonadotrophin-releasing hormone drives melatonin receptor down-regulation in the developing pituitary gland. by Johnston JD, Messager S, Ebling FJ, Williams LM, Barrett P, Hazlerigg DG.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151426

•

Impact of UVA exposure on psychological parameters and circulating serotonin and melatonin. by Gambichler T, Bader A, Vojvodic M, Bechara FG, Sauermann K, Altmeyer P, Hoffmann K.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113771

•

Independence of circadian entrainment state and responses to melatonin in male Siberian hamsters. by Gorman MR.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=270046

3 4

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

58

Melatonin

•

Mechanism-based inhibition of the melatonin rhythm enzyme: Pharmacologic exploitation of active site functional plasticity. by Khalil EM, De Angelis J, Ishii M, Cole PA.; 1999 Oct 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22936

•

Mediation of the Short-Loop Negative Feedback of Luteinizing Hormone on LHReleasing Hormone Release by Melatonin-Induced Inhibition of LH-Release from the Pars Tuberalis. by Nakazawa K, Marubayashi U, McCann SM.; 1991 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=52344

•

Melatonin reduces TNF-a induced expression of MAdCAM-1 via inhibition of NF-kB. by Sasaki M, Jordan P, Joh T, Itoh M, Jenkins M, Pavlick K, Minagar A, Alexander SJ.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=111062

•

Molecular Characterization of a Second Melatonin Receptor Expressed in Human Retina and Brain: The Mel1b Melatonin Receptor. by Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF.; 1995 Sep 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41041

•

Pineal Control of Aging: Effect of Melatonin and Pineal Grafting on Aging Mice. by Pierpaoli W, Regelson W.; 1994 Jan 18; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43034

•

Potentiation of Isoniazid Activity against Mycobacterium tuberculosis by Melatonin. by Wiid I, Hoal-van Helden E, Hon D, Lombard C, van Helden P.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89241

•

Red light accelerates and melatonin retards metamorphosis of frog tadpoles. by Joshi BN, Mohinuddin K.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=212554

•

Refractoriness to melatonin occurs independently at multiple brain sites in Siberian hamsters. by Freeman DA, Zucker I.; 2001 May 22; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33488

•

Role of a pineal cAMP-operated arylalkylamine N-acetyltransferase /14-3-3-binding switch in melatonin synthesis. by Ganguly S, Gastel JA, Weller JL, Schwartz C, Jaffe H, Namboodiri MA, Coon SL, Hickman AB, Rollag M, Obsil T, Beauverger P, Ferry G, Boutin JA, Klein DC.; 2001 Jul 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=35471

•

Seasonal neuroplasticity in the songbird telencephalon: A role for melatonin. by Bentley GE, Van't Hof TJ, Ball GF.; 1999 Apr 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16391

•

Targeted Disruption of the Mouse Mel1b Melatonin Receptor. by Jin X, von Gall C, Pieschl RL, Gribkoff VK, Stehle JH, Reppert SM, Weaver DR.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140714

•

Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. by Montes LG, Uribe MP, Sotres JC, Martin GH.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161743

Studies

59

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with melatonin, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “melatonin” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for melatonin (hyperlinks lead to article summaries): •

A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly. Author(s): Cardinali DP, Gvozdenovich E, Kaplan MR, Fainstein I, Shifis HA, Perez Lloret S, Albornoz L, Negri A. Source: Neuroendocrinol Lett. 2002 February; 23(1): 55-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11880863&dopt=Abstract

•

A multifactorial approach employing melatonin to accelerate resynchronization of sleep-wake cycle after a 12 time-zone westerly transmeridian flight in elite soccer athletes. Author(s): Cardinali DP, Bortman GP, Liotta G, Perez Lloret S, Albornoz LE, Cutrera RA, Batista J, Ortega Gallo P. Source: Journal of Pineal Research. 2002 January; 32(1): 41-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11841599&dopt=Abstract

•

A phase II study of chemoneuroimmunotherapy with platinum, subcutaneous lowdose interleukin-2 and the pineal neurohormone melatonin (P.I.M.) as a second-line therapy in metastatic melanoma patients progressing on dacarbazine plus interferonalpha. Author(s): Lissoni P, Vaghi M, Ardizzoia A, Malugani F, Fumagalli E, Bordin V, Fumagalli L, Bordoni A, Mengo S, Gardani GS, Tancini G. Source: In Vivo. 2002 March-April; 16(2): 93-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12073777&dopt=Abstract

6

PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

60

Melatonin

•

A possible link between melatonin levels, stress and coronary heart disease. Author(s): Gerber AM, Oosthuizen GM, Crous A. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 2002 October; 92(10): 794-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12432803&dopt=Abstract

•

A role for melatonin in breast disease and the menopause. Author(s): Oosthuizen GM, Joubert G, du Toit RS. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 2001 July; 91(7): 576-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11544972&dopt=Abstract

•

A role for melatonin in PCOS? Author(s): Cagnacci A, Volpe A. Source: Fertility and Sterility. 2002 May; 77(5): 1089; Author Reply 1089-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12009381&dopt=Abstract

•

A week of simulated night work delays salivary melatonin onset. Author(s): Roach GD, Burgess H, Lamond N, Dorrian J, Holmes A, Fletcher A, McCulloch K, Dawson D. Source: J Hum Ergol (Tokyo). 2001 December; 30(1-2): 255-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564892&dopt=Abstract

•

Actigraphic sleep-wake patterns and urinary 6-sulfatoxymelatonin excretion in patients with Alzheimer's disease. Author(s): Luboshitzky R, Shen-Orr Z, Tzischichinsky O, Maldonado M, Herer P, Lavie P. Source: Chronobiology International. 2001 May; 18(3): 513-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11475420&dopt=Abstract

•

Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. Author(s): Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Gerner E, Rollag MD. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2001 August 15; 21(16): 6405-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11487664&dopt=Abstract

•

Acute modifications in the levels of daytime melatonin do not influence leptin in postmenopausal women. Author(s): Cagnacci A, Malmusi S, Zanni A, Arangino S, Cagnacci P, Volpe A. Source: Journal of Pineal Research. 2002 August; 33(1): 57-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12121486&dopt=Abstract

Studies

61

•

Acute phase proteins, body temperature and urinary melatonin under the influence of bright and dim light intensities during the daytime. Author(s): Kanikowska D, Hirata Y, Hyun K, Tokura H. Source: Journal of Physiological Anthropology and Applied Human Science. 2001 November; 20(6): 333-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11840685&dopt=Abstract

•

Adaptation of the circadian rhythm of 6-sulphatoxymelatonin to a shift schedule of seven nights followed by seven days in offshore oil installation workers. Author(s): Gibbs M, Hampton S, Morgan L, Arendt J. Source: Neuroscience Letters. 2002 June 7; 325(2): 91-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12044629&dopt=Abstract

•

Age, lens transmittance, and the possible effects of light on melatonin suppression. Author(s): Charman WN. Source: Ophthalmic & Physiological Optics : the Journal of the British College of Ophthalmic Opticians (Optometrists). 2003 March; 23(2): 181-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12641706&dopt=Abstract

•

Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30-110 yr of age. Author(s): Zhao ZY, Xie Y, Fu YR, Bogdan A, Touitou Y. Source: Chronobiology International. 2002 November; 19(6): 1171-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511033&dopt=Abstract

•

AII amacrine cells express the MT1 melatonin receptor in human and macaque retina. Author(s): Scher J, Wankiewicz E, Brown GM, Fujieda H. Source: Experimental Eye Research. 2003 September; 77(3): 375-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12907170&dopt=Abstract

•

All-night exposure to EMF does not alter urinary melatonin, 6-OHMS or immune measures in older men and women. Author(s): Graham C, Sastre A, Cook MR, Gerkovich MM. Source: Journal of Pineal Research. 2001 September; 31(2): 109-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555165&dopt=Abstract

•

Alterations in the circadian rhythm of salivary melatonin begin during middle-age. Author(s): Zhou JN, Liu RY, van Heerikhuize J, Hofman MA, Swaab DF. Source: Journal of Pineal Research. 2003 January; 34(1): 11-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12485366&dopt=Abstract

62

Melatonin

•

Alzheimer's disease: roles for mitochondrial damage, the hydroxyl radical, and cerebrospinal fluid deficiency of melatonin. Author(s): Maurizi CP. Source: Medical Hypotheses. 2001 August; 57(2): 156-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11461164&dopt=Abstract

•

An action spectrum for melatonin suppression: evidence for a novel non-rod, noncone photoreceptor system in humans. Author(s): Thapan K, Arendt J, Skene DJ. Source: The Journal of Physiology. 2001 August 15; 535(Pt 1): 261-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11507175&dopt=Abstract

•

Arrhythmicity in a child with septo-optic dysplasia and establishment of sleep-wake cyclicity with melatonin. Author(s): Rivkees SA. Source: The Journal of Pediatrics. 2001 September; 139(3): 463-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11562632&dopt=Abstract

•

Behavioral pharmacology of melatonin. Author(s): Kulkarni SK, Shaji AV. Source: Methods Find Exp Clin Pharmacol. 1998 April; 20(3): 237-47. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9646286&dopt=Abstract

•

Beta 1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome. Author(s): De Leersnyder H, Bresson JL, de Blois MC, Souberbielle JC, Mogenet A, Delhotal-Landes B, Salefranque F, Munnich A. Source: Journal of Medical Genetics. 2003 January; 40(1): 74-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525548&dopt=Abstract

•

Beta-amyloid modulates tyrosine kinase B receptor expression in SHSY5Y neuroblastoma cells: influence of the antioxidant melatonin. Author(s): Olivieri G, Otten U, Meier F, Baysang G, Dimitriades-Schmutz B, MullerSpahn F, Savaskan E. Source: Neuroscience. 2003; 120(3): 659-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12895507&dopt=Abstract

•

Bioavailability of melatonin in humans after day-time administration of D(7) melatonin. Author(s): Fourtillan JB, Brisson AM, Gobin P, Ingrand I, Decourt JP, Girault J. Source: Biopharmaceutics & Drug Disposition. 2000 January; 21(1): 15-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11038434&dopt=Abstract

Studies

63

•

Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Author(s): Reiter RJ, Tan DX, Manchester LC, Qi W. Source: Cell Biochemistry and Biophysics. 2001; 34(2): 237-56. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11898866&dopt=Abstract

•

Biology of G protein-coupled melatonin receptors in the epididymis and prostate of mammals. Author(s): Shiu SY, Li L, Wong JT, Pang SF. Source: Chinese Medical Journal. 1997 August; 110(8): 648-55. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9594273&dopt=Abstract

•

Biology of mammalian photoperiodism and the critical role of the pineal gland and melatonin. Author(s): Malpaux B, Migaud M, Tricoire H, Chemineau P. Source: Journal of Biological Rhythms. 2001 August; 16(4): 336-47. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11506379&dopt=Abstract

•

Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5fluorouracil-containing combinations. Author(s): Cerea G, Vaghi M, Ardizzoia A, Villa S, Bucovec R, Mengo S, Gardani G, Tancini G, Lissoni P. Source: Anticancer Res. 2003 March-April; 23(2C): 1951-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820485&dopt=Abstract

•

Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus aloe vera in untreatable advanced solid neoplasms. Author(s): Lissoni P, Giani L, Zerbini S, Trabattoni P, Rovelli F. Source: Natural Immunity. 1998; 16(1): 27-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9789122&dopt=Abstract

•

Blood pressure and melatonin in chronic renal failure. Author(s): Viljoen M, Levay PF, van Rensburg BW. Source: Clinical Nephrology. 2001 August; 56(2): 177-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11522098&dopt=Abstract

•

Brief report: melatonin facilitates sleep in individuals with mental retardation and insomnia. Author(s): Niederhofer H, Staffen W, Mair A, Pittschieler K. Source: Journal of Autism and Developmental Disorders. 2003 August; 33(4): 469-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959427&dopt=Abstract

64

Melatonin

•

Bright light exposure during the daytime affects circadian rhythms of urinary melatonin and salivary immunoglobulin A. Author(s): Park SJ, Tokura H. Source: Chronobiology International. 1999 May; 16(3): 359-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10373104&dopt=Abstract

•

Bright light exposure of a large skin area does not affect melatonin or bilirubin levels in humans. Author(s): Lindblom N, Hatonen T, Laakso M, Alila-Johansson A, Laipio M, Turpeinen U. Source: Biological Psychiatry. 2000 December 1; 48(11): 1098-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11094143&dopt=Abstract

•

Bright light imagery does not suppress melatonin. Author(s): Byrne B, Rollag MD, Hanifin JP, Reed C, Brainard GC. Source: Journal of Pineal Research. 2000 August; 29(1): 62-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10949542&dopt=Abstract

•

Bright light suppresses melatonin in blind patients with neuronal ceroidlipofuscinoses. Author(s): Hatonen T, Laakso ML, Heiskala H, Alila-Johansson A, Sainio K, Santavuori P. Source: Neurology. 1998 May; 50(5): 1445-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9596003&dopt=Abstract

•

Bright light therapy and melatonin in motor restless behaviour in dementia: a placebo-controlled study. Author(s): Haffmans PM, Sival RC, Lucius SA, Cats Q, van Gelder L. Source: International Journal of Geriatric Psychiatry. 2001 January; 16(1): 106-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11180494&dopt=Abstract

•

Bright light, dark and melatonin can promote circadian adaptation in night shift workers. Author(s): Burgess HJ, Sharkey KM, Eastman CI. Source: Sleep Medicine Reviews. 2002 October; 6(5): 407-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531129&dopt=Abstract

•

Can melatonin prevent or treat jet lag? Author(s): Smucny J. Source: American Family Physician. 2002 December 1; 66(11): 2087-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12484689&dopt=Abstract

Studies

65

•

Capturing the circadian rhythms of free-running blind people with 0.5 mg melatonin. Author(s): Lewy AJ, Bauer VK, Hasler BP, Kendall AR, Pires ML, Sack RL. Source: Brain Research. 2001 November 9; 918(1-2): 96-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11684046&dopt=Abstract

•

Case study of circadian rhythm sleep disorder following haloperidol treatment: reversal by risperidone and melatonin. Author(s): Ayalon L, Hermesh H, Dagan Y. Source: Chronobiology International. 2002 September; 19(5): 947-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12405556&dopt=Abstract

•

Cerebrovascular melatonin MT1-receptor alterations in patients with Alzheimer's disease. Author(s): Savaskan E, Olivieri G, Brydon L, Jockers R, Krauchi K, Wirz-Justice A, Muller-Spahn F. Source: Neuroscience Letters. 2001 July 27; 308(1): 9-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11445273&dopt=Abstract

•

Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Author(s): Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R. Source: Current Topics in Medicinal Chemistry. 2002 February; 2(2): 181-97. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11899100&dopt=Abstract

•

Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial. Author(s): Nickelsen T, Samel A, Vejvoda M, Wenzel J, Smith B, Gerzer R. Source: Chronobiology International. 2002 September; 19(5): 915-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12405554&dopt=Abstract

•

Circadian rhythm of melatonin in patients with colorectal carcinoma. Author(s): Kos-Kudla B, Ostrowska Z, Kozlowski A, Marek B, Ciesielska-Kopacz N, Kudla M, Kajdaniuk D, Strzelczyk J, Staszewicz P. Source: Neuroendocrinol Lett. 2002 June; 23(3): 239-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12080285&dopt=Abstract

•

Circadian rhythm of melatonin in postmenopausal asthmatic women with hormone replacement therapy. Author(s): Kos-Kudla B, Ostrowska Z, Marek B, Kajdaniuk D, Ciesielska-Kopacz N, Kudla M, Mazur B, Glogowska-Szelag J, Nasiek M. Source: Neuroendocrinol Lett. 2002 June; 23(3): 243-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12080286&dopt=Abstract

66

Melatonin

•

Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer. Author(s): Haus E, Dumitriu L, Nicolau GY, Bologa S, Sackett-Lundeen L. Source: Chronobiology International. 2001 July; 18(4): 709-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11587092&dopt=Abstract

•

Circadian rhythms of oviposition and feeding activity in Japanese quail: effects of cyclic administration of melatonin. Author(s): Houdelier C, Guyomarc'h C, Lumineau S, Richard JP. Source: Chronobiology International. 2002 November; 19(6): 1107-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511029&dopt=Abstract

•

Circadian serum melatonin profiles in patients suffering from chronic renal failure. Author(s): Karasek M, Szuflet A, Chrzanowski W, Zylinska K, Swietoslawski J. Source: Neuroendocrinol Lett. 2002 April; 23 Suppl 1: 97-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019361&dopt=Abstract

•

Circadian urinary 6-sulphatoxymelatonin, cortisol excretion and locomotor activity in airline pilots during transmeridian flights. Author(s): Tresguerres JA, Ariznavarreta C, Granados B, Martin M, Villanua MA, Golombek DA, Cardinali DP. Source: Journal of Pineal Research. 2001 August; 31(1): 16-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11485000&dopt=Abstract

•

Circadian variations of melatonin concentration in saliva and blood content of immunocompetent cells in healthy individuals. Author(s): Litvinenko GI, Shurlygina AV, Malysheva OA, Kudaeva OT, Shirinskii VS, Kozlov VA, Trufakin VA. Source: Bulletin of Experimental Biology and Medicine. 2002 May; 133(5): 500-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12420073&dopt=Abstract

•

Clearance of melatonin and 6-sulfatoxymelatonin by hemodialysis in patients with end-stage renal disease. Author(s): Ludemann P, Zwernemann S, Lerchl A. Source: Journal of Pineal Research. 2001 October; 31(3): 222-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11589756&dopt=Abstract

•

Coadministration of melatonin and fluoxetine does not improve the 3-month outcome following ECT. Author(s): Grunhaus L, Hirschman S, Dolberg OT, Schreiber S, Dannon PN. Source: The Journal of Ect. 2001 June; 17(2): 124-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11417923&dopt=Abstract

Studies

67

•

Comparison of the effect of fatty alcohols on the permeation of melatonin between porcine and human skin. Author(s): Andega S, Kanikkannan N, Singh M. Source: Journal of Controlled Release : Official Journal of the Controlled Release Society. 2001 November 9; 77(1-2): 17-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11689256&dopt=Abstract

•

Conversion of L-tryptophan to serotonin and melatonin in human melanoma cells. Author(s): Slominski A, Semak I, Pisarchik A, Sweatman T, Szczesniewski A, Wortsman J. Source: Febs Letters. 2002 January 30; 511(1-3): 102-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11821057&dopt=Abstract

•

Correlating retinal function with melatonin secretion in subjects with an early or late circadian phase. Author(s): Rufiange M, Dumont M, Lachapelle P. Source: Investigative Ophthalmology & Visual Science. 2002 July; 43(7): 2491-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12091455&dopt=Abstract

•

Correlation between serum melatonin circadian rhythm and intensive care unit psychosis after thoracic esophagectomy. Author(s): Miyazaki T, Kuwano H, Kato H, Ando H, Kimura H, Inose T, Ohno T, Suzuki M, Nakajima M, Manda R, Fukuchi M, Tsukada K. Source: Surgery. 2003 June; 133(6): 662-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12796735&dopt=Abstract

•

Cyproterone acetate-ethinyl estradiol treatment alters urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women. Author(s): Luboshitzky R, Herer P, Shen-Orr Z. Source: Neuroendocrinol Lett. 2002 August; 23(4): 309-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12195232&dopt=Abstract

•

Decoding photoperiodic time and melatonin in mammals: what can we learn from the pars tuberalis? Author(s): Hazlerigg DG, Morgan PJ, Messager S. Source: Journal of Biological Rhythms. 2001 August; 16(4): 326-35. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11506378&dopt=Abstract

•

Decreased nocturnal melatonin levels during acute myocardial infarction. Author(s): Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia MJ, Sanchez J, Marrero F, de Armas-Trujillo D. Source: Journal of Pineal Research. 2002 November; 33(4): 248-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390508&dopt=Abstract

68

Melatonin

•

Decreased nocturnal synthesis of melatonin in patients with coronary artery disease. Author(s): Yaprak M, Altun A, Vardar A, Aktoz M, Ciftci S, Ozbay G. Source: International Journal of Cardiology. 2003 May; 89(1): 103-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12727015&dopt=Abstract

•

Depression and endogenous melatonin in postmenopausal women. Author(s): Tuunainen A, Kripke DF, Elliott JA, Assmus JD, Rex KM, Klauber MR, Langer RD. Source: Journal of Affective Disorders. 2002 May; 69(1-3): 149-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12103461&dopt=Abstract

•

Design and synthesis of 3-phenyl tetrahydronaphthalenic derivatives as new selective MT2 melatoninergic ligands. Author(s): Yous S, Durieux-Poissonnier S, Lipka-Belloli E, Guelzim H, Bochu C, Audinot V, Boutin JA, Delagrange P, Bennejean C, Renard P, Lesieur D. Source: Bioorganic & Medicinal Chemistry. 2003 March 6; 11(5): 753-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538005&dopt=Abstract

•

Design and synthesis of naphthalenic dimers as selective MT1 melatoninergic ligands. Author(s): Descamps-Francois C, Yous S, Chavatte P, Audinot V, Bonnaud A, Boutin JA, Delagrange P, Bennejean C, Renard P, Lesieur D. Source: Journal of Medicinal Chemistry. 2003 March 27; 46(7): 1127-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12646022&dopt=Abstract

•

Determination of free and total (free plus protein-bound) melatonin in plasma and cerebrospinal fluid by high-performance liquid chromatography with fluorescence detection. Author(s): Rizzo V, Porta C, Moroni M, Scoglio E, Moratti R. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2002 July 5; 774(1): 17-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052718&dopt=Abstract

•

Determination of melatonin in human plasma with solid-phase extraction, highperformance liquid chromatography and fluorescence detection. Author(s): Romsing S, Ulfberg J, Bergqvist Y. Source: Scandinavian Journal of Clinical and Laboratory Investigation. 2003; 63(1): 81-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729073&dopt=Abstract

Studies

69

•

Determination of the dose of agomelatine, a melatoninergic agonist and selective 5HT(2C) antagonist, in the treatment of major depressive disorder: a placebocontrolled dose range study. Author(s): Loo H, Hale A, D'haenen H. Source: International Clinical Psychopharmacology. 2002 September; 17(5): 239-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12177586&dopt=Abstract

•

Development of a high-throughput bioassay to screen melatonin receptor agonists using human melatonin receptor expressing CHO cells. Author(s): Yokoyama T, Kato N, Yamada N. Source: Neuroscience Letters. 2003 June 19; 344(1): 45-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12781918&dopt=Abstract

•

Differential coupling of the extreme C-terminus of G protein alpha subunits to the G protein-coupled melatonin receptors. Author(s): Drew JE, Barrett P, Conway S, Delagrange P, Morgan PJ. Source: Biochimica Et Biophysica Acta. 2002 October 21; 1592(2): 185-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379482&dopt=Abstract

•

Differential expression of high-affinity melatonin receptors (MT1) in normal and malignant human breast tissue. Author(s): Dillon DC, Easley SE, Asch BB, Cheney RT, Brydon L, Jockers R, Winston JS, Brooks JS, Hurd T, Asch HL. Source: American Journal of Clinical Pathology. 2002 September; 118(3): 451-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12219788&dopt=Abstract

•

Diurnal profile of melatonin secretion in the acute phase of major depression and in remission. Author(s): Rabe-Jablonska J, Szymanska A. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2001 September-October; 7(5): 946-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11535940&dopt=Abstract

•

Does hepatic metabolism of melatonin affect the endogenous serum melatonin level in man? Author(s): Ursing C, Hartter S, von Bahr C, Tybring G, Bertilsson L, Rojdmark S. Source: J Endocrinol Invest. 2002 May; 25(5): 459-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12035944&dopt=Abstract

•

Does melatonin improve sleep in older people? A randomised crossover trial. Author(s): Baskett JJ, Broad JB, Wood PC, Duncan JR, Pledger MJ, English J, Arendt J. Source: Age and Ageing. 2003 March; 32(2): 164-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615559&dopt=Abstract

70

Melatonin

•

Does melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro? Author(s): Cos S, Mediavilla MD, Fernandez R, Gonzalez-Lamuno D, Sanchez-Barcelo EJ. Source: Journal of Pineal Research. 2002 March; 32(2): 90-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12071473&dopt=Abstract

•

Does the negative correlation found in breast cancer patients between plasma melatonin and insulin-like growth factor-I concentrations imply the existence of an additional mechanism of oncostatic melatonin influence involved in defense? Author(s): Kajdaniuk D, Marek B, Kos-Kudla B, Zwirska-Korczala K, Ostrowska Z, Buntner B, Szymszal J. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2002 June; 8(6): Cr457-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12070440&dopt=Abstract

•

Dose-dependent stimulation of melatonin secretion after administration of Agnus castus. Author(s): Dericks-Tan JS, Schwinn P, Hildt C. Source: Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association. 2003 February; 111(1): 446. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12605350&dopt=Abstract

•

Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Author(s): Serfaty M, Kennell-Webb S, Warner J, Blizard R, Raven P. Source: International Journal of Geriatric Psychiatry. 2002 December; 17(12): 1120-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461760&dopt=Abstract

•

Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. Author(s): Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. Source: Journal of Nippon Medical School = Nihon Ika Daigaku Zasshi. 2003 August; 70(4): 334-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12928714&dopt=Abstract

•

Effect of controlled-release melatonin on sleep quality, mood, and quality of life in subjects with seasonal or weather-associated changes in mood and behaviour. Author(s): Leppamaki S, Partonen T, Vakkuri O, Lonnqvist J, Partinen M, Laudon M. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 2003 May; 13(3): 137-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729938&dopt=Abstract

Studies

71

•

Effect of melatonin and all-trans retinoic acid on the proliferation and induction of the apoptotic pathway in the culture of human breast cancer cell line MCF-7. Author(s): Czeczuga-Semeniuk E, Wolczynski S, Anchim T, Dzieciol J, Dabrowska M, Pietruczuk M. Source: Pol J Pathol. 2002; 53(2): 59-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12140868&dopt=Abstract

•

Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Author(s): Suhner A, Schlagenhauf P, Hofer I, Johnson R, Tschopp A, Steffen R. Source: Aviation, Space, and Environmental Medicine. 2001 July; 72(7): 638-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11471907&dopt=Abstract

•

Effectiveness of melatonin in the treatment of sleep disturbances in children with Asperger disorder. Author(s): Paavonen EJ, Nieminen-von Wendt T, Vanhala R, Aronen ET, von Wendt L. Source: Journal of Child and Adolescent Psychopharmacology. 2003 Spring; 13(1): 83-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804129&dopt=Abstract

•

Effects of bright light and melatonin on sleep propensity, temperature, and cardiac activity at night. Author(s): Burgess HJ, Sletten T, Savic N, Gilbert SS, Dawson D. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 2001 September; 91(3): 1214-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11509518&dopt=Abstract

•

Effects of electric and magnetic fields from high-power lines on female urinary excretion of 6-sulfatoxymelatonin. Author(s): Levallois P, Dumont M, Touitou Y, Gingras S, Masse B, Gauvin D, Kroger E, Bourdages M, Douville P. Source: American Journal of Epidemiology. 2001 October 1; 154(7): 601-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11581093&dopt=Abstract

•

Effects of electromagnetic radiation (bright light, extremely low-frequency magnetic fields, infrared radiation) on the circadian rhythm of melatonin synthesis, rectal temperature, and heart rate. Author(s): Griefahn B, Kunemund C, Blaszkewicz M, Lerchl A, Degen GH. Source: Ind Health. 2002 October; 40(4): 320-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12502234&dopt=Abstract

72

Melatonin

•

Effects of Kampo herbal medicine on plasma melatonin concentration in patients. Author(s): Watanabe H, Kobayashi T, Tomii M, Sekiguchi Y, Uchida K, Aoki T, Cyong JC. Source: The American Journal of Chinese Medicine. 2002; 30(1): 65-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12067098&dopt=Abstract

•

Effects of melatonin on the proliferation and cis-diamminedichloroplatinum (CDDP) sensitivity of cultured human ovarian cancer cells. Author(s): Futagami M, Sato S, Sakamoto T, Yokoyama Y, Saito Y. Source: Gynecologic Oncology. 2001 September; 82(3): 544-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11520153&dopt=Abstract

•

Effects of pressure on the skin exerted by clothing on responses of urinary catecholamines and cortisol, heart rate and nocturnal urinary melatonin in humans. Author(s): Mori Y, Kioka E, Tokura H. Source: International Journal of Biometeorology. 2002 December; 47(1): 1-5. Epub 2002 September 12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12461604&dopt=Abstract

•

Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol, dehydroepiandrosterone sulfate, and somatomedin C in elderly women. Author(s): Pawlikowski M, Kolomecka M, Wojtczak A, Karasek M. Source: Neuroendocrinol Lett. 2002 April; 23 Suppl 1: 17-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019346&dopt=Abstract

•

Effects of the 1900 MHz electromagnetic field emitted from cellular phone on nocturnal melatonin secretion. Author(s): Jarupat S, Kawabata A, Tokura H, Borkiewicz A. Source: Journal of Physiological Anthropology and Applied Human Science. 2003 January; 22(1): 61-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12672984&dopt=Abstract

•

Effects of VDT tasks with a bright display at night on melatonin, core temperature, heart rate, and sleepiness. Author(s): Higuchi S, Motohashi Y, Liu Y, Ahara M, Kaneko Y. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 2003 May; 94(5): 1773-6. Epub 2003 January 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12533495&dopt=Abstract

Studies

73

•

Elevated serum melatonin is associated with the nocturnal worsening of asthma. Author(s): Sutherland ER, Ellison MC, Kraft M, Martin RJ. Source: The Journal of Allergy and Clinical Immunology. 2003 September; 112(3): 513-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13679809&dopt=Abstract

•

Emergence and evolution of the circadian rhythm of melatonin in children. Author(s): Ardura J, Gutierrez R, Andres J, Agapito T. Source: Hormone Research. 2003; 59(2): 66-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12589109&dopt=Abstract

•

Evaluation of gene expression in human lymphocytes activated in the presence of melatonin. Author(s): Capelli E, Campo I, Panelli S, Damiani G, Barbone MG, Lucchelli A, Cuccia M. Source: International Immunopharmacology. 2002 June; 2(7): 885-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12188030&dopt=Abstract

•

Evaluation of plasma levels of melatonin after midazolam or sodium thiopental anesthesia in children. Author(s): Munoz-Hoyos A, Heredia F, Moreno F, Garcia JJ, Molina-Carballo A, Escames G, Acuna-Castroviejo D. Source: Journal of Pineal Research. 2002 May; 32(4): 253-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11982795&dopt=Abstract

•

Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase. Author(s): Buxton OM, Lee CW, L'Hermite-Baleriaux M, Turek FW, Van Cauter E. Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2003 March; 284(3): R714-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571075&dopt=Abstract

•

Extraocular light exposure does not phase shift saliva melatonin rhythms in sleeping subjects. Author(s): Lushington K, Galka R, Sassi LN, Kennaway DJ, Dawson D. Source: Journal of Biological Rhythms. 2002 August; 17(4): 377-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12164253&dopt=Abstract

•

Extrapineal melatonin in pathology: new perspectives for diagnosis, prognosis and treatment of illness. Author(s): Kvetnoy I. Source: Neuroendocrinol Lett. 2002 April; 23 Suppl 1: 92-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019360&dopt=Abstract

74

Melatonin

•

Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. Author(s): Garfinkel D, Zisapel N, Wainstein J, Laudon M. Source: Archives of Internal Medicine. 1999 November 8; 159(20): 2456-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10665894&dopt=Abstract

•

Feasibility and functionality of OROS melatonin in healthy subjects. Author(s): Shah J, Langmuir V, Gupta SK. Source: Journal of Clinical Pharmacology. 1999 June; 39(6): 606-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10354964&dopt=Abstract

•

Fibromyalgia and melatonin: are they related? Author(s): Webb SM. Source: Clinical Endocrinology. 1998 August; 49(2): 161-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9828900&dopt=Abstract

•

Fibromyalgia--a syndrome associated with decreased nocturnal melatonin secretion. Author(s): Wikner J, Hirsch U, Wetterberg L, Rojdmark S. Source: Clinical Endocrinology. 1998 August; 49(2): 179-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9828904&dopt=Abstract

•

First-night effect of melatonin treatment in patients with chronic schizophrenia. Author(s): Shamir E, Rotenberg VS, Laudon M, Zisapel N, Elizur A. Source: Journal of Clinical Psychopharmacology. 2000 December; 20(6): 691-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11106143&dopt=Abstract

•

Flight attendants, breast cancer, and melatonin. Author(s): Lerchl A. Source: Lancet. 1998 October 24; 352(9137): 1388-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9802299&dopt=Abstract

•

Flight attendants, breast cancer, and melatonin. Author(s): Gurwitz D. Source: Lancet. 1998 October 24; 352(9137): 1389-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9802301&dopt=Abstract

•

Flight attendants, breast cancer, and melatonin. Author(s): Barker ME, Stookey JD. Source: Lancet. 1998 October 24; 352(9137): 1389. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9802300&dopt=Abstract

Studies

75

•

Fluvoxamine but not citalopram increases serum melatonin in healthy subjects-- an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. Author(s): von Bahr C, Ursing C, Yasui N, Tybring G, Bertilsson L, Rojdmark S. Source: European Journal of Clinical Pharmacology. 2000 May; 56(2): 123-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10877005&dopt=Abstract

•

Fluvoxamine strongly inhibits melatonin metabolism in a patient with low-amplitude melatonin profile. Author(s): Grozinger M, Hartter S, Wang X, Roschke J, Hiemke C, Rose DM. Source: Archives of General Psychiatry. 2000 August; 57(8): 812-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10920471&dopt=Abstract

•

Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Author(s): Reiter RJ, Acuna-Castroviejo D, Tan DX, Burkhardt S. Source: Annals of the New York Academy of Sciences. 2001 June; 939: 200-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11462772&dopt=Abstract

•

Free-running of plasma melatonin rhythm prior to full manifestation of a non-24 hour sleep-wake syndrome. Author(s): Hashimoto S, Nakamura K, Honma S, Honma K. Source: Psychiatry and Clinical Neurosciences. 1998 April; 52(2): 264-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9628187&dopt=Abstract

•

Functional activity of serotoninergic and melatoninergic systems expressed in the skin. Author(s): Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J. Source: Journal of Cellular Physiology. 2003 July; 196(1): 144-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12767050&dopt=Abstract

•

Functional expression of MT2 (Mel1b) melatonin receptors in human PAZ6 adipocytes. Author(s): Brydon L, Petit L, Delagrange P, Strosberg AD, Jockers R. Source: Endocrinology. 2001 October; 142(10): 4264-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11564683&dopt=Abstract

•

Further evidences for neuroprotective effects of melatonin. Author(s): Franceschini D, Skaper SD, Floreani M, Borin G, Giusti P. Source: Advances in Experimental Medicine and Biology. 1999; 467: 207-15. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10721058&dopt=Abstract

76

Melatonin

•

Future of melatonin as a therapeutic agent. Author(s): Karasek M, Reiter RJ, Cardinali DP, Pawlikowski M. Source: Neuroendocrinol Lett. 2002 April; 23 Suppl 1: 118-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019364&dopt=Abstract

•

Gastric toxicity and mucosal ulceration induced by oxygen-derived reactive species: protection by melatonin. Author(s): Bandyopadhyay D, Biswas K, Bhattacharyya M, Reiter RJ, Banerjee RK. Source: Current Molecular Medicine. 2001 September; 1(4): 501-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11899094&dopt=Abstract

•

Gastrointestinal melatonin: cellular identification and biological role. Author(s): Kvetnoy IM, Ingel IE, Kvetnaia TV, Malinovskaya NK, Rapoport SI, Raikhlin NT, Trofimov AV, Yuzhakov VV. Source: Neuroendocrinol Lett. 2002 April; 23(2): 121-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12011798&dopt=Abstract

•

Gastrointestinal melatonin: localization, function, and clinical relevance. Author(s): Bubenik GA. Source: Digestive Diseases and Sciences. 2002 October; 47(10): 2336-48. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12395907&dopt=Abstract

•

Gene and protein expression profiles of anti- and pro-apoptotic actions of dopamine, R-apomorphine, green tea polyphenol (-)-epigallocatechine-3-gallate, and melatonin. Author(s): Weinreb O, Mandel S, Youdim MB. Source: Annals of the New York Academy of Sciences. 2003 May; 993: 351-61; Discussion 387-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853328&dopt=Abstract

•

Gene regulation by melatonin. Author(s): Carlberg C. Source: Annals of the New York Academy of Sciences. 2000; 917: 387-96. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11268365&dopt=Abstract

•

General anaesthesia for surgery can influence circulating melatonin during daylight hours. Author(s): Reber A, Huber PR, Ummenhofer W, Gurtler CM, Zurschmiede C, Drewe J, Schneider M. Source: Acta Anaesthesiologica Scandinavica. 1998 October; 42(9): 1050-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9809087&dopt=Abstract

Studies

77

•

Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters. Author(s): Simonneaux V, Ribelayga C. Source: Pharmacological Reviews. 2003 June; 55(2): 325-95. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773631&dopt=Abstract

•

Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and controls. Author(s): Ebisawa T, Uchiyama M, Kajimura N, Kamei Y, Shibui K, Kim K, Kudo Y, Iwase T, Sugishita M, Jodoi T, Ikeda M, Ozeki Y, Watanabe T, Sekimoto M, Katoh M, Yamada N, Toyoshima R, Okawa M, Takahashi K, Yamauchi T. Source: Neuroscience Letters. 2000 February 11; 280(1): 29-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10696804&dopt=Abstract

•

Geomagnetic activity influences the melatonin secretion at latitude 70 degrees N. Author(s): Weydahl A, Sothern RB, Cornelissen G, Wetterberg L. Source: Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2001; 55 Suppl 1: 57S-62S. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11774869&dopt=Abstract

•

Geomagnetic disturbances are associated with reduced nocturnal excretion of a melatonin metabolite in humans. Author(s): Burch JB, Reif JS, Yost MG. Source: Neuroscience Letters. 1999 May 14; 266(3): 209-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10465710&dopt=Abstract

•

GR196429: a nonindolic agonist at high-affinity melatonin receptors. Author(s): Beresford IJ, Browning C, Starkey SJ, Brown J, Foord SM, Coughlan J, North PC, Dubocovich ML, Hagan RM. Source: The Journal of Pharmacology and Experimental Therapeutics. 1998 June; 285(3): 1239-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9618428&dopt=Abstract

•

Growth and fatty acid metabolism of human breast cancer (MCF-7) xenografts in nude rats: impact of constant light-induced nocturnal melatonin suppression. Author(s): Blask DE, Dauchy RT, Sauer LA, Krause JA, Brainard GC. Source: Breast Cancer Research and Treatment. 2003 June; 79(3): 313-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12846415&dopt=Abstract

78

Melatonin

•

Growth-inhibitory activity of melatonin on human androgen-independent DU 145 prostate cancer cells. Author(s): Marelli MM, Limonta P, Maggi R, Motta M, Moretti RM. Source: The Prostate. 2000 November 1; 45(3): 238-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11074526&dopt=Abstract

•

High nocturnal melatonin in adolescents with chronic fatigue syndrome. Author(s): Knook L, Kavelaars A, Sinnema G, Kuis W, Heijnen CJ. Source: The Journal of Clinical Endocrinology and Metabolism. 2000 October; 85(10): 3690-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11061525&dopt=Abstract

•

High physiological levels of melatonin in the bile of mammals. Author(s): Tan D, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ. Source: Life Sciences. 1999 October 29; 65(23): 2523-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10622237&dopt=Abstract

•

High sensitivity of the human circadian melatonin rhythm to resetting by short wavelength light. Author(s): Lockley SW, Brainard GC, Czeisler CA. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4502-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970330&dopt=Abstract

•

High-performance liquid chromatographic analysis of melatonin in human plasma and rabbit serum with on-line column enrichment. Author(s): Bechgaard E, Lindhardt K, Martinsen L. Source: J Chromatogr B Biomed Sci Appl. 1998 August 7; 712(1-2): 177-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9698240&dopt=Abstract

•

How does the melatonin receptor decode a photoperiodic signal in the pars tuberalis? Author(s): Morgan PJ, Messager S, Webster C, Barrett P, Ross A. Source: Advances in Experimental Medicine and Biology. 1999; 460: 165-74. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10810511&dopt=Abstract

•

Human aging and melatonin. Clinical relevance. Author(s): Touitou Y. Source: Experimental Gerontology. 2001 July; 36(7): 1083-100. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11404053&dopt=Abstract

Studies

79

•

Human melatonin regulation is not mediated by the three cone photopic visual system. Author(s): Brainard GC, Hanifin JP, Rollag MD, Greeson J, Byrne B, Glickman G, Gerner E, Sanford B. Source: The Journal of Clinical Endocrinology and Metabolism. 2001 January; 86(1): 4336. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11232036&dopt=Abstract

•

Human melatonin suppression by light: a case for scotopic efficiency. Author(s): Rea MS, Bullough JD, Figueiro MG. Source: Neuroscience Letters. 2001 February 16; 299(1-2): 45-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11166934&dopt=Abstract

•

Hypermelatoninemia in women with polycystic ovarian syndrome. Author(s): Tarquini R, Bruni V, Perfetto F, Bigozzi L, Tapparini L, Tarquini B. Source: The European Journal of Contraception & Reproductive Health Care : the Official Journal of the European Society of Contraception. 1996 December; 1(4): 349-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9678118&dopt=Abstract

•

Hypersensitivity of melatonin suppression in response to light in patients with delayed sleep phase syndrome. Author(s): Aoki H, Ozeki Y, Yamada N. Source: Chronobiology International. 2001 March; 18(2): 263-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11379666&dopt=Abstract

•

Hypnotic action of melatonin during daytime administration and its comparison with triazolam. Author(s): Satomura T, Sakamoto T, Shirakawa S, Tsutsumi Y, Mukai M, Ohyama T, Uchimura N, Maeda H. Source: Psychiatry and Clinical Neurosciences. 2001 June; 55(3): 303-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11422884&dopt=Abstract

•

Hypnotic activity of melatonin. Author(s): Stone BM, Turner C, Mills SL, Nicholson AN. Source: Sleep. 2000 August 1; 23(5): 663-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10947034&dopt=Abstract

•

Hypothermic action of exogenously administered melatonin is dose-dependent in humans. Author(s): Satoh K, Mishima K. Source: Clinical Neuropharmacology. 2001 November-December; 24(6): 334-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11801808&dopt=Abstract

80

Melatonin

•

Identification of cysteines involved in ligand binding to the human melatonin MT(2) receptor. Author(s): Mseeh F, Gerdin MJ, Dubocovich MI. Source: European Journal of Pharmacology. 2002 August 2; 449(1-2): 29-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163103&dopt=Abstract

•

Illumination of upper and middle visual fields produces equivalent suppression of melatonin in older volunteers. Author(s): Smith JS, Kripke DF, Elliott JA, Youngstedt SD. Source: Chronobiology International. 2002 September; 19(5): 883-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12405551&dopt=Abstract

•

Immunomodulatory effects of melatonin in asthma. Author(s): Sutherland ER, Martin RJ, Ellison MC, Kraft M. Source: American Journal of Respiratory and Critical Care Medicine. 2002 October 15; 166(8): 1055-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12379548&dopt=Abstract

•

Impact of UVA exposure on psychological parameters and circulating serotonin and melatonin. Author(s): Gambichler T, Bader A, Vojvodic M, Bechara FG, Sauermann K, Altmeyer P, Hoffmann K. Source: Bmc Dermatology [electronic Resource]. 2002 April 12; 2(1): 6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11952999&dopt=Abstract

•

Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis. Author(s): Mundigler G, Delle-Karth G, Koreny M, Zehetgruber M, Steindl-Munda P, Marktl W, Ferti L, Siostrzonek P. Source: Critical Care Medicine. 2002 March; 30(3): 536-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11990911&dopt=Abstract

•

Impaired nocturnal melatonin secretion in non-dipper hypertensive patients. Author(s): Jonas M, Garfinkel D, Zisapel N, Laudon M, Grossman E. Source: Blood Pressure. 2003; 12(1): 19-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12699131&dopt=Abstract

•

Impaired nocturnal synthesis of melatonin in patients with cardiac syndrome X. Author(s): Altun A, Yaprak M, Aktoz M, Vardar A, Betul UA, Ozbay G. Source: Neuroscience Letters. 2002 July 19; 327(2): 143-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12098655&dopt=Abstract

Studies

81

•

Importance and relevance of melatonin to human biological rhythms. Author(s): Arendt J. Source: Journal of Neuroendocrinology. 2003 April; 15(4): 427-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12622845&dopt=Abstract

•

Important amino acids for the function of the human MT1 melatonin receptor. Author(s): Kokkola T, Foord SM, Watson MA, Vakkuri O, Laitinen JT. Source: Biochemical Pharmacology. 2003 May 1; 65(9): 1463-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12732358&dopt=Abstract

•

Increased 6-sulfatoxymelatonin excretion in women with polycystic ovary syndrome. Author(s): Luboshitzky R, Qupti G, Ishay A, Shen-Orr Z, Futerman B, Linn S. Source: Fertility and Sterility. 2001 September; 76(3): 506-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11532473&dopt=Abstract

•

Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production. Author(s): Nakamura Y, Tamura H, Takayama H, Kato H. Source: Fertility and Sterility. 2003 October; 80(4): 1012-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14556825&dopt=Abstract

•

Inferior retinal light exposure is more effective than superior retinal exposure in suppressing melatonin in humans. Author(s): Glickman G, Hanifin JP, Rollag MD, Wang J, Cooper H, Brainard GC. Source: Journal of Biological Rhythms. 2003 February; 18(1): 71-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568246&dopt=Abstract

•

Influence of adjuvant chemotherapy with cyclophosphamide, methotrexate and 5fluorouracil on plasma melatonin and chosen hormones in breast cancer premenopausal patients. Author(s): Kajdaniuk D, Marek B, Kos-Kudla B. Source: Journal of Clinical Pharmacy and Therapeutics. 2001 August; 26(4): 297-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11493373&dopt=Abstract

•

Integrative care--inducing sleep with melatonin. Author(s): Eliopoulos C. Source: Director. 2003 Summer; 11(3): 122-3. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13678024&dopt=Abstract

82

Melatonin

•

Interaction of serotonin and melatonin with sodium, potassium, calcium, lithium and aluminium. Author(s): Lack B, Daya S, Nyokong T. Source: Journal of Pineal Research. 2001 September; 31(2): 102-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555164&dopt=Abstract

•

Interactions of melatonin with the liver microsomal cytochrome P450 system of rats and humans in vitro and effects on the P450 system and the antioxidative status in rat liver after acute treatment. Author(s): Klinger W, Karge E, Demme U, Kretzschmar M. Source: Eur J Drug Metab Pharmacokinet. 2001 January-June; 26(1-2): 31-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11554431&dopt=Abstract

•

Involvement of reactive oxygen species in gastric ulceration: protection by melatonin. Author(s): Bandyopadhyay D, Biswas K, Bhattacharyya M, Reiter RJ, Banerjee RK. Source: Indian J Exp Biol. 2002 June; 40(6): 693-705. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12587717&dopt=Abstract

•

Involvement of the mt1 melatonin receptor in human breast cancer. Author(s): Ram PT, Dai J, Yuan L, Dong C, Kiefer TL, Lai L, Hill SM. Source: Cancer Letters. 2002 May 28; 179(2): 141-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11888668&dopt=Abstract

•

Is melatonin likely to help children with neurodevelopmental disability and chronic severe sleep problems? Author(s): Willey C, Phillips B. Source: Archives of Disease in Childhood. 2002 September; 87(3): 260. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12193452&dopt=Abstract

•

Is there a role for melatonin in supportive care? Author(s): Lissoni P. Source: Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer. 2002 March; 10(2): 110-6. Epub 2001 November 13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11862501&dopt=Abstract

•

Jet lag/night shift, blindness and melatonin. Author(s): Arendt J. Source: Trans Med Soc Lond. 1997-98; 114: 7-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10824248&dopt=Abstract

Studies

83

•

Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial. Author(s): Spitzer RL, Terman M, Williams JB, Terman JS, Malt UF, Singer F, Lewy AJ. Source: The American Journal of Psychiatry. 1999 September; 156(9): 1392-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10484950&dopt=Abstract

•

Jet lag: minimizing it's effects with critically timed bright light and melatonin administration. Author(s): Parry BL. Source: Journal of Molecular Microbiology and Biotechnology. 2002 September; 4(5): 463-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12432956&dopt=Abstract

•

Jet-lag and shift work: (2). Therapeutic use of melatonin. Author(s): Arendt J. Source: Journal of the Royal Society of Medicine. 1999 August; 92(8): 402-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10656005&dopt=Abstract

•

Lack of calmodulin antagonism of melatonin in T-lymphocyte activation. Author(s): Wolfler A, Schauenstein K, Liebmann PM. Source: Life Sciences. 1998; 63(10): 835-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9734703&dopt=Abstract

•

Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients. Author(s): Siegrist C, Benedetti C, Orlando A, Beltran JM, Tuchscherr L, Noseda CM, Brusco LI, Cardinali DP. Source: Journal of Pineal Research. 2001 January; 30(1): 34-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11168905&dopt=Abstract

•

Lack of melatonin response to acute administration of nifedipine and diltiazem in healthy men. Author(s): Kancheva R, Zofkova I, Hill M, Kanchev L. Source: Physiological Research / Academia Scientiarum Bohemoslovaca. 2000; 49 Suppl 1: S119-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10984081&dopt=Abstract

84

Melatonin

•

Larger phase angle between sleep propensity and melatonin rhythms in sighted humans with non-24-hour sleep-wake syndrome. Author(s): Uchiyama M, Shibui K, Hayakawa T, Kamei Y, Ebisawa T, Tagaya H, Okawa M, Takahashi K. Source: Sleep. 2002 February 1; 25(1): 83-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11833864&dopt=Abstract

•

Late nocturnal sleep onset impairs a melatonin shower in young children. Author(s): Kohyama J. Source: Neuroendocrinol Lett. 2002 October-December; 23(5-6): 385-6. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12500157&dopt=Abstract

•

Ligand efficacy and potency at recombinant human MT2 melatonin receptors: evidence for agonist activity of some mt1-antagonists. Author(s): Nonno R, Pannacci M, Lucini V, Angeloni D, Fraschini F, Stankov BM. Source: British Journal of Pharmacology. 1999 July; 127(5): 1288-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10455277&dopt=Abstract

•

Light during darkness, melatonin suppression and cancer progression. Author(s): Blask DE, Dauchy RT, Sauer LA, Krause JA, Brainard GC. Source: Neuroendocrinol Lett. 2002 July; 23 Suppl 2: 52-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163849&dopt=Abstract

•

Light emitting diodes can be used to phase delay the melatonin rhythm. Author(s): Wright HR, Lack LC, Partridge KJ. Source: Journal of Pineal Research. 2001 November; 31(4): 350-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11703565&dopt=Abstract

•

Localization, physiological significance and possible clinical implication of gastrointestinal melatonin. Author(s): Bubenik GA. Source: Biological Signals and Receptors. 2001 November-December; 10(6): 350-66. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11721091&dopt=Abstract

•

Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men. Author(s): Luboshitzky R, Levi M, Shen-Orr Z, Blumenfeld Z, Herer P, Lavie P. Source: Human Reproduction (Oxford, England). 2000 January; 15(1): 60-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10611189&dopt=Abstract

Studies

85

•

Long-Term stability of 6-hydroxymelatonin sulfate in 24-h urine samples stored at -20 degrees C. Author(s): Griefahn B, Remer T, Blaszkewicz M, Brode P. Source: Endocrine. 2001 July; 15(2): 199-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11720246&dopt=Abstract

•

Low ACTH and high melatonin concentrations in amniotic fluid as hormonal markers of high risk of fetal abnormalities. Preliminary studies. Author(s): Ciesla W. Source: Prenatal Diagnosis. 1998 September; 18(9): 980-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9793987&dopt=Abstract

•

Low doses of melatonin and diurnal effects on thermoregulation and tolerance to uncompensable heat stress. Author(s): McLellan TM, Gannon GA, Zamecnik J, Gil V, Brown GM. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 1999 July; 87(1): 308-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10409589&dopt=Abstract

•

Low melatonin production in infants with a life-threatening event. Author(s): Sivan Y, Laudon M, Kuint J, Zisapel N. Source: Developmental Medicine and Child Neurology. 2000 July; 42(7): 487-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10972422&dopt=Abstract

•

Low urinary 6-sulphatoxymelatonin levels in patients with coronary artery disease. Author(s): Girotti L, Lago M, Ianovsky O, Carbajales J, Elizari MV, Brusco LI, Cardinali DP. Source: Journal of Pineal Research. 2000 October; 29(3): 138-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11034110&dopt=Abstract

•

Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Author(s): Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA. Source: Chronobiology International. 2002 May; 19(3): 649-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12069043&dopt=Abstract

•

Magnetic fields and the melatonin hypothesis: a study of workers chronically exposed to 50-Hz magnetic fields. Author(s): Touitou Y, Lambrozo J, Camus F, Charbuy H. Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2003 June; 284(6): R1529-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736182&dopt=Abstract

86

Melatonin

•

Melatonin ameliorates neurologic damage and neurophysiologic deficits in experimental models of stroke. Author(s): Reiter RJ, Sainz RM, Lopez-Burillo S, Mayo JC, Manchester LC, Tan DX. Source: Annals of the New York Academy of Sciences. 2003 May; 993: 35-47; Discussion 48-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853293&dopt=Abstract

•

Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Author(s): Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ. Source: Cellular and Molecular Life Sciences : Cmls. 2003 July; 60(7): 1407-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943228&dopt=Abstract

•

Melatonin and immune function: hype or hypothesis? Author(s): Hotchkiss AK, Nelson RJ. Source: Critical Reviews in Immunology. 2002; 22(5-6): 351-71. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12803316&dopt=Abstract

•

Melatonin and mammary cancer: a short review. Author(s): Sanchez-Barcelo EJ, Cos S, Fernandez R, Mediavilla MD. Source: Endocrine-Related Cancer. 2003 June; 10(2): 153-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790777&dopt=Abstract

•

Melatonin effect on seizures in children with severe neurologic deficit disorders. Author(s): Peled N, Shorer Z, Peled E, Pillar G. Source: Epilepsia. 2001 September; 42(9): 1208-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11580772&dopt=Abstract

•

Melatonin elicits nuclear exclusion of the human androgen receptor and attenuates its activity. Author(s): Rimler A, Culig Z, Levy-Rimler G, Lupowitz Z, Klocker H, Matzkin H, Bartsch G, Zisapel N. Source: The Prostate. 2001 October 1; 49(2): 145-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11582594&dopt=Abstract

•

Melatonin excretion with affect disorders over age 60. Author(s): Kripke DF, Youngstedt SD, Rex KM, Klauber MR, Elliott JA. Source: Psychiatry Research. 2003 May 1; 118(1): 47-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12759161&dopt=Abstract

Studies

87

•

Melatonin for the treatment of tardive dyskinesia. Author(s): Nelson LA, McGuire JM, Hausafus SN. Source: The Annals of Pharmacotherapy. 2003 July-August; 37(7-8): 1128-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12841828&dopt=Abstract

•

Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study. Author(s): Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG. Source: European Journal of Pediatrics. 2003 July; 162(7-8): 554-5. Epub 2003 June 03. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12783318&dopt=Abstract

•

Melatonin in plants. Author(s): Reiter RJ, Tan DX, Burkhardt S, Manchester LC. Source: Nutrition Reviews. 2001 September; 59(9): 286-90. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11570431&dopt=Abstract

•

Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease. Author(s): Matsubara E, Bryant-Thomas T, Pacheco Quinto J, Henry TL, Poeggeler B, Herbert D, Cruz-Sanchez F, Chyan YJ, Smith MA, Perry G, Shoji M, Abe K, Leone A, Grundke-Ikbal I, Wilson GL, Ghiso J, Williams C, Refolo LM, Pappolla MA, Chain DG, Neria E. Source: Journal of Neurochemistry. 2003 June; 85(5): 1101-8. Erratum In: J Neurochem. 2003 September; 86(5): 1312. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12753069&dopt=Abstract

•

Melatonin phase-shifts human circadian rhythms with no evidence of changes in the duration of endogenous melatonin secretion or the 24-hour production of reproductive hormones. Author(s): Rajaratnam SM, Dijk DJ, Middleton B, Stone BM, Arendt J. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4303-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12970302&dopt=Abstract

•

Melatonin protects against oxidative mitochondrial damage induced in rat placenta by ischemia and reperfusion. Author(s): Okatani Y, Wakatsuki A, Shinohara K, Taniguchi K, Fukaya T. Source: Journal of Pineal Research. 2001 September; 31(2): 173-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555174&dopt=Abstract

88

Melatonin

•

Melatonin response to clonidine administration in depression: indication of presynaptic alpha2-adrenoceptor dysfunction. Author(s): Paparrigopoulos T, Psarros C, Bergiannaki JD, Varsou E, Dafni U, Stefanis C. Source: Journal of Affective Disorders. 2001 August; 65(3): 307-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11511411&dopt=Abstract

•

Melatonin, light therapy, and jet lag. Author(s): Lathrop NJ, Lentz M. Source: Air Medical Journal. 2001 September-October; 20(5): 30-4. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11552110&dopt=Abstract

•

Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart. Author(s): Reiter RJ, Tan DX. Source: Cardiovascular Research. 2003 April 1; 58(1): 10-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12667942&dopt=Abstract

•

Methylphenidate and melatonin for sleep disorder with optic glioma. Author(s): Zotter H, Kerbl R, Millner M, Kurz R. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2001 September; 40(9): 992-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11556641&dopt=Abstract

•

Molecular pharmacology, regulation and function of mammalian melatonin receptors. Author(s): Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI. Source: Frontiers in Bioscience : a Journal and Virtual Library. 2003 September 1; 8: D1093-108. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12957828&dopt=Abstract

•

Mutagenesis studies of the human MT2 melatonin receptor. Author(s): Gerdin MJ, Mseeh F, Dubocovich ML. Source: Biochemical Pharmacology. 2003 July 15; 66(2): 315-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12826274&dopt=Abstract

•

Neural basis and biological function of masking by light in mammals: suppression of melatonin and locomotor activity. Author(s): Redlin U. Source: Chronobiology International. 2001 September; 18(5): 737-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11763983&dopt=Abstract

Studies

89

•

Neuroimmunotherapy of untreatable metastatic solid tumors with subcutaneous lowdose interleukin-2, melatonin and naltrexone: modulation of interleukin-2-induced antitumor immunity by blocking the opioid system. Author(s): Lissoni P, Malugani F, Malysheva O, Kozlov V, Laudon M, Conti A, Maestroni G. Source: Neuroendocrinol Lett. 2002 August; 23(4): 341-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12195238&dopt=Abstract

•

New issues about melatonin and its effects on the digestive system. Author(s): Motilva V, Cabeza J, Alarcon de la Lastra C. Source: Current Pharmaceutical Design. 2001 July; 7(10): 909-31. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11472247&dopt=Abstract

•

New options to test the melatonin hypothesis. Author(s): Erren TC, Piekarski C. Source: Epidemiology (Cambridge, Mass.). 1999 November; 10(6): 785. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10535799&dopt=Abstract

•

Nimodipine potentiates the light-induced suppression of melatonin. Author(s): Benloucif S, Bauer GL, Dubocovich ML, Finkel SI, Zee PC. Source: Neuroscience Letters. 1999 September 3; 272(1): 67-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10507544&dopt=Abstract

•

Nitrosation of melatonin by nitric oxide: a computational study. Author(s): Turjanski AG, Saenz DA, Doctorovich F, Estrin DA, Rosenstein RE. Source: Journal of Pineal Research. 2001 September; 31(2): 97-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555163&dopt=Abstract

•

No association of 6-sulfatoxymelatonin with in-bed 60-Hz magnetic field exposure or illumination level among older adults. Author(s): Youngstedt SD, Kripke DF, Elliott JA, Assmus JD. Source: Environmental Research. 2002 July; 89(3): 201-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12176004&dopt=Abstract

•

No effects of pulsed radio frequency electromagnetic fields on melatonin, cortisol, and selected markers of the immune system in man. Author(s): Radon K, Parera D, Rose DM, Jung D, Vollrath L. Source: Bioelectromagnetics. 2001 May; 22(4): 280-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11298390&dopt=Abstract

90

Melatonin

•

No evidence for a phase delay in human circadian rhythms after a single morning melatonin administration. Author(s): Wirz-Justice A, Werth E, Renz C, Muller S, Krauchi K. Source: Journal of Pineal Research. 2002 January; 32(1): 1-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11841593&dopt=Abstract

•

No evidence for extraocular light induced phase shifting of human melatonin, cortisol and thyrotropin rhythms. Author(s): Lindblom N, Heiskala H, Hatonen T, Mustanoja S, Alfthan H, AlilaJohansson A, Laakso ML. Source: Neuroreport. 2000 March 20; 11(4): 713-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10757506&dopt=Abstract

•

No melatonin suppression by illumination of popliteal fossae or eyelids. Author(s): Jean-Louis G, Kripke DF, Cole RJ, Elliot JA. Source: Journal of Biological Rhythms. 2000 June; 15(3): 265-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10885880&dopt=Abstract

•

Nocturnal 6-hydroxymelatonin sulfate excretion in female workers exposed to magnetic fields. Author(s): Juutilainen J, Stevens RG, Anderson LE, Hansen NH, Kilpelainen M, Kumlin T, Laitinen JT, Sobel E, Wilson BW. Source: Journal of Pineal Research. 2000 March; 28(2): 97-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10709971&dopt=Abstract

•

Nocturnal cortisol and melatonin secretion in primary insomnia. Author(s): Riemann D, Klein T, Rodenbeck A, Feige B, Horny A, Hummel R, Weske G, Al-Shajlawi A, Voderholzer U. Source: Psychiatry Research. 2002 December 15; 113(1-2): 17-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12467942&dopt=Abstract

•

Nocturnal melatonin patterns in children. Author(s): Salti R, Galluzzi F, Bindi G, Perfetto F, Tarquini R, Halberg F, Cornelissen G. Source: The Journal of Clinical Endocrinology and Metabolism. 2000 June; 85(6): 2137-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10852442&dopt=Abstract

•

Nocturnal melatonin secretion and its modification by treatment in patients with sleep disorders. Author(s): Rodenbeck A, Huether G, Ruther E, Hajak G. Source: Advances in Experimental Medicine and Biology. 1999; 467: 89-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10721043&dopt=Abstract

Studies

91

•

Nocturnal melatonin secretion is not suppressed by light exposure behind the knee in humans. Author(s): Hebert M, Martin SK, Eastman CI. Source: Neuroscience Letters. 1999 October 22; 274(2): 127-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10553954&dopt=Abstract

•

Nonentrained circadian rhythms of melatonin in submariners scheduled to an 18hour day. Author(s): Kelly TL, Neri DF, Grill JT, Ryman D, Hunt PD, Dijk DJ, Shanahan TL, Czeisler CA. Source: Journal of Biological Rhythms. 1999 June; 14(3): 190-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10452330&dopt=Abstract

•

Novel mechanism of action hypothesized for stellate ganglion block related to melatonin. Author(s): Uchida K, Tateda T, Hino H. Source: Medical Hypotheses. 2002 October; 59(4): 446-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12208186&dopt=Abstract

•

Nuclear exclusion of the androgen receptor by melatonin. Author(s): Rimler A, Culig Z, Lupowitz Z, Zisapel N. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2002 May; 81(1): 7784. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12127045&dopt=Abstract

•

Nuclear receptors are involved in the enhanced IL-6 production by melatonin in U937 cells. Author(s): Guerrero JM, Pozo D, Garcia-Maurino S, Carrillo A, Osuna C, Molinero P, Calvo JR. Source: Biological Signals and Receptors. 2000 May-August; 9(3-4): 197-202. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10899704&dopt=Abstract

•

Ocular input for human melatonin regulation: relevance to breast cancer. Author(s): Glickman G, Levin R, Brainard GC. Source: Neuroendocrinol Lett. 2002 July; 23 Suppl 2: 17-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163843&dopt=Abstract

•

Of rodents and ungulates and melatonin: creating a uniform code for darkness by different signaling mechanisms. Author(s): Stehle JH, von Gall C, Schomerus C, Korf HW. Source: Journal of Biological Rhythms. 2001 August; 16(4): 312-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11506377&dopt=Abstract

92

Melatonin

•

Oncostatic action of melatonin: facts and question marks. Author(s): Pawlikowski M, Winczyk K, Karasek M. Source: Neuroendocrinol Lett. 2002 April; 23 Suppl 1: 24-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019348&dopt=Abstract

•

Optimization of light and melatonin to phase-shift human circadian rhythms. Author(s): Skene DJ. Source: Journal of Neuroendocrinology. 2003 April; 15(4): 438-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12622847&dopt=Abstract

•

Oral melatonin in neurologically disabled children. Author(s): Wurtman RJ, Zhdanova II. Source: Lancet. 1998 June 27; 351(9120): 1963-4; Author Reply 1964. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9654294&dopt=Abstract

•

Oral melatonin in neurologically disabled children. Author(s): Manev H, Uz T. Source: Lancet. 1998 June 27; 351(9120): 1963; Author Reply 1964. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9654293&dopt=Abstract

•

Orally given melatonin may serve as a probe drug for cytochrome P450 1A2 activity in vivo: a pilot study. Author(s): Hartter S, Ursing C, Morita S, Tybring G, von Bahr C, Christensen M, Rojdmark S, Bertilsson L. Source: Clinical Pharmacology and Therapeutics. 2001 July; 70(1): 10-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11452239&dopt=Abstract

•

Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice. Author(s): Collins A, Yuan L, Kiefer TL, Cheng Q, Lai L, Hill SM. Source: Cancer Letters. 2003 January 10; 189(1): 49-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12445677&dopt=Abstract

•

Over-the-counter melatonin products and contamination. Author(s): Naylor S, Gleich GJ. Source: American Family Physician. 1999 January 15; 59(2): 284, 287-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9930125&dopt=Abstract

Studies

93

•

Over-the-counter psychotropics: a review of melatonin, St John's wort, valerian, and kava-kava. Author(s): Heiligenstein E, Guenther G. Source: Journal of American College Health : J of Ach. 1998 May; 46(6): 271-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9609974&dopt=Abstract

•

Oxidative damage in the central nervous system: protection by melatonin. Author(s): Reiter RJ. Source: Progress in Neurobiology. 1998 October; 56(3): 359-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9770244&dopt=Abstract

•

Oxidative stress induced by phenylketonuria in the rat: Prevention by melatonin, vitamin E, and vitamin C. Author(s): Martinez-Cruz F, Pozo D, Osuna C, Espinar A, Marchante C, Guerrero JM. Source: Journal of Neuroscience Research. 2002 August 15; 69(4): 550-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12210848&dopt=Abstract

•

Peak of circadian melatonin rhythm occurs later within the sleep of older subjects. Author(s): Duffy JF, Zeitzer JM, Rimmer DW, Klerman EB, Dijk DJ, Czeisler CA. Source: American Journal of Physiology. Endocrinology and Metabolism. 2002 February; 282(2): E297-303. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11788360&dopt=Abstract

•

Perioperative melatonin secretion in patients undergoing coronary artery bypass grafting. Author(s): Guo X, Kuzumi E, Charman SC, Vuylsteke A. Source: Anesthesia and Analgesia. 2002 May; 94(5): 1085-91, Table of Contents. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11973167&dopt=Abstract

•

Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. Author(s): Cuzzocrea S, Reiter RJ. Source: European Journal of Pharmacology. 2001 August 24; 426(1-2): 1-10. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11525764&dopt=Abstract

•

Pharmacological actions of melatonin in acute and chronic inflammation. Author(s): Cuzzocrea S, Reiter RJ. Source: Current Topics in Medicinal Chemistry. 2002 February; 2(2): 153-65. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11899098&dopt=Abstract

94

Melatonin

•

Phototransduction for human melatonin suppression. Author(s): Rea MS, Bullough JD, Figueiro MG. Source: Journal of Pineal Research. 2002 May; 32(4): 209-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11982788&dopt=Abstract

•

Pineal dysfunction (low melatonin production) as a cause of sudden death in a longterm survivor of Langerhans cell histiocytosis? Author(s): Imashuku S, Morimoto Y, Morimoto A, Yamamoto T, Hibi S, Todo S. Source: Medical and Pediatric Oncology. 2003 August; 41(2): 151-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12825223&dopt=Abstract

•

Pineal gland hormone and idiopathic scoliosis: possible effect of melatonin on sleeprelated postural mechanisms. Author(s): Pompeiano O, Manzoni D, Miele F. Source: Arch Ital Biol. 2002 April; 140(2): 129-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12004644&dopt=Abstract

•

Polyunsaturated fatty acids, melatonin, and cancer prevention. Author(s): Sauer LA, Dauchy RT, Blask DE. Source: Biochemical Pharmacology. 2001 June 15; 61(12): 1455-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11377374&dopt=Abstract

•

Postoperative delirium and melatonin levels in elderly patients. Author(s): Shigeta H, Yasui A, Nimura Y, Machida N, Kageyama M, Miura M, Menjo M, Ikeda K. Source: American Journal of Surgery. 2001 November; 182(5): 449-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11754849&dopt=Abstract

•

Postoperative delirium, plasma melatonin, and light. Author(s): Sher L. Source: Medical Hypotheses. 2001 March; 56(3): 411-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11359373&dopt=Abstract

•

Potential anticarcinogenic action of melatonin and other antioxidants mediated by antioxidative mechanisms. Author(s): Karbownik M. Source: Neuroendocrinol Lett. 2002 April; 23 Suppl 1: 39-44. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019350&dopt=Abstract

Studies

95

•

Potential biological consequences of excessive light exposure: melatonin suppression, DNA damage, cancer and neurodegenerative diseases. Author(s): Reiter RJ. Source: Neuroendocrinol Lett. 2002 July; 23 Suppl 2: 9-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12163841&dopt=Abstract

•

Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist. Author(s): Vachharajani NN, Yeleswaram K, Boulton DW. Source: Journal of Pharmaceutical Sciences. 2003 April; 92(4): 760-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12661062&dopt=Abstract

•

Presence and effects of melatonin in Trypanosoma cruzi. Author(s): Macias M, Rodriguez-Cabezas MN, Reiter RJ, Osuna A, Acuna-Castroviejo D. Source: Journal of Pineal Research. 1999 September; 27(2): 86-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10496144&dopt=Abstract

•

Presence of melatonin in the human hepatobiliary-gastrointestinal tract. Author(s): Messner M, Huether G, Lorf T, Ramadori G, Schworer H. Source: Life Sciences. 2001 June 22; 69(5): 543-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11510949&dopt=Abstract

•

Pretreatment circadian period in free-running blind people may predict the phase angle of entrainment to melatonin. Author(s): Lewy AJ, Hasler BP, Emens JS, Sack RL. Source: Neuroscience Letters. 2001 November 9; 313(3): 158-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11682151&dopt=Abstract

•

Profile of 24-h light exposure and circadian phase of melatonin secretion in night workers. Author(s): Dumont M, Benhaberou-Brun D, Paquet J. Source: Journal of Biological Rhythms. 2001 October; 16(5): 502-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11669423&dopt=Abstract

•

Prooxidant activity of melatonin promotes fas-induced cell death in human leukemic Jurkat cells. Author(s): Wolfler A, Caluba HC, Abuja PM, Dohr G, Schauenstein K, Liebmann PM. Source: Febs Letters. 2001 August 3; 502(3): 127-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11583113&dopt=Abstract

96

Melatonin

•

Protective effect of melatonin against cytotoxic actions of malondialdehyde: an in vitro study on human erythrocytes. Author(s): Allegra M, Gentile C, Tesoriere L, Livrea MA. Source: Journal of Pineal Research. 2002 April; 32(3): 187-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12074103&dopt=Abstract

•

Protective effect of melatonin on neural cells against the cytotoxicity of oxyradicals. Author(s): An Y, Liu E, Liu X, Yang F, Han F, Dai Q. Source: Chinese Medical Sciences Journal = Chung-Kuo I Hsueh K'o Hsueh Tsa Chih / Chinese Academy of Medical Sciences. 2000 March; 15(1): 40-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12899398&dopt=Abstract

•

Quantitative determination of melatonin in human plasma and cerebrospinal fluid with high-performance liquid chromatography and fluorescence detection. Author(s): Sastre Torano J, Rijn-Bikker P, Merkus P, Guchelaar HJ. Source: Biomedical Chromatography : Bmc. 2000 August; 14(5): 306-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10960829&dopt=Abstract

•

Questionable benefit of melatonin for antioxidant pharmacologic therapy. Author(s): Wolfler A, Abuja PM, Linkesch W, Schauenstein K, Liebmann PM. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2002 October 1; 20(19): 4127-8; Author Reply 4128-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12351615&dopt=Abstract

•

Radioimmunoassay of N-acetyl-N-formyl-5-methoxykynuramine (AFMK): a melatonin oxidative metabolite. Author(s): Harthe C, Claudy D, Dechaud H, Vivien-Roels B, Pevet P, Claustrat B. Source: Life Sciences. 2003 August 8; 73(12): 1587-97. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12865098&dopt=Abstract

•

Rapid determination of serum melatonin by ESI-MS-MS with direct sample injection. Author(s): Yang S, Zheng X, Xu Y, Zhou X. Source: Journal of Pharmaceutical and Biomedical Analysis. 2002 October 15; 30(3): 78190. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12367704&dopt=Abstract

•

Re: Mann--melatonin for ulcerative colitis? Author(s): Jan JE, Freeman RD. Source: The American Journal of Gastroenterology. 2003 June; 98(6): 1446. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818299&dopt=Abstract

Studies

97

•

Reaction of melatonin with hemoglobin-derived oxoferryl radicals and inhibition of the hydroperoxide-induced hemoglobin denaturation in red blood cells. Author(s): Tesoriere L, Allegra M, D'Arpa D, Butera D, Livrea MA. Source: Journal of Pineal Research. 2001 September; 31(2): 114-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555166&dopt=Abstract

•

Reactive oxygen and nitrogen species and cellular and organismal decline: amelioration with melatonin. Author(s): Reiter RJ, Tan DX, Burkhardt S. Source: Mechanisms of Ageing and Development. 2002 April 30; 123(8): 1007-19. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12044950&dopt=Abstract

•

Re-entrainment of the circadian rhythms of plasma melatonin in an 11-h eastward bound flight. Author(s): Takahashi T, Sasaki M, Itoh H, Yamadera W, Ozone M, Obuchi K, Matsunaga N, Sano H, Hayashida KI. Source: Psychiatry and Clinical Neurosciences. 2001 June; 55(3): 275-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11422873&dopt=Abstract

•

Regarding the article 'Does the negative correlation found in breast cancer patients between plasma melatonin and insulin-like growth factor-1 concentrations imply the existence of an additional mechanism of oncostatic melatonin influence involved in defense?' by Kajdaniuk et al. Author(s): Iizuka N. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2002 October; 8(10): Le42-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12434788&dopt=Abstract

•

Relationship between amyloid beta protein and melatonin metabolite in a study of electric utility workers. Author(s): Noonan CW, Reif JS, Burch JB, Ichinose TY, Yost MG, Magnusson K. Source: Journal of Occupational and Environmental Medicine / American College of Occupational and Environmental Medicine. 2002 August; 44(8): 769-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12185798&dopt=Abstract

•

Reproducibility of the circadian rhythms of serum cortisol and melatonin in healthy subjects: a study of three different 24-h cycles over six weeks. Author(s): Selmaoui B, Touitou Y. Source: Life Sciences. 2003 November 14; 73(26): 3339-49. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14572876&dopt=Abstract

98

Melatonin

•

Residential magnetic fields, light-at-night, and nocturnal urinary 6sulfatoxymelatonin concentration in women. Author(s): Davis S, Kaune WT, Mirick DK, Chen C, Stevens RG. Source: American Journal of Epidemiology. 2001 October 1; 154(7): 591-600. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11581092&dopt=Abstract

•

Residual effects of daytime administration of melatonin on performance relevant to flight. Author(s): Nave R, Iani C, Herer P, Gopher D, Lavie P. Source: Behavioural Brain Research. 2002 April 1; 131(1-2): 87-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11844575&dopt=Abstract

•

Resynchronization of hormonal rhythms after an eastbound flight in humans: effects of slow-release caffeine and melatonin. Author(s): Pierard C, Beaumont M, Enslen M, Chauffard F, Tan DX, Reiter RJ, Fontan A, French J, Coste O, Lagarde D. Source: European Journal of Applied Physiology. 2001 July; 85(1-2): 144-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11513308&dopt=Abstract

•

REVIEW. Melatonin and the thyroid gland. Author(s): Lewinski A, Karbownik M. Source: Neuroendocrinol Lett. 2002 April; 23 Suppl 1: 73-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12019356&dopt=Abstract

•

Role of a pineal cAMP-operated arylalkylamine N-acetyltransferase/14-3-3-binding switch in melatonin synthesis. Author(s): Ganguly S, Gastel JA, Weller JL, Schwartz C, Jaffe H, Namboodiri MA, Coon SL, Hickman AB, Rollag M, Obsil T, Beauverger P, Ferry G, Boutin JA, Klein DC. Source: Proceedings of the National Academy of Sciences of the United States of America. 2001 July 3; 98(14): 8083-8. Epub 2001 June 26. Erratum In: Proc Natl Acad Sci U S a 2001 November 20; 98(24): 14186. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11427721&dopt=Abstract

•

Role of melatonin in the regulation of human circadian rhythms and sleep. Author(s): Cajochen C, Krauchi K, Wirz-Justice A. Source: Journal of Neuroendocrinology. 2003 April; 15(4): 432-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12622846&dopt=Abstract

•

Role of morning melatonin administration and attenuation of sunlight exposure in improving adaptation of night-shift workers. Author(s): Yoon IY, Song BG. Source: Chronobiology International. 2002 September; 19(5): 903-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12405553&dopt=Abstract

Studies

99

•

Severe bleeding symptoms in refractory idiopathic thrombocytopenic purpura: a case successfully treated with melatonin. Author(s): Todisco M, Casaccia P, Rossi N. Source: American Journal of Therapeutics. 2003 March-April; 10(2): 135-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12629593&dopt=Abstract

•

Short-term exposure to melatonin differentially affects the functional sensitivity and trafficking of the hMT1 and hMT2 melatonin receptors. Author(s): Gerdin MJ, Masana MI, Ren D, Miller RJ, Dubocovich ML. Source: The Journal of Pharmacology and Experimental Therapeutics. 2003 March; 304(3): 931-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12604667&dopt=Abstract

•

Sleep logs of young adults with self-selected sleep times predict the dim light melatonin onset. Author(s): Martin SK, Eastman CI. Source: Chronobiology International. 2002 July; 19(4): 695-707. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12182497&dopt=Abstract

•

Spontaneous central melatonin secretion and resorption kinetics of exogenous melatonin: a ventricular CSF study. Author(s): Debus OM, Lerchl A, Bothe HW, Bremer J, Fiedler B, Franssen M, Koehring J, Steils M, Kurlemann G. Source: Journal of Pineal Research. 2002 November; 33(4): 213-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12390503&dopt=Abstract

•

Stability of sleep timing against the melatonin secretion rhythm with advancing age: clinical implications. Author(s): Tozawa T, Mishima K, Satoh K, Echizenya M, Shimizu T, Hishikawa Y. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4689-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14557442&dopt=Abstract

•

Study of circadian melatonin secretion pattern at different stages of Parkinson's disease. Author(s): Bordet R, Devos D, Brique S, Touitou Y, Guieu JD, Libersa C, Destee A. Source: Clinical Neuropharmacology. 2003 March-April; 26(2): 65-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12671525&dopt=Abstract

100 Melatonin

•

Sulphatoxymelatonin excretion during opiate withdrawal: a preliminary study. Author(s): Bearn J, Gupta R, Stewart D, English J, Gossop M. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2002 May; 26(4): 677-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12188099&dopt=Abstract

•

Synthesis of a novel series of benzocycloalkene derivatives as melatonin receptor agonists. Author(s): Fukatsu K, Uchikawa O, Kawada M, Yamano T, Yamashita M, Kato K, Hirai K, Hinuma S, Miyamoto M, Ohkawa S. Source: Journal of Medicinal Chemistry. 2002 September 12; 45(19): 4212-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12213062&dopt=Abstract

•

Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. Author(s): Uchikawa O, Fukatsu K, Tokunoh R, Kawada M, Matsumoto K, Imai Y, Hinuma S, Kato K, Nishikawa H, Hirai K, Miyamoto M, Ohkawa S. Source: Journal of Medicinal Chemistry. 2002 September 12; 45(19): 4222-39. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12213063&dopt=Abstract

•

Synthesis of new arylalkoxy amido derivatives as melatoninergic ligands. Author(s): Pegurier C, Morellato L, Chahed E, Andrieux J, Nicolas JP, Boutin JA, Bennejean C, Delagrange P, Langlois M, Mathe-Allainmat M. Source: Bioorganic & Medicinal Chemistry. 2003 March 6; 11(5): 789-800. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12538010&dopt=Abstract

•

The association of neurofibromatosis 1 and spinal deformity with primary hyperparathyroidism and osteomalacia: might melatonin have a role? Author(s): Abdel-Wanis ME, Kawahara N, Tomita K. Source: Journal of Orthopaedic Science : Official Journal of the Japanese Orthopaedic Association. 2001; 6(2): 193-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11484109&dopt=Abstract

•

The effect of antidepressants on serum melatonin levels in endogenous depression. Author(s): Varma A, Kaul RK, Varma P, Kalra V, Malhotra V. Source: J Assoc Physicians India. 2002 October; 50: 1262-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12568211&dopt=Abstract

•

The effect of variations in pH and temperature on stability of melatonin in aqueous solution. Author(s): Daya S, Walker RB, Glass BD, Anoopkumar-Dukie S. Source: Journal of Pineal Research. 2001 September; 31(2): 155-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11555171&dopt=Abstract

Studies

101

•

The effects of bright light and nighttime melatonin administration on cardiac activity. Author(s): Sletten T, Burgess H, Savic N, Gilbert S, Dawson D. Source: J Hum Ergol (Tokyo). 2001 December; 30(1-2): 273-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14564895&dopt=Abstract

•

The human myometrium as a target for melatonin. Author(s): Schlabritz-Loutsevitch N, Hellner N, Middendorf R, Muller D, Olcese J. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 February; 88(2): 908-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12574232&dopt=Abstract

•

The reliability of melatonin synthesis as an indicator of the individual circadian phase position. Author(s): Griefahn B, Roemer HC, Kuenemund C, Blaszkewicz M, Gerngross H. Source: Military Medicine. 2003 August; 168(8): 674-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12943046&dopt=Abstract

•

The therapeutic potential of melatonin in migraines and other headache types. Author(s): Gagnier JJ. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2001 August; 6(4): 383-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11578254&dopt=Abstract

•

The utility of melatonin in reducing cerebral damage resulting from ischemia and reperfusion. Author(s): Cheung RT. Source: Journal of Pineal Research. 2003 April; 34(3): 153-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614473&dopt=Abstract

•

The validity and feasibility of saliva melatonin assessment in the elderly. Author(s): Gooneratne NS, Metlay JP, Guo W, Pack FM, Kapoor S, Pack AI. Source: Journal of Pineal Research. 2003 March; 34(2): 88-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562499&dopt=Abstract

•

Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. Author(s): Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J, Heinze Martin G. Source: Journal of Psychiatry & Neuroscience : Jpn. 2003 May; 28(3): 191-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12790159&dopt=Abstract

102 Melatonin

•

Urinary 6-sulfatoxymelatonin excretion and aging: new results and a critical review of the literature. Author(s): Kennaway DJ, Lushington K, Dawson D, Lack L, van den Heuvel C, Rogers N. Source: Journal of Pineal Research. 1999 November; 27(4): 210-20. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10551768&dopt=Abstract

•

Use of melatonin in recovery from jet-lag following an eastward flight across 10 timezones. Author(s): Edwards BJ, Atkinson G, Waterhouse J, Reilly T, Godfrey R, Budgett R. Source: Ergonomics. 2000 October; 43(10): 1501-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11083131&dopt=Abstract

•

Use of melatonin in the treatment of phase shift and sleep disorders. Author(s): Skene DJ, Lockley SW, Arendt J. Source: Advances in Experimental Medicine and Biology. 1999; 467: 79-84. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10721041&dopt=Abstract

•

Use of melatonin to treat sleep disorders in tuberous sclerosis. Author(s): O'Callaghan FJ, Clarke AA, Hancock E, Hunt A, Osborne JP. Source: Developmental Medicine and Child Neurology. 1999 February; 41(2): 123-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10075098&dopt=Abstract

•

Use of slow-release melatonin in treatment-resistant depression. Author(s): Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, Brown GM. Source: Journal of Psychiatry & Neuroscience : Jpn. 2000 January; 25(1): 48-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10721684&dopt=Abstract

•

Using melatonin to chase away the monday morning blues. Author(s): Lewy AJ. Source: Sleep. 2001 May 1; 24(3): 271. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11322708&dopt=Abstract

•

Variations in 6-sulphatoxymelatonin excretion and oral temperature under a 12-hour shiftwork environment. Author(s): Vangelova KK, Dalbokova DL. Source: Rev Environ Health. 1998 October-December; 13(4): 221-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9987817&dopt=Abstract

Studies

103

•

Vitamin E consumption induced by oxidative stress in red blood cells is enhanced by melatonin and reduced by N-acetylserotonin. Author(s): Barsacchi R, Kusmic C, Damiani E, Carloni P, Greci L, Donato L. Source: Free Radical Biology & Medicine. 1998 May; 24(7-8): 1187-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9626573&dopt=Abstract

•

Weak vasoconstrictor activity of melatonin in human umbilical artery: relation to nitric oxide-scavenging action. Author(s): Okatani Y, Wakatsuki A, Watanabe K, Taniguchi K, Fukaya T. Source: European Journal of Pharmacology. 2001 April 6; 417(1-2): 125-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11301067&dopt=Abstract

•

What constitutes a physiological concentration of melatonin? Author(s): Reiter RJ, Tan DX. Source: Journal of Pineal Research. 2003 January; 34(1): 79-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12485376&dopt=Abstract

•

What is melatonin? Is it a useful treatment for sleep problems in autism? Author(s): Lord C. Source: Journal of Autism and Developmental Disorders. 1998 August; 28(4): 345-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9711493&dopt=Abstract

105

CHAPTER 2. NUTRITION AND MELATONIN Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and melatonin.

Finding Nutrition Studies on Melatonin The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “melatonin” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

106 Melatonin

The following is a typical result when searching for recently indexed consumer information on melatonin: •

Sleepless in Seattle: Kalamazoo and Tulsa too: does food play a role? Source: Albertson, E. Environmental-nutrition (USA). (June 1997). volume 20(6) page 1, 6.

Additional consumer oriented references include: •

Sleep and supplements: the great melatonin debate. Source: Anonymous Johns-Hopkins-Med-Lett-Health-After-50. 2002 April; 14(2): 3 10421882

The following information is typical of that found when using the “Full IBIDS Database” to search for “melatonin” (or a synonym): •

Age-related changes in 24-hour rhythms of norepinephrine content and serotonin turnover in rat pineal gland: effect of melatonin treatment. Author(s): Departamento de Bioquimica y Biologia Molecular III, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. Source: Pazo, D Cardinali, D P Cano, P Reyes Toso, C A Esquifino, A I Neurosignals. 2002 Mar-April; 11(2): 81-7 1424-862X

•

Behavioral effects of chronic melatonin and pregnenolone injections in a myelin mutant rat (taiep). Author(s): Department of Psychology, Saint Louis University, St Louis, MO 63103, USA. Source: Bloom, C M Anch, A M Dyche, J S J-Gen-Psychol. 2002 July; 129(3): 226-37 00221309

•

Bright light, dark and melatonin can promote circadian adaptation in night shift workers. Author(s): Biological Rhythms Research Laboratory, Rush-Presbyterian-St Luke'sMedical Center, 1645 W. Jackson Blvd, Suite 425, Chicago, IL 60612, USA. Source: Burgess, H J Sharkey, K M Eastman, C I Sleep-Med-Revolume 2002 October; 6(5): 407-20 1087-0792

•

Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Author(s): Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio 78229-3900, USA. Source: Tan, D X Reiter, R J Manchester, L C Yan, M T El Sawi, M Sainz, R M Mayo, J C Kohen, R Allegra, M Hardeland, R Curr-Top-Med-Chem. 2002 February; 2(2): 181-97 1568-0266

•

Circadian rhythm of melatonin in patients with colorectal carcinoma. Author(s): Department of Pathophysiology and Endocrinology, Silesian Medical University, Zabrze, Poland. [email protected] Source: Kos Kudla, B Ostrowska, Z Kozlowski, A Marek, B Ciesielska Kopacz, N Kudla, M Kajdaniuk, D Strzelczyk, J Staszewicz, P Neuroendocrinol-Lett. 2002 June; 23(3): 23942 0172-780X

•

Circadian variations of melatonin concentration in saliva and blood content of immunocompetent cells in healthy individuals. Author(s): Institute of Clinical and Experimental Lymphology, Siberian Division of the Russian Academy of Medical Sciences, Novosibirsk.

Nutrition

107

Source: Litvinenko, G I Shurlygina, A V Malysheva, O A Kudaeva, O T Shirinskii, V S Kozlov, V A Trufakin, V A Bull-Exp-Biol-Med. 2002 May; 133(5): 500-2 0007-4888 •

Comparison of the chemopreventive potentials of melatonin and vitamin E plus selenium on 7,12-dimethylbenz[a]anthracene-induced inhibition of mouse liver antioxidant enzymes. Author(s): Inonu University, Faculty of Education, Department of Chemical Education, 44069 Malatya, Turkey. Source: Batcioglu, K Karagozler, A A Genc, M Celik, S Eur-J-Cancer-Prevolume 2002 February; 11(1): 57-61 0959-8278

•

Control of melatonin synthesis in the mammalian pineal gland: the critical role of serotonin acetylation. Author(s): Section on Neuroendocrinology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4480, USA. Source: Ganguly, S Coon, S L Klein, D C Cell-Tissue-Res. 2002 July; 309(1): 127-37 0302766X

•

Cyclosporine A-induced kidney alterations are limited by melatonin in rats: an electron microscope study. Author(s): Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy. Source: Stacchiotti, A Lavazza, A Rezzani, R Bianchi, R Ultrastruct-Pathol. 2002 MarApril; 26(2): 81-7 0191-3123

•

Cytoprotection by melatonin and growth hormone in early rat myocardial infarction as revealed by Feulgen DNA staining. Author(s): Departamento de Fisiologia, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina. Source: Castagnino, H E Lago, N Centrella, J M Calligaris, S D Farina, S Sarchi, M I Cardinali, D P Neuroendocrinol-Lett. 2002 Oct-December; 23(5-6): 391-5 0172-780X

•

Daily rhythm in serum melatonin and leptin levels in the Syrian hamster (Mesocricetus auratus). Author(s): Department of Biology, Faculty of Arts and Sciences, Abant Izzet Baysal University, Bolu, 14280, Turkey. [email protected] Source: Gunduz, B Comp-Biochem-Physiol-A-Mol-Integr-Physiol. 2002 June; 132(2): 393401 1095-6433

•

Determination of the dose of agomelatine, a melatoninergic agonist and selective 5HT(2C) antagonist, in the treatment of major depressive disorder: a placebocontrolled dose range study. Author(s): Service Hospitalo Universitaire de Sante Mentale et de Therapeutique, Hopital Sainte Anne, Paris, France. [email protected] Source: Loo, H Hale, A D'haenen, H Int-Clin-Psychopharmacol. 2002 September; 17(5): 239-47 0268-1315

•

Developmental pattern of tachykinins during aging in several organs: effect of exogenous melatonin. Author(s): Dpto. Biologia Functional, Area Fisiologia, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain. Source: Fernandez Alvarez, C Debeljuk, L Diaz Rodriguez, E Diaz Lopez, B Peptides. 2002 September; 23(9): 1617-23 0196-9781

108 Melatonin

•

Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells. Author(s): Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978 Israel. Source: Rimler, A Lupowitz, Z Zisapel, N Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 45-9 0172-780X

•

Distribution of melatonin MT1 receptor immunoreactivity in human retina. Author(s): Department of Gerontopsychiatry, Psychiatric University Clinic, University of Basel, Wilhelm Klein-Strasse 27, CH-4025 Basel, Switzerland. [email protected] Source: Savaskan, E Wirz Justice, A Olivieri, G Pache, M Krauchi, K Brydon, L Jockers, R Muller Spahn, F Meyer, P J-Histochem-Cytochem. 2002 April; 50(4): 519-26 0022-1554

•

Does the negative correlation found in breast cancer patients between plasma melatonin and insulin-like growth factor-I concentrations imply the existence of an additional mechanism of oncostatic melatonin influence involved in defense? Author(s): Department of Pathophysiology & Endocrinology, Silesian Medical University, Zabrze, Poland. Source: Kajdaniuk, D Marek, B Kos Kudla, B Zwirska Korczala, K Ostrowska, Z Buntner, B Szymszal, J Med-Sci-Monit. 2002 June; 8(6): CR457-61 1234-1010

•

Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Author(s): Royal Free and University College Medical School, London, UK. [email protected] Source: Serfaty, M Kennell Webb, S Warner, J Blizard, R Raven, P Int-J-GeriatrPsychiatry. 2002 December; 17(12): 1120-7 0885-6230

•

Effect of melatonin administration on qPer2, qPer3, and qClock gene expression in the suprachiasmatic nucleus of Japanese quail. Author(s): Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. Source: Yasuo, S Yoshimura, T Bartell, P A Iigo, M Makino, E Okabayashi, N Ebihara, S Eur-J-Neurosci. 2002 October; 16(8): 1541-6 0953-816X

•

Effect of vehicles on the transdermal delivery of melatonin across porcine skin in vitro. Author(s): College of Pharmacy and Pharmaceutical Sciences, Florida A and M University, Tallahassee, FL 32307, USA. Source: Kikwai, L Kanikkannan, N Babu, R J Singh, M J-Control-Release. 2002 October 4; 83(2): 307-11 0168-3659

•

Effects of electromagnetic radiation (bright light, extremely low-frequency magnetic fields, infrared radiation) on the circadian rhythm of melatonin synthesis, rectal temperature, and heart rate. Author(s): Institute for Occupational Physiology, University of Dortmund, Ardeystr. 67, D-44139 Dortmund, Fed. Rep. Germany. Source: Griefahn, B Kunemund, C Blaszkewicz, M Lerchl, A Degen, G H Ind-Health. 2002 October; 40(4): 320-7 0019-8366

•

Effects of Kampo herbal medicine on plasma melatonin concentration in patients. Author(s): Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, Japan. Source: Watanabe, H Kobayashi, T Tomii, M Sekiguchi, Y Uchida, K Aoki, T Cyong, J C Am-J-Chin-Med. 2002; 30(1): 65-71 0192-415X

Nutrition

109

•

Effects of melatonin and melatonin receptors ligand N-[(4-methoxy-1H-indol-2yl)methyl]propanamide on murine Colon 38 cancer growth in vitro and in vivo. Author(s): Department of Experimental Endocrinology and Hormone Diagnostics, Institute of Endocrinology, Medical University of Lodz, Lodz, Poland. Source: Winczyk, K Pawlikowski, M Lawnicka, H Kunert Radek, J Spadoni, G Tarzia, G Karasek, M Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 50-4 0172-780X

•

Effects of nitric oxide synthase inhibitors and melatonin on the hyperglycemic response to streptozotocin in rats. Author(s): Department of Physiology and Pharmacology, Federal University of Ceara, P.O. Box 3157, Rua Cel. Nunes de Melo 1127, 60430-270 Fortaleza, CE, Brazil. [email protected] Source: Rao, V S Santos, F A Silva, R M Teixiera, M G Vascul-Pharmacol. 2002 March; 38(3): 127-30 1537-1891

•

Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol, dehydroepiandrosterone sulfate, and somatomedin C in elderly women. Author(s): Department of Experimental Endocrinology and Hormone Diagnostics, Institute of Endocrinology, Medical University of Lodz, 91-425 Lodz, Sterling Str.3, Poland. [email protected] Source: Pawlikowski, M Kolomecka, M Wojtczak, A Karasek, M Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 17-9 0172-780X

•

Entrainment of circadian activity rhythms in rats to melatonin administered at T cycles different from 24 hours. Author(s): ULP UMR-CNRS 7518, Neurobiologie des fonctions rythmiques et saisonnieres, Universite Louis Pasteur, Strasbourg, France. Source: Slotten, H A Pitrosky, B Krekling, S Pevet, P Neurosignals. 2002 Mar-April; 11(2): 73-80 1424-862X

•

In the rat, exogenous melatonin increases the amplitude of pineal melatonin secretion by a direct action on the circadian clock. Author(s): Laboratoire de Neurobiologie des Rythmes, UMR 7518 CNRS/Universite Louis Pasteur, Strasbourg, France. [email protected] Source: Bothorel, B Barassin, S Saboureau, M Perreau, S Vivien Roels, B Malan, A Pevet, P Eur-J-Neurosci. 2002 September; 16(6): 1090-8 0953-816X

•

Influence of melatonin on chicken lymphocytes in vitro: involvement of membrane receptors. Author(s): Department of Vertebrate Physiology, University of Warsaw, Poland. [email protected] Source: Markowska, M Mrozkowiak, A Skwarlo Sonta, K Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 67-72 0172-780X

•

Inhibition of 2-nitropropane-induced cellular proliferation, DNA synthesis and histopathological changes by melatonin. Author(s): Department of Zoology, Faculty of Science, Assiut University, Assiut, 71516, Egypt. [email protected] Source: El Sokkary, G H Neuroendocrinol-Lett. 2002 August; 23(4): 335-40 0172-780X

•

Interaction of melatonin with model membranes and possible implications in its photoprotective activity. Author(s): Department of Pharmacology of Natural Substances and General Physiology, University of Rome, La Sapienza, Italy. [email protected]

110 Melatonin

Source: Saija, A Tomaino, A Trombetta, D Pellegrino, M L Tita, B Caruso, S Castelli, F Eur-J-Pharm-Biopharm. 2002 March; 53(2): 209-15 0939-6411 •

Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Author(s): Department of Psychiatry, Oregon Health & Science University, Portland, USA. Source: Lewy, A J Emens, J S Sack, R L Hasler, B P Bernert, R A Chronobiol-Int. 2002 May; 19(3): 649-58 0742-0528

•

Mammalian melatonin receptors: molecular biology and signal transduction. Author(s): Department of Neurobiology, University of Massachusetts Medical School, Worcester, 01605, USA. Source: von Gall, C Stehle, J H Weaver, D R Cell-Tissue-Res. 2002 July; 309(1): 151-62 0302-766X

•

Melatonin and circadian rhythms. Author(s): Department of Obstetrics and Gynaecology, Adelaide University, Medical School, South Australia. Source: Kennaway, D J Wright, H Curr-Top-Med-Chem. 2002 February; 2(2): 199-209 1568-0266

•

Melatonin and zopiclone: the relationship between sleep propensity and body temperature. Author(s): Centre for Sleep Research, University of South Australia, Woodville. [email protected] Source: Holmes, A L Gilbert, S S Dawson, D Sleepage 2002 May 1; 25(3): 301-6 0161-8105

•

Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Author(s): Laboratory of Experimental Neuroendocrinology/Oncology, Bassett Research Institute, Cooperstown, NY 13326, USA. [email protected] Source: Blask, D E Sauer, L A Dauchy, R T Curr-Top-Med-Chem. 2002 February; 2(2): 113-32 1568-0266

•

Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Author(s): Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada. Source: Pringsheim, T Magnoux, E Dobson, C F Hamel, E Aube, M Headache. 2002 September; 42(8): 787-92 0017-8748

•

Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. Author(s): Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California 92357, USA. Source: Koyama, H Nakade, O Takada, Y Kaku, T Lau, K H J-Bone-Miner-Res. 2002 July; 17(7): 1219-29 0884-0431

•

Melatonin attenuates the intensity of beta-endorphin immunoreactivity in the arcuate nucleus of rat hypothalamus. Author(s): State Key Laboratory of Medical Neurobiology, Department of Neurobiology, Shanghai Medical University, Shanghai 200032, China. [email protected] Source: Yu, C X Wu, G C Xu, S F Chen, C H Sheng-Li-Xue-Bao. 2000 June; 52(3): 263-6 0371-0874

Nutrition

111

•

Melatonin in clinical oncology. Author(s): Center for Research in Medical and Natural Sciences (MNF), University of Tubingen, D-72074 Tubingen, Germany. [email protected] Source: Bartsch, C Bartsch, H Karasek, M Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 30-8 0172-780X

•

Melatonin in immunity: comparative aspects. Author(s): Department of Vertebrate Physiology, Warsaw University, Warsaw, Poland. [email protected] Source: Skwarlo Sonta, K Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 61-6 0172-780X

•

Melatonin in the unicellular Tetrahymena pyriformis: effects of different lighting conditions. Author(s): Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary. Source: Kohidai, L Vakkuri, O Keresztesi, M Leppaluoto, J Csaba, G Cell-Biochem-Funct. 2002 September; 20(3): 269-72 0263-6484

•

Melatonin reduces TNF-a induced expression of MAdCAM-1 via inhibition of NFkappaB. Author(s): LSU Health Sciences Center-Shreveport Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport, Louisiana 71130-3932, USA. [email protected] Source: Sasaki, M Jordan, P Joh, T Itoh, M Jenkins, M Pavlick, K Minagar, A Alexander, S J BMC-Gastroenterol. 2002 April 24; 2(1): 9 1471-230X

•

Melatonin, mitochondrial homeostasis and mitochondrial-related diseases. Author(s): Instituto de Biotecnologia, Departamento de Fisiologia, Universidad de Granada, Spain. [email protected] Source: Acuna, C D Escames, G Carazo, A Leon, J Khaldy, H Reiter, R J Curr-Top-MedChem. 2002 February; 2(2): 133-51 1568-0266

•

Melatonin, serotonin, and tryptamine in some egyptian food and medicinal plants. Author(s): Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. [email protected] Source: Badria, F A J-Med-Food. 2002 Fall; 5(3): 153-7 1096-620X

•

Melatonin-immune system relationships. Author(s): Department of Medical Biochemistry and Molecular Biology, The University of Seville School of Medicine and Virgen Macarena Hospital, Spain. [email protected] Source: Guerrero, J M Reiter, R J Curr-Top-Med-Chem. 2002 February; 2(2): 167-79 15680266

•

Modulation of circadian rhythm of discharges of suprachiasmatic nucleus neurons in rat hypothalamic slices by melatonin. Author(s): Laboratory of Neurobiology, Suzhou Medical College, Suzhou 215007, China. [email protected] Source: Zhou, X J Jiang, X H Yu, G D Yin, Q Z Sheng-Li-Xue-Bao. 2000 June; 52(3): 215-9 0371-0874

•

Neuroimmunotherapy of untreatable metastatic solid tumors with subcutaneous lowdose interleukin-2, melatonin and naltrexone: modulation of interleukin-2-induced antitumor immunity by blocking the opioid system. Author(s): Division of Radiation Oncology, S. Gerardo Hospital, 20052 Monza (Milan), Italy. Source: Lissoni, P Malugani, F Malysheva, O Kozlov, V Laudon, M Conti, A Maestroni, G Neuroendocrinol-Lett. 2002 August; 23(4): 341-4 0172-780X

112 Melatonin

•

Nimesulide and melatonin in mammary carcinogenesis prevention in female Sprague-Dawley rats. Author(s): Institute of Animal Physiology, P. J. Safarik University, 041 67 Kosice, Slovak Republic. Source: Kubatka, P Kalicka, K Chamilova, M Ahlersova, E Ahlers, I Bojkova, B Adamekova, E Neoplasma. 2002; 49(4): 255-9 0028-2685

•

Organisation of the circadian system in melatonin-proficient C3H and melatonindeficient C57BL mice: a comparative investigation. Author(s): Dr. Senckenbergische Anatomie, Institute of Anatomy II, Johann Wolfgang Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. [email protected] Source: Stehle, J H von Gall, C Korf, H W Cell-Tissue-Res. 2002 July; 309(1): 173-82 0302766X

•

Pharmacological actions of melatonin in acute and chronic inflammation. Author(s): Institute of Pharmacology, School of Medicine, University of Messina, Gazzi, Italy. [email protected] Source: Cuzzocrea, S Reiter, R J Curr-Top-Med-Chem. 2002 February; 2(2): 153-65 15680266

•

Possible involvement of the nuclear RZR/ROR-alpha receptor in the antitumor action of melatonin on murine Colon 38 cancer. Author(s): Department of Experimental Endocrinology and Hormone Diagnostics, Institute of Endocrinology, Medical University of Lodz, Lodz, Poland. Source: Winczyk, K Pawlikowski, M Guerrero, J M Karasek, M Tumour-Biol. 2002 SepOctober; 23(5): 298-302 1010-4283

•

Potential anticarcinogenic action of melatonin and other antioxidants mediated by antioxidative mechanisms. Author(s): Department of Thyroidology, Institute of Endocrinology Medical University of Lodz, Poland. [email protected] Source: Karbownik, M Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 39-44 0172-780X

•

Potential protective effect of melatonin against dibromoacetonitrile-induced oxidative stress in mouse stomach. Author(s): Department of Pharmacology and Toxicology, Faculty of Pharmacy, AlAzhar University, Nasr City, Cairo, Egypt. [email protected] Source: Abdel Wahab, M H Arafa, H M El Mahdy, M A Abdel Naim, A B PharmacolRes. 2002 September; 46(3): 287-93 1043-6618

•

Protective role of melatonin and a combination of vitamin C and vitamin E on lung toxicity induced by chlorpyrifos-ethyl in rats. Author(s): Suleyman Demirel University, Faculty of Medicine, Department of Histology, Isparta, Turkey. Source: Karaoz, E Gultekin, F Akdogan, M Oncu, M Gokcimen, A Exp-Toxicol-Pathol. 2002 August; 54(2): 97-108 0940-2993

•

Sleep logs of young adults with self-selected sleep times predict the dim light melatonin onset. Author(s): Biological Rhythms Research Laboratory, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. Source: Martin, S K Eastman, C I Chronobiol-Int. 2002 July; 19(4): 695-707 0742-0528

Nutrition

113

•

Stimulatory effects of LH on release of melatonin and activities of its synthesizing enzymes NAT and HIOMT in organ-cultured pineal glands of female rats. Author(s): Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan. Source: Hosaka, T Mimuro, T Hamada, N Itoh, M T Ishizuka, B Horm-Metab-Res. 2002 August; 34(8): 441-5 0018-5043

•

Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Author(s): Department of Pharmacology, National Research Centre, Tahrir St, Dokki, Cairo, Egypt. Source: El Shenawy, S M Abdel Salam, O M Baiuomy, A R El Batran, S Arbid, M S Pharmacol-Res. 2002 September; 46(3): 235-43 1043-6618

•

Suprachiasmatic control of melatonin synthesis in rats: inhibitory and stimulatory mechanisms. Author(s): Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, Netherlands. [email protected] Source: Perreau Lenz, S Kalsbeek, A Garidou, M L Wortel, J van der Vliet, J van Heijningen, C Simonneaux, V Pevet, P Buijs, R M Eur-J-Neurosci. 2003 January; 17(2): 221-8 0953-816X

•

Termination of neuroendocrine refractoriness to melatonin in Siberian hamsters (Phodopus sungorus). Author(s): Department of Integrative Biology, University of California at Berkeley, Berkeley, CA, USA. [email protected] Source: Kauffman, A S Freeman, D A Zucker, I J-Neuroendocrinol. 2003 February; 15(2): 191-6 0953-8194

•

The chronobiotic properties of melatonin. Author(s): Laboratoire de Neurobiologie des Rythmes, UMR 7518, CNRS, Universite L. Pasteur, 12 rue de l'Universite, 67000 Strasbourg, France. [email protected] Source: Pevet, P Bothorel, B Slotten, H Saboureau, M Cell-Tissue-Res. 2002 July; 309(1): 183-91 0302-766X

•

The effect of melatonin on peripheral blood cells during total body irradiation in rats. Author(s): Department of Radiation Oncology, Medical School of Ataturk University, Erzurum, Turkey. [email protected] Source: Koc, M Buyukokuroglu, M E Taysi, S Biol-Pharm-Bull. 2002 May; 25(5): 656-7 0918-6158

•

The effect of pyridoxine administration on melatonin secretion in normal men. Author(s): Endocrine Institute, Haemek Medical Center, Afula, Israel. luboshitzky_ r@ clalit.org.il Source: Luboshitzky, R Ophir, U Nave, R Epstein, R Shen Orr, Z Herer, P Neuroendocrinol-Lett. 2002 June; 23(3): 213-7 0172-780X

•

The effects of treatment with melatonin on the ultrastructure of mouse Leydig cells: a quantitative study. Author(s): Departamento de Morfologia, Centro Biomedico, Universidade Federal do Espirito Santo, CEP 29040-090, Vitoria, ES, Brazil. [email protected] Source: Redins, C A Redins, G M Novaes, J C Braz-J-Biol. 2002 August; 62(3): 517-23 1519-6984

114 Melatonin

•

The induction of low nocturnal secretion of melatonin caused by reverse feeding rhythms depends on availability of macronutrient diets. Author(s): Laboratoire de chronobiologie, Hopital du Sacre-Coeur de Montreal, 5400 Boulevard Gouin Ouest, Montreal, Que., Canada H4J 1C5. Source: Selmaoui, B Thibault, L Nutr-Neurosci. 2002 December; 5(6): 417-26 1028-415X

•

The lack of vasoconstrictor effect of the pineal hormone melatonin in an animal model predictive of antimigraine activity. Author(s): Department of Pharmacology, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands. Source: Tom, B De Vries, P Heiligers, J P Willems, E W Scalbert, E Delagrange, P Saxena, P R Cephalalgia. 2001 July; 21(6): 656-63 0333-1024

•

The mt1 melatonin receptor and RORbeta receptor are co-localized in specific TSHimmunoreactive cells in the pars tuberalis of the rat pituitary. Author(s): Neurobiologie des Rythmes, CNRS-UMR 7518, IFR 37, Universite Louis Pasteur, Strasbourg, France. [email protected] Source: Klosen, P Bienvenu, C Demarteau, O Dardente, H Guerrero, H Pevet, P Masson Pevet, M J-Histochem-Cytochem. 2002 December; 50(12): 1647-57 0022-1554

•

The protective effects of melatonin, vitamin E and octreotide on retinal edema during ischemia-reperfusion in the guinea pig retina. Author(s): Department of Ophthalmology, School of Medicine, Firat University, Elazig, Turkey. [email protected] Source: Yilmaz, T Celebi, S Kukner, A S Eur-J-Ophthalmol. 2002 Nov-December; 12(6): 443-9 1120-6721

•

The relationship between the daily profile of chosen biochemical markers of bone metabolism and melatonin and other hormone secretion in rats under physiological conditions. Author(s): Department of Clinical Biochemistry, Silesian Medical Academy, Pl. Traugutta 2, 41-800 Zabrze, Poland. [email protected] Source: Ostrowska, Z Kos Kudla, B Marek, B Kajdaniuk, D Ciesielska Kopacz, N Neuroendocrinol-Lett. 2002 Oct-December; 23(5-6): 417-25 0172-780X

•

The role of neurofibromin and melatonin in pathogenesis of pseudarthrosis after spinal fusion for neurofibromatous scoliosis. Author(s): Department of Orthopaedic Surgery, Faculty of Medicine, Kanazawa University, Japan. [email protected] Source: Abdel Wanis, M E Kawahara, N Med-Hypotheses. 2002 May; 58(5): 395-8 03069877

•

The use of melatonin in Alzheimer's disease. Author(s): Departament of Physiology, Faculty of Medicine, University of Buenos Aires, Argentina. [email protected] Source: Cardinali, D P Brusco, L I Liberczuk, C Furio, A M Neuroendocrinol-Lett. 2002 April; 23 Suppl 1: 20-3 0172-780X

•

The validity of the temporal parameters of the daily rhythm of melatonin levels as an indicator of morningness. Author(s): Institute for Occupational Physiology, University of Dortmund, Germany. [email protected] Source: Griefahn, B Chronobiol-Int. 2002 May; 19(3): 561-77 0742-0528

Nutrition

115

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

•

The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

•

The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

•

The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

•

The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

•

Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

•

Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

•

Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

•

Google: http://directory.google.com/Top/Health/Nutrition/

•

Healthnotes: http://www.healthnotes.com/

•

Open Directory Project: http://dmoz.org/Health/Nutrition/

•

Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

•

WebMDHealth: http://my.webmd.com/nutrition

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

116 Melatonin

The following is a specific Web list relating to melatonin; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Vitamins Vitamin B6 Source: Healthnotes, Inc.; www.healthnotes.com

•

Minerals Cisplatin Source: Healthnotes, Inc.; www.healthnotes.com Fluoxetine Source: Healthnotes, Inc.; www.healthnotes.com

117

CHAPTER 3. ALTERNATIVE MEDICINE AND MELATONIN Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to melatonin. At the conclusion of this chapter, we will provide additional sources.

The Combined Health Information Database The Combined Health Information Database (CHID) is a bibliographic database produced by health-related agencies of the U.S. federal government (mostly from the National Institutes of Health) that can offer concise information for a targeted search. The CHID database is updated four times a year at the end of January, April, July, and October. Check the titles, summaries, and availability of CAM-related information by using the “Simple Search” option at the following Web site: http://chid.nih.gov/simple/simple.html. In the drop box at the top, select “Complementary and Alternative Medicine.” Then type “melatonin” (or synonyms) in the second search box. We recommend that you select 100 “documents per page” and to check the “whole records” options. The following was extracted using this technique: •

Alternative Medicines Gain in Popularity, Merit Closer Scrutiny Source: Journal of the National Cancer Institute. 91(13): 1104-1105. July 7, 1999. Summary: This journal article discusses current research into complementary and alternative medicine (CAM) therapies for cancer. The National Center for Complementary and Alternative Medicine (NCCAM), established as the Office of Alternative Medicine in 1991, gained its status as a center in the fall of 1998. NCCAM supports 13 clinical research centers to examine the efficacy, safety, and validity of CAM therapies, and to support basic, preclinical, clinical, and epidemiological studies of these therapies. The National Cancer Institute (NCI) recently formed the Office of Cancer Complementary and Alternative Medicine, which works directly with NCCAM. The NCI office will help support studies of interest to cancer research. The University of Texas Center for Alternative Medicine Research (UT-CAM) is the NCCAM-supported center specializing in alternative therapies and prevention for cancer. UT-CAM is studying such therapies as melatonin, mistletoe, the herbal extract Flor-Essence, and

118 Melatonin

714-X. Other natural therapies being studied include green tea, ginseng, oleander, Chinese herbal medicines, and dietary approaches.

National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to melatonin and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “melatonin” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to melatonin: •

“Macbeth does murder sleep”. The mysterious mythic melatonin morass. Author(s): Mack RB. Source: N C Med J. 1996 May-June; 57(3): 162-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8935364&dopt=Abstract

•

A comparative study of the effects of cholesterol, beta-sitosterol, beta-sitosterol glucoside, dehydroepiandrosterone sulphate and melatonin on in vitro lipid peroxidation. Author(s): van Rensburg SJ, Daniels WM, van Zyl JM, Taljaard JJ. Source: Metabolic Brain Disease. 2000 December; 15(4): 257-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11383550&dopt=Abstract

•

A counter antigonadotrophic effect of melatonin in male rats. Author(s): Reiter RJ, Blask DE, Vaughan MK. Source: Neuroendocrinology. 1975; 19(1): 72-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1207873&dopt=Abstract

•

A novel interaction between inhibitory melatonin receptors and protein kinase Cdependent signal transduction in ovine pars tuberalis cells. Author(s): Ross AW, Webster CA, Thompson M, Barrett P, Morgan PJ. Source: Endocrinology. 1998 April; 139(4): 1723-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9528955&dopt=Abstract

•

A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies. Author(s): Lissoni P, Bolis S, Brivio F, Fumagalli L. Source: Anticancer Res. 2000 May-June; 20(3B): 2103-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10928160&dopt=Abstract

•

A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin

Alternative Medicine 119

as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. Author(s): Lissoni P, Paolorossi F, Ardizzoia A, Barni S, Chilelli M, Mancuso M, Tancini G, Conti A, Maestroni GJ. Source: Journal of Pineal Research. 1997 August; 23(1): 15-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9379341&dopt=Abstract •

A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer. Author(s): Lissoni P, Meregalli S, Fossati V, Paolorossi F, Barni S, Tancini G, Frigerio F. Source: Tumori. 1994 December 31; 80(6): 464-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7900237&dopt=Abstract

•

A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Author(s): Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM. Source: Psychosomatic Medicine. 2001 January-February; 63(1): 40-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11211063&dopt=Abstract

•

A wake-up call for caution. If insomnia is the patient's problem, is over-the-counter melatonin the cure? Author(s): Butler RN. Source: Geriatrics. 1996 February; 51(2): 14, 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8631528&dopt=Abstract

•

Acute increases in night-time plasma melatonin levels following a period of meditation. Author(s): Tooley GA, Armstrong SM, Norman TR, Sali A. Source: Biological Psychology. 2000 May; 53(1): 69-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10876066&dopt=Abstract

•

Acutely administered melatonin reduces oxidative damage in lung and brain induced by hyperbaric oxygen. Author(s): Pablos MI, Reiter RJ, Chuang JI, Ortiz GG, Guerrero JM, Sewerynek E, Agapito MT, Melchiorri D, Lawrence R, Deneke SM. Source: Journal of Applied Physiology (Bethesda, Md. : 1985). 1997 August; 83(2): 354-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9262426&dopt=Abstract

•

Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma. Author(s): Lissoni P, Brivio O, Brivio F, Barni S, Tancini G, Crippa D, Meregalli S.

120 Melatonin

Source: Journal of Pineal Research. 1996 November; 21(4): 239-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8989723&dopt=Abstract •

Aging-dependent changes in the effect of daily melatonin supplementation on rat metabolic and behavioral responses. Author(s): Rasmussen DD, Mitton DR, Larsen SA, Yellon SM. Source: Journal of Pineal Research. 2001 August; 31(1): 89-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11485011&dopt=Abstract

•

Alteration of orphanin FQ immunoreactivity and ppOFQ mRNA by combination of melatonin with electroacupuncture. Author(s): Zhou MM, Yu CX, Wang MZ, Cao XD, Wu GC. Source: Acupuncture & Electro-Therapeutics Research. 2001; 26(1-2): 49-58. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11394493&dopt=Abstract

•

Antigonadal actions of olfactory and light deprivation. II. Effects of pinealectomy or melatonin injections in olfactory bulb deafferented or bulbectomized male rats. Author(s): Mediavilla MD, Sanchez-Barcelo EJ, Sanchez-Criado JE, Cos S, Cortines MD. Source: Journal of Pineal Research. 1985; 2(2): 191-200. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3831307&dopt=Abstract

•

Antioxidant activity of melatonin in Chinese hamster ovarian cells: changes in cellular proliferation and differentiation. Author(s): Sainz RM, Mayo JC, Tan DX, Lopez-Burillo S, Natarajan M, Reiter RJ. Source: Biochemical and Biophysical Research Communications. 2003 March 14; 302(3): 625-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615081&dopt=Abstract

•

Are there hangover-effects on physical performance when melatonin is ingested by athletes before nocturnal sleep? Author(s): Atkinson G, Buckley P, Edwards B, Reilly T, Waterhouse J. Source: International Journal of Sports Medicine. 2001 April; 22(3): 232-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11354528&dopt=Abstract

•

Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5fluorouracil-containing combinations. Author(s): Cerea G, Vaghi M, Ardizzoia A, Villa S, Bucovec R, Mengo S, Gardani G, Tancini G, Lissoni P. Source: Anticancer Res. 2003 March-April; 23(2C): 1951-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820485&dopt=Abstract

Alternative Medicine 121

•

Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus aloe vera in untreatable advanced solid neoplasms. Author(s): Lissoni P, Giani L, Zerbini S, Trabattoni P, Rovelli F. Source: Natural Immunity. 1998; 16(1): 27-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9789122&dopt=Abstract

•

Calcium ion dependency and the role of inositol phosphates in melatonin-induced encystment of dinoflagellates. Author(s): Tsim ST, Wong JT, Wong YH. Source: Journal of Cell Science. 1997 June; 110 ( Pt 12): 1387-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9217324&dopt=Abstract

•

Case study of circadian rhythm sleep disorder following haloperidol treatment: reversal by risperidone and melatonin. Author(s): Ayalon L, Hermesh H, Dagan Y. Source: Chronobiology International. 2002 September; 19(5): 947-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12405556&dopt=Abstract

•

Central nervous system depressant activities of melatonin in rats and mice. Author(s): Shaji AV, Kulkarni SK. Source: Indian J Exp Biol. 1998 March; 36(3): 257-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9754058&dopt=Abstract

•

Chronome of urinary 6-sulfoxy-melatonin excretion, circulating CA125, cancer progression and therapeutic response. Author(s): Cornelissen G, Berg H, Haus E, Halberg F. Source: In Vivo. 1995 July-August; 9(4): 375-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8555437&dopt=Abstract

•

Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4. Author(s): Maestroni GJ, Conti A, Lissoni P. Source: Cancer Research. 1994 September 1; 54(17): 4740-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7914829&dopt=Abstract

•

Comparison of melatonin products against USP's nutritional supplements standards and other criteria. Author(s): Hahm H, Kujawa J, Augsburger L. Source: Journal of the American Pharmaceutical Association (Washington,D.C. : 1996). 1999 January-February; 39(1): 27-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9990184&dopt=Abstract

122 Melatonin

•

Comparison of the antioxidant activity of melatonin and pinoline in vitro. Author(s): Pahkla R, Zilmer M, Kullisaar T, Rago L. Source: Journal of Pineal Research. 1998 March; 24(2): 96-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9510434&dopt=Abstract

•

Contribution of CYP1A2 in the hepatic metabolism of melatonin: studies with isolated microsomal preparations and liver slices. Author(s): Skene DJ, Papagiannidou E, Hashemi E, Snelling J, Lewis DF, Fernandez M, Ioannides C. Source: Journal of Pineal Research. 2001 November; 31(4): 333-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11703563&dopt=Abstract

•

Daily melatonin supplementation in mice increases atherosclerosis in proximal aorta. Author(s): Tailleux A, Torpier G, Bonnefont-Rousselot D, Lestavel S, Lemdani M, Caudeville B, Furman C, Foricher R, Gardes-Albert M, Lesieur D, Rolando C, Teissier E, Fruchart JC, Clavey V, Fievet C, Duriez P. Source: Biochemical and Biophysical Research Communications. 2002 May 10; 293(3): 1114-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12051775&dopt=Abstract

•

Daily profiles of plasma prolactin (PRL), growth hormone (GH), insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), testosterone, and melatonin, and of pituitary PRL mRNA and GH mRNA in male long evans rats in acute phase of adjuvant arthritis. Author(s): Roman O, Seres J, Herichova I, Zeman M, Jurcovicova J. Source: Chronobiology International. 2003 September; 20(5): 823-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14535356&dopt=Abstract

•

Deleterious effects of Echinacea purpurea and melatonin on myeloid cells in mouse spleen and bone marrow. Author(s): Currier NL, Sicotte M, Miller SC. Source: Journal of Leukocyte Biology. 2001 August; 70(2): 274-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11493619&dopt=Abstract

•

Determination of melatonin and monoamines in rat pineal using reversed-phase ioninteraction chromatography with fluorescence detection. Author(s): Mills MH, Finlay DC, Haddad PR. Source: Journal of Chromatography. 1991 March 8; 564(1): 93-102. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1907292&dopt=Abstract

•

Determination of melatonin in biological samples by capillary electrophoresis. Author(s): Kim YO, Chung HJ, Chung ST, Kim JH, Park JH, Han SY, Kil KS, Cho DH.

Alternative Medicine 123

Source: J Chromatogr A. 1999 July 30; 850(1-2): 369-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10457499&dopt=Abstract •

Dietary docosahexaenoic acid-enriched phospholipids normalize urinary melatonin excretion in adult (n-3) polyunsaturated fatty acid-deficient rats. Author(s): Zaouali-Ajina M, Gharib A, Durand G, Gazzah N, Claustrat B, Gharib C, Sarda N. Source: The Journal of Nutrition. 1999 November; 129(11): 2074-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10539787&dopt=Abstract

•

DNA oxidatively damaged by chromium(III) and H(2)O(2) is protected by the antioxidants melatonin, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, resveratrol and uric acid. Author(s): Burkhardt S, Reiter RJ, Tan DX, Hardeland R, Cabrera J, Karbownik M. Source: The International Journal of Biochemistry & Cell Biology. 2001 August; 33(8): 775-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11404181&dopt=Abstract

•

Docosahexaenoic acid reduces both cyclic nucleotide and melatonin synthesis in rat pinealocytes. Author(s): Monia ZA, Abdallah G, Claude G, Sarda N. Source: Prostaglandins & Other Lipid Mediators. 1998 April; 55(5-6): 291-300. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9653768&dopt=Abstract

•

Dose-dependent stimulation of melatonin secretion after administration of Agnus castus. Author(s): Dericks-Tan JS, Schwinn P, Hildt C. Source: Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association. 2003 February; 111(1): 446. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12605350&dopt=Abstract

•

Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer. Author(s): Ghielmini M, Pagani O, de Jong J, Pampallona S, Conti A, Maestroni G, Sessa C, Cavalli F. Source: British Journal of Cancer. 1999 June; 80(7): 1058-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10362116&dopt=Abstract

•

Echinacea purpurea and melatonin augment natural-killer cells in leukemic mice and prolong life span. Author(s): Currier NL, Miller SC.

124 Melatonin

Source: Journal of Alternative and Complementary Medicine (New York, N.Y.). 2001 June; 7(3): 241-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11439845&dopt=Abstract •

Effect of an n-3 fatty acid-deficient diet on the adenosine-dependent melatonin release in cultured rat pineal. Author(s): Gazzah N, Gharib A, Delton I, Moliere P, Durand G, Christon R, Lagarde M, Sarda N. Source: Journal of Neurochemistry. 1993 September; 61(3): 1057-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8360673&dopt=Abstract

•

Effect of cyclic changes in environmental lighting and ambient temperature on the daily rhythm in melatonin excretion by rats. Author(s): Adler J, Lynch HJ, Wurtman RJ. Source: Brain Research. 1979 March 9; 163(1): 111-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=427536&dopt=Abstract

•

Effect of melatonin and electroacupuncture (EA) on NK cell activity, interleukin-2 production and POMC-derived peptides in traumatic rats. Author(s): Huang YS, Jiang JW, Wu GC, Cao XD. Source: Acupuncture & Electro-Therapeutics Research. 2002; 27(2): 95-105. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12269723&dopt=Abstract

•

Effect of melatonin and linolenic acid on mammary cancer in transgenic mice with cneu breast cancer oncogene. Author(s): Rao GN, Ney E, Herbert RA. Source: Breast Cancer Research and Treatment. 2000 December; 64(3): 287-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11200779&dopt=Abstract

•

Effect of melatonin on 24h changes in plasma protein levels during the preclinical phase of Freund's adjuvant arthritis in rats. Author(s): Agrasal C, Esquifino AI, Garcia-Bonacho M, Reyes-Toso CF, Cardinali DP. Source: Chronobiology International. 2001 May; 18(3): 435-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11475414&dopt=Abstract

•

Effect of melatonin on the human electrocardiogram and simple reaction time responses. Author(s): Wynn VT, Arendt J. Source: Journal of Pineal Research. 1988; 5(5): 427-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3171889&dopt=Abstract

Alternative Medicine 125

•

Effect of melatonin supplementation on the ontogeny of immunity in the Large White turkey poult. Author(s): Moore CB, Siopes TD. Source: Poultry Science. 2002 December; 81(12): 1898-903. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12512584&dopt=Abstract

•

Effect of melatonin supplementation on the sexual development in European quail (Coturnix coturnix). Author(s): Guyomarc'h C, Lumineau S, Vivien-Roels B, Richard J, Deregnaucourt S. Source: Behavioural Processes. 2001 March 13; 53(1-2): 121-130. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11254999&dopt=Abstract

•

Effect of melatonin treatment on 24-hour rhythms of serum ACTH, growth hormone, prolactin, luteinizing hormone and insulin in rats injected with Freund's adjuvant. Author(s): Esquifino AI, Castrillon P, Garcia-Bonacho M, Vara E, Cardinali DP. Source: Journal of Pineal Research. 1999 August; 27(1): 15-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10451020&dopt=Abstract

•

Effect of serotonin and melatonin on the electrophysiological behaviour of the plasma membrane. Author(s): Nikitopoulou-Maratou G, Georgatou E, Molyvdas PA. Source: Advances in Experimental Medicine and Biology. 1981; 133: 299-318. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6797271&dopt=Abstract

•

Effects and mechanisms of melatonin on inflammatory and immune responses of adjuvant arthritis rat. Author(s): Chen Q, Wei W. Source: International Immunopharmacology. 2002 September; 2(10): 1443-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12400874&dopt=Abstract

•

Effects of certain micronutrients and melatonin on plasma lipid, lipid peroxidation, and homocysteine levels in rats. Author(s): Baydas G, Yilmaz O, Celik S, Yasar A, Gursu MF. Source: Archives of Medical Research. 2002 November-December; 33(6): 515-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12505094&dopt=Abstract

•

Effects of dimethylthiourea, melatonin, and hyperbaric oxygen therapy on the survival of reimplanted rabbit auricular composite grafts. Author(s): Lim AA, Wall MP, Greinwald JH Jr. Source: Otolaryngology and Head and Neck Surgery. 1999 September; 121(3): 231-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10471863&dopt=Abstract

126 Melatonin

•

Effects of Kampo herbal medicine on plasma melatonin concentration in patients. Author(s): Watanabe H, Kobayashi T, Tomii M, Sekiguchi Y, Uchida K, Aoki T, Cyong JC. Source: The American Journal of Chinese Medicine. 2002; 30(1): 65-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12067098&dopt=Abstract

•

Effects of lighting conditions and melatonin supplementation on the cellular and humoral immune responses in Japanese quail Coturnix coturnix japonica. Author(s): Moore CB, Siopes TD. Source: General and Comparative Endocrinology. 2000 July; 119(1): 95-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10882554&dopt=Abstract

•

Effects of melatonin on 24-h rhythms of neuroendocrine and immune changes in Freund's adjuvant-induced arthritis. Author(s): Esquifino AI, Cardinali DP. Source: Neuroendocrinol Lett. 1999; 20(3-4): 163-166. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11462109&dopt=Abstract

•

Effects of melatonin on lipid peroxidation induced by oxygen radicals. Author(s): Longoni B, Salgo MG, Pryor WA, Marchiafava PL. Source: Life Sciences. 1998; 62(10): 853-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9496707&dopt=Abstract

•

Effects of melatonin on startle reflex in rat. Author(s): Datta PC, Hoehler FK, Sandman CA. Source: Peptides. 1981; 2 Suppl 1: 155-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7267402&dopt=Abstract

•

Effects of tamoxifen, melatonin, coenzyme Q10, and L-carnitine supplementation on bacterial growth in the presence of mycotoxins. Author(s): Atroshi F, Rizzo A, Westermarck T, Ali-vehmas T. Source: Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 1998 October; 38(4): 289-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9774492&dopt=Abstract

•

Evaluating the role of melatonin in the long-term treatment of delayed sleep phase syndrome (DSPS). Author(s): Dagan Y, Yovel I, Hallis D, Eisenstein M, Raichik I. Source: Chronobiology International. 1998 March; 15(2): 181-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9562922&dopt=Abstract

•

Evaluation of the antioxidant activity of melatonin in vitro. Author(s): Marshall KA, Reiter RJ, Poeggeler B, Aruoma OI, Halliwell B.

Alternative Medicine 127

Source: Free Radical Biology & Medicine. 1996; 21(3): 307-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8855441&dopt=Abstract •

Exogenous melatonin: quantitative enhancement in vivo of cells mediating nonspecific immunity. Author(s): Currier NL, Sun LZ, Miller SC. Source: Journal of Neuroimmunology. 2000 May 1; 104(2): 101-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10713348&dopt=Abstract

•

Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin. Author(s): Bonilla E, Medina-Leendertz S, Diaz S. Source: Experimental Gerontology. 2002 May; 37(5): 629-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11909680&dopt=Abstract

•

Factors that influence radioimmunoassay of human plasma melatonin: a modified column procedure to eliminate interference. Author(s): Lahiri DK, Davis D, Adkins M, Nurnberger JI Jr. Source: Biochemical Medicine and Metabolic Biology. 1993 February; 49(1): 36-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8439449&dopt=Abstract

•

Forskolin and camptothecin induce a 30 kDa protein associated with melatonin production in Y79 human retinoblastoma cells. Author(s): Janavs JL, Florez JC, Pierce ME, Takahashi JS. Source: The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 1995 January; 15(1 Pt 1): 298-309. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7823135&dopt=Abstract

•

Free-running of plasma melatonin rhythm prior to full manifestation of a non-24 hour sleep-wake syndrome. Author(s): Hashimoto S, Nakamura K, Honma S, Honma K. Source: Psychiatry and Clinical Neurosciences. 1998 April; 52(2): 264-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9628187&dopt=Abstract

•

Gene and protein expression profiles of anti- and pro-apoptotic actions of dopamine, R-apomorphine, green tea polyphenol (-)-epigallocatechine-3-gallate, and melatonin. Author(s): Weinreb O, Mandel S, Youdim MB. Source: Annals of the New York Academy of Sciences. 2003 May; 993: 351-61; Discussion 387-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12853328&dopt=Abstract

•

Growth Factors: Thrombopoietic Property of the Pineal Hormone Melatonin. Author(s): Lissoni P, Mandala M, Rossini F, Fumagalli L, Barni S.

128 Melatonin

Source: Hematology (Amsterdam, Netherlands). 1999; 4(4): 335-343. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11399574&dopt=Abstract •

Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumorbearing mice. Author(s): Maestroni GJ, Covacci V, Conti A. Source: Cancer Research. 1994 May 1; 54(9): 2429-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8162592&dopt=Abstract

•

Influence of adjuvant chemotherapy with cyclophosphamide, methotrexate and 5fluorouracil on plasma melatonin and chosen hormones in breast cancer premenopausal patients. Author(s): Kajdaniuk D, Marek B, Kos-Kudla B. Source: Journal of Clinical Pharmacy and Therapeutics. 2001 August; 26(4): 297-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11493373&dopt=Abstract

•

Influence of low-frequency magnetic field of different characteristics on serum melatonin concentrations in humans. Author(s): Karasek M, Woldanska-Okonska M, Czernicki J, Zylinska K, Swietoslawski J. Source: Advances in Experimental Medicine and Biology. 1999; 460: 459-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10810547&dopt=Abstract

•

Inhibition of androgen-sensitive LNCaP prostate cancer growth in vivo by melatonin: association of antiproliferative action of the pineal hormone with mt1 receptor protein expression. Author(s): Xi SC, Siu SW, Fong SW, Shiu SY. Source: The Prostate. 2001 January 1; 46(1): 52-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11170132&dopt=Abstract

•

Involvement of cytochrome P-450 isozymes in melatonin metabolism and clinical implications. Author(s): Yeleswaram K, Vachharajani N, Santone K. Source: Journal of Pineal Research. 1999 April; 26(3): 190-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10231734&dopt=Abstract

•

Ischemia/reperfusion-induced arrhythmias in the isolated rat heart: prevention by melatonin. Author(s): Tan DX, Manchester LC, Reiter RJ, Qi W, Kim SJ, El-Sokkary GH. Source: Journal of Pineal Research. 1998 October; 25(3): 184-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9745988&dopt=Abstract

Alternative Medicine 129

•

Long-term melatonin administration increases polyunsaturated fatty acid percentage in plasma lipids of hypercholesterolemic rats. Author(s): Pita ML, Hoyos M, Martin-Lacave I, Osuna C, Fernandez-Santos JM, Guerrero JM. Source: Journal of Pineal Research. 2002 April; 32(3): 179-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12074102&dopt=Abstract

•

Long-term melatonin supplementation does not recover the impairment of natural killer cell activity and lymphocyte proliferation in aging mice. Author(s): Provinciali M, Di Stefano G, Bulian D, Stronati S, Fabris N. Source: Life Sciences. 1997; 61(9): 857-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9284078&dopt=Abstract

•

Long-term supplementation with melatonin delays reproductive senescence in rats, without an effect on number of primordial follicles. Author(s): Meredith S, Jackson K, Dudenhoeffer G, Graham L, Epple J. Source: Experimental Gerontology. 2000 May; 35(3): 343-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10832055&dopt=Abstract

•

Magnetic fields (MF) of 50 Hz at 1.2 microT as well as 100 microT cause uncoupling of inhibitory pathways of adenylyl cyclase mediated by melatonin 1a receptor in MFsensitive MCF-7 cells. Author(s): Ishido M, Nitta H, Kabuto M. Source: Carcinogenesis. 2001 July; 22(7): 1043-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11408347&dopt=Abstract

•

Meditation, melatonin and breast/prostate cancer: hypothesis and preliminary data. Author(s): Massion AO, Teas J, Hebert JR, Wertheimer MD, Kabat-Zinn J. Source: Medical Hypotheses. 1995 January; 44(1): 39-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7776900&dopt=Abstract

•

Melatonin administration affects plasma total sialic acid and lipid peroxidation levels in streptozotocin induced diabetic rats. Author(s): Gorgun FM, Ozturk Z, Gumustas MK, Kokogu E. Source: Journal of Toxicology and Environmental Health. Part A. 2002 May 24; 65(10): 695-700. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12028824&dopt=Abstract

•

Melatonin and deprivation myopia in chickens. Author(s): Hoffmann M, Schaeffel F. Source: Neurochemistry International. 1996 January; 28(1): 95-107. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8746769&dopt=Abstract

130 Melatonin

•

Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Author(s): Blask DE, Sauer LA, Dauchy RT. Source: Current Topics in Medicinal Chemistry. 2002 February; 2(2): 113-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11899096&dopt=Abstract

•

Melatonin as biological response modifier in cancer patients. Author(s): Neri B, de Leonardis V, Gemelli MT, di Loro F, Mottola A, Ponchietti R, Raugei A, Cini G. Source: Anticancer Res. 1998 March-April; 18(2B): 1329-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9615811&dopt=Abstract

•

Melatonin for insomnia and jet lag. Author(s): Turow V. Source: Pediatrics. 1996 March; 97(3): 439. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8604288&dopt=Abstract

•

Melatonin for the masses. Antiaging entrepreneurs peddle therapies that promise to cheat the clock. Author(s): Greene J. Source: Hospitals & Health Networks / Aha. 1998 November 20; 72(22): 32-4, 3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9849506&dopt=Abstract

•

Melatonin in Chinese medicinal herbs. Author(s): Chen G, Huo Y, Tan DX, Liang Z, Zhang W, Zhang Y. Source: Life Sciences. 2003 May 23; 73(1): 19-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12726883&dopt=Abstract

•

Melatonin in feverfew and other medicinal plants. Author(s): Murch SJ, Simmons CB, Saxena PK. Source: Lancet. 1997 November 29; 350(9091): 1598-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9393344&dopt=Abstract

•

Melatonin inhibits calcitonin gene-related peptide-induced vasodilation and increase in cAMP in rat middle cerebral arteries. Author(s): Viswanathan M. Source: European Journal of Pharmacology. 2001 Mar16; 415(2-3): 247-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11275006&dopt=Abstract

•

Melatonin might be one possible medium of electroacupuncture anti-seizures. Author(s): Chao DM, Chen G, Cheng JS.

Alternative Medicine 131

Source: Acupuncture & Electro-Therapeutics Research. 2001; 26(1-2): 39-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11394492&dopt=Abstract •

Melatonin prevents oxidative damage to protein and lipid induced by ascorbateFe(3+)-EDTA: Comparison with glutathione and alpha-tocopherol. Author(s): Kim SJ, Reiter RJ, Qi W, Tan Dx D, Cabrera J. Source: Neuroendocrinol Lett. 2000; 21(4): 269-276. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11455364&dopt=Abstract

•

Melatonin protects against ischaemic-reperfusion myocardial damage. Author(s): Salie R, Harper I, Cillie C, Genade S, Huisamen B, Moolman J, Lochner A. Source: Journal of Molecular and Cellular Cardiology. 2001 February; 33(2): 343-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11162138&dopt=Abstract

•

Melatonin reduces UV-induced reactive oxygen species in a dose-dependent manner in IL-3-stimulated leukocytes. Author(s): Fischer TW, Scholz G, Knoll B, Hipler UC, Elsner P. Source: Journal of Pineal Research. 2001 August; 31(1): 39-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11485003&dopt=Abstract

•

Melatonin regulates glucocorticoid receptor: an answer to its antiapoptotic action in thymus. Author(s): Sainz RM, Mayo JC, Reiter RJ, Antolin I, Esteban MM, Rodriguez C. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 1999 September; 13(12): 1547-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10463946&dopt=Abstract

•

Melatonin supplementation does not prevent photostimulatory effects of night interruption lighting in Japanese quail. Author(s): Meyer W. Source: Journal of Pineal Research. 1998 March; 24(2): 102-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9510435&dopt=Abstract

•

Melatonin supplementation for severe and intractable sleep disturbance in young people with genetically determined developmental disabilities: short review and commentary. Author(s): Turk J. Source: Journal of Medical Genetics. 2003 November; 40(11): 793-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14627665&dopt=Abstract

•

Melatonin supplementation from early morning auto-urine drinking. Author(s): Mills MH, Faunce TA.

132 Melatonin

Source: Medical Hypotheses. 1991 November; 36(3): 195-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1787809&dopt=Abstract •

Melatonin supplementation restores cellular proliferation and DNA synthesis in the splenic and thymic lymphocytes of old rats. Author(s): El-Sokkary GH, Reiter RJ, Abdel-Ghaffar SKh. Source: Neuroendocrinol Lett. 2003 June-August; 24(3-4): 215-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14523360&dopt=Abstract

•

Melatonin supplements for aging. Author(s): Sandyk R. Source: The International Journal of Neuroscience. 1996 November; 87(3-4): 219-24. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9003982&dopt=Abstract

•

Melatonin suppresses reactive oxygen species in UV-irradiated leukocytes more than vitamin C and trolox. Author(s): Fischer TW, Scholz G, Knoll B, Hipler UC, Elsner P. Source: Skin Pharmacology and Applied Skin Physiology. 2002 September-October; 15(5): 367-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12239433&dopt=Abstract

•

Melatonin, serotonin, and tryptamine in some egyptian food and medicinal plants. Author(s): Badria FA. Source: Journal of Medicinal Food. 2002 Fall; 5(3): 153-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12495587&dopt=Abstract

•

Melatonin. Author(s): Cupp MJ. Source: American Family Physician. 1997 October 1; 56(5): 1421-5, 1428. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9337764&dopt=Abstract

•

Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. Author(s): Tan DX, Manchester LC, Hardeland R, Lopez-Burillo S, Mayo JC, Sainz RM, Reiter RJ. Source: Journal of Pineal Research. 2003 January; 34(1): 75-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12485375&dopt=Abstract

•

Melatonin: cellular effects on live stentors correlated with the inhibition of colchicine-binding to microtubule protein. Author(s): Winston M, Johnson E, Kelleher JK, Banerjee S, Margulis L.

Alternative Medicine 133

Source: Cytobios. 1974 May-June; 9(36): 237-43. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4368903&dopt=Abstract •

Melatonin: inhibition of microtubule-based oral morphogenesis in Stentor coeruleus. Author(s): Banerjee S, Kerrr V, Winston M, Kelleher JK, Margulis L. Source: J Protozool. 1972 February; 19(1): 108-13. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4257768&dopt=Abstract

•

Melatonin-induced organelle movement in melanophores is coupled to tyrosine phosphorylation of a high molecular weight protein. Author(s): Karlsson AM, Lerner MR, Unett D, Lundstrom I, Svensson SP. Source: Cellular Signalling. 2000 July; 12(7): 469-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10989282&dopt=Abstract

•

Modification of physical movement in old C57BL/6 mice by DHEA and melatonin supplementation. Author(s): Araghi-Niknam M, Lane L, Watson RR. Source: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.). 1999 July; 221(3): 193-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10404036&dopt=Abstract

•

Modulation of cytokine production by dehydroepiandrosterone (DHEA) plus melatonin (MLT) supplementation of old mice. Author(s): Inserra P, Zhang Z, Ardestani SK, Araghi-Niknam M, Liang B, Jiang S, Shaw D, Molitor M, Elliott K, Watson RR. Source: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.). 1998 May; 218(1): 76-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9572155&dopt=Abstract

•

Music therapy and melatonin. Author(s): Eagle C. Source: Alternative Therapies in Health and Medicine. 2000 May; 6(3): 120-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10802913&dopt=Abstract

•

Music therapy increases serum melatonin levels in patients with Alzheimer's disease. Author(s): Kumar AM, Tims F, Cruess DG, Mintzer MJ, Ironson G, Loewenstein D, Cattan R, Fernandez JB, Eisdorfer C, Kumar M. Source: Alternative Therapies in Health and Medicine. 1999 November; 5(6): 49-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10550905&dopt=Abstract

134 Melatonin

•

N-3 fatty acid deficiency in the rat pineal gland: effects on phospholipid molecular species composition and endogenous levels of melatonin and lipoxygenase products. Author(s): Zhang H, Hamilton JH, Salem N Jr, Kim HY. Source: Journal of Lipid Research. 1998 July; 39(7): 1397-403. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9684742&dopt=Abstract

•

Nighttime changes in norepinephrine and melatonin content and serotonin turnover in pineal glands of young and old rats injected with Freund's adjuvant. Author(s): Cano P, Cardinali DP, Chacon F, Reyes Toso CF, Esquifino AI. Source: Neuroendocrinol Lett. 2002 February; 23(1): 49-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11880862&dopt=Abstract

•

Non-invasive evaluation of the effects of opening & closing of eyes, and of exposure to a minute light beam, as well as to electrical or magnetic field on the melatonin, serotonin, & other neuro-transmitters of human pineal gland representation areas & the heart. Author(s): Omura Y, Losco BM, Takeshige C. Source: Acupuncture & Electro-Therapeutics Research. 1993 April-June; 18(2): 125-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7902642&dopt=Abstract

•

Non-vertebrate melatonin. Author(s): Hardeland R, Poeggeler B. Source: Journal of Pineal Research. 2003 May; 34(4): 233-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12662344&dopt=Abstract

•

On the in vitro antioxidative properties of melatonin. Author(s): Gulcin I, Buyukokuroglu ME, Oktay M, Kufrevioglu OI. Source: Journal of Pineal Research. 2002 October; 33(3): 167-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12220332&dopt=Abstract

•

Over-the-counter psychotropics: a review of melatonin, St John's wort, valerian, and kava-kava. Author(s): Heiligenstein E, Guenther G. Source: Journal of American College Health : J of Ach. 1998 May; 46(6): 271-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9609974&dopt=Abstract

•

Oxidative stress in streptozotocin-induced diabetic rats: effects of garlic oil and melatonin. Author(s): Anwar MM, Meki AR. Source: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology. 2003 August; 135(4): 539-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12890544&dopt=Abstract

Alternative Medicine 135

•

Pharmacological effects of intravenous melatonin: comparative studies with thiopental and propofol. Author(s): Naguib M, Hammond DL, Schmid PG 3rd, Baker MT, Cutkomp J, Queral L, Smith T. Source: British Journal of Anaesthesia. 2003 April; 90(4): 504-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12644425&dopt=Abstract

•

Pinealectomy but not melatonin supplementation affects the diurnal variations in 125I-melatonin binding sites in the rat brain. Author(s): Oaknin-Bendahan S, Anis Y, Nir I, Zisapel N. Source: J Basic Clin Physiol Pharmacol. 1992 July-September; 3(3): 253-68. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1338490&dopt=Abstract

•

Predictors of subjective sleepiness induced by melatonin administration. Author(s): Jean-Louis G, von Gizycki H, Zizi F. Source: Journal of Psychosomatic Research. 1999 October; 47(4): 355-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10616229&dopt=Abstract

•

Pretreatment with melatonin reduces volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model. Author(s): Pei Z, Pang SF, Cheung RT. Source: Journal of Pineal Research. 2002 April; 32(3): 168-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12074100&dopt=Abstract

•

Prevention of immune dysfunction and vitamin E loss by dehydroepiandrosterone and melatonin supplementation during murine retrovirus infection. Author(s): Zhang Z, Araghi-Niknam M, Liang B, Inserra P, Ardestani SK, Jiang S, Chow S, Watson RR. Source: Immunology. 1999 February; 96(2): 291-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10233708&dopt=Abstract

•

Receptor-mediated modulation of avian caecal muscle contraction by melatonin: role of tyrosine protein kinase. Author(s): Poon AM, Kravtsov GM, Pang SF. Source: Journal of Pineal Research. 2002 April; 32(3): 199-208. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12074105&dopt=Abstract

•

Recovery of nocturnal melatonin concentration takes place within one week following cessation of 50 Hz circularly polarized magnetic field exposure for six weeks. Author(s): Kato M, Honma K, Shigemitsu T, Shiga Y.

136 Melatonin

Source: Bioelectromagnetics. 1994; 15(5): 489-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7802715&dopt=Abstract •

Rejuvenation of degenerative thymus by oral melatonin administration and the antagonistic action of melatonin against hydroxyl radical-induced apoptosis of cultured thymocytes in mice. Author(s): Tian YM, Li PP, Jiang XF, Zhang GY, Dai YR. Source: Journal of Pineal Research. 2001 October; 31(3): 214-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11589755&dopt=Abstract

•

Response to melatonin in brain areas implicated in the sexual cycle of the rat. Author(s): Lopez BD, Fernandez BM. Source: Brain Research. 1984 April 2; 296(2): 333-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6538453&dopt=Abstract

•

Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3. Author(s): Cadenas S, Barja G. Source: Free Radical Biology & Medicine. 1999 June; 26(11-12): 1531-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10401619&dopt=Abstract

•

Resynchronization of blood pressure circadian rhythm after westward trans-7meridian flight with and without melatonin treatment. Author(s): Barattini P, Dolci C, Montaruli A, Roveda E, Carandente F. Source: Aviation, Space, and Environmental Medicine. 2001 March; 72(3): 221-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11277289&dopt=Abstract

•

Retinal melatonin is not involved in corneal mitotic rhythms in the Japanese quail: effects of formoguanamine hydrochloride and eye-lid suture. Author(s): Oishi T, Mohri Y, Kaneko T, Sasaki M, Hattori A, Obara Y, Masuda A. Source: Journal of Pineal Research. 1996 October; 21(3): 149-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8981259&dopt=Abstract

•

RNA synthesis inhibitors increase melatonin production in Y79 human retinoblastoma cells. Author(s): Janavs JL, Pierce ME, Takahashi JS. Source: Brain Research. Molecular Brain Research. 1994 April; 23(1-2): 47-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8028483&dopt=Abstract

•

Role of morning melatonin administration and attenuation of sunlight exposure in improving adaptation of night-shift workers. Author(s): Yoon IY, Song BG.

Alternative Medicine 137

Source: Chronobiology International. 2002 September; 19(5): 903-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12405553&dopt=Abstract •

Seasonal affective disorder: response to light as measured by electroencephalogram, melatonin suppression, and cerebral blood flow. Author(s): Murphy DG, Murphy DM, Abbas M, Palazidou E, Binnie C, Arendt J, Campos Costa D, Checkley SA. Source: The British Journal of Psychiatry; the Journal of Mental Science. 1993 September; 163: 327-31, 335-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8401961&dopt=Abstract

•

Some sweet and bitter tastants stimulate inhibitory pathway of adenylyl cyclase via melatonin and alpha 2-adrenergic receptors in Xenopus laevis melanophores. Author(s): Zubare-Samuelov M, Peri I, Tal M, Tarshish M, Spielman AI, Naim M. Source: American Journal of Physiology. Cell Physiology. 2003 November; 285(5): C1255-62. Epub 2003 July 02. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12839835&dopt=Abstract

•

Studies on the role of the retinal dopamine/melatonin system in experimental refractive errors in chickens. Author(s): Schaeffel F, Bartmann M, Hagel G, Zrenner E. Source: Vision Research. 1995 May; 35(9): 1247-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7610585&dopt=Abstract

•

Suppression of hypothalamic pro-opiomelanocortin (POMC) gene expression by daily melatonin supplementation in aging rats. Author(s): Rasmussen DD, Marck BT, Boldt BM, Yellon SM, Matsumoto AM. Source: Journal of Pineal Research. 2003 March; 34(2): 127-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562504&dopt=Abstract

•

The effect of intraperitoneal melatonin supplementation on the release of thyroid hormones and testosterone in rats with hyperthyroid. Author(s): Mogulkoc R, Baltaci AK. Source: Neuroendocrinol Lett. 2003 October; 24(5): 345-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14647010&dopt=Abstract

•

The effects of melatonin and Ginkgo biloba extract on memory loss and choline acetyltransferase activities in the brain of rats infused intracerebroventricularly with beta-amyloid 1-40. Author(s): Tang F, Nag S, Shiu SY, Pang SF. Source: Life Sciences. 2002 October 18; 71(22): 2625-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12354581&dopt=Abstract

138 Melatonin

•

The hypnotic and analgesic effects of 2-bromomelatonin. Author(s): Naguib M, Baker MT, Spadoni G, Gregerson M. Source: Anesthesia and Analgesia. 2003 September; 97(3): 763-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933398&dopt=Abstract

•

The influence of 1.2 microT, 60 Hz magnetic fields on melatonin- and tamoxifeninduced inhibition of MCF-7 cell growth. Author(s): Blackman CF, Benane SG, House DE. Source: Bioelectromagnetics. 2001 February; 22(2): 122-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11180258&dopt=Abstract

•

The pineal gland and spontaneous abortions: implications for therapy with melatonin and magnetic field. Author(s): Sandyk R, Anastasiadis PG, Anninos PA, Tsagas N. Source: The International Journal of Neuroscience. 1992 February; 62(3-4): 243-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1305609&dopt=Abstract

•

The protection of long chain polyunsaturated fatty acids by melatonin during nonenzymatic lipid peroxidation of rat liver microsomes. Author(s): Leaden P, Barrionuevo J, Catala A. Source: Journal of Pineal Research. 2002 April; 32(3): 129-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12074095&dopt=Abstract

•

The role of free oxygen radicals in noise induced hearing loss: effects of melatonin and methylprednisolone. Author(s): Karlidag T, Yalcin S, Ozturk A, Ustundag B, Gok U, Kaygusuz I, Susaman N. Source: Auris, Nasus, Larynx. 2002 April; 29(2): 147-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11893449&dopt=Abstract

•

The therapeutic potential of melatonin in migraines and other headache types. Author(s): Gagnier JJ. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2001 August; 6(4): 383-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11578254&dopt=Abstract

•

T-helper-2 lymphocytes as a peripheral target of melatonin. Author(s): Maestroni GJ. Source: Journal of Pineal Research. 1995 March; 18(2): 84-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7629695&dopt=Abstract

Alternative Medicine 139

•

Weak magnetic fields change extinction of a conditioned reaction and daytime melatonin levels in the rat. Author(s): Jentsch A, Lehmann M, Schone E, Thoss F, Zimmermann G. Source: Neuroscience Letters. 1993 July 9; 157(1): 79-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8233036&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

•

AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

•

Chinese Medicine: http://www.newcenturynutrition.com/

•

drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html

•

Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

•

Google: http://directory.google.com/Top/Health/Alternative/

•

Healthnotes: http://www.healthnotes.com/

•

MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

•

Open Directory Project: http://dmoz.org/Health/Alternative/

•

HealthGate: http://www.tnp.com/

•

WebMDHealth: http://my.webmd.com/drugs_and_herbs

•

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

•

Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to melatonin; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Age-Related Cognitive Decline Source: Healthnotes, Inc.; www.healthnotes.com AIDS and HIV Source: Integrative Medicine Communications; www.drkoop.com Alzheimer's Disease Source: Integrative Medicine Communications; www.drkoop.com

140 Melatonin

Anorexia Nervosa Source: Integrative Medicine Communications; www.drkoop.com Anxiety and Panic Attacks Source: Prima Communications, Inc.www.personalhealthzone.com Atherosclerosis Source: Integrative Medicine Communications; www.drkoop.com Autoimmune Conditions Source: Integrative Medicine Communications; www.drkoop.com Bone Loss Source: Integrative Medicine Communications; www.drkoop.com Brain Cancer Source: Integrative Medicine Communications; www.drkoop.com Breast Cancer Source: Healthnotes, Inc.; www.healthnotes.com Breast Cancer Source: Integrative Medicine Communications; www.drkoop.com Burns Source: Healthnotes, Inc.; www.healthnotes.com Cancer Source: Integrative Medicine Communications; www.drkoop.com Cancer Prevention (Reducing the Risk) Source: Prima Communications, Inc.www.personalhealthzone.com Cluster Headache Source: Healthnotes, Inc.; www.healthnotes.com Colon Cancer Source: Healthnotes, Inc.; www.healthnotes.com Depression Source: Healthnotes, Inc.; www.healthnotes.com Depression Source: Integrative Medicine Communications; www.drkoop.com Epilepsy Source: Healthnotes, Inc.; www.healthnotes.com Erythema Source: Integrative Medicine Communications; www.drkoop.com

Alternative Medicine 141

Fibromyalgia Source: Healthnotes, Inc.; www.healthnotes.com Fibromyalgia Source: Integrative Medicine Communications; www.drkoop.com Glaucoma Source: Healthnotes, Inc.; www.healthnotes.com Glaucoma Source: Integrative Medicine Communications; www.drkoop.com Insomnia Source: Healthnotes, Inc.; www.healthnotes.com Insomnia Source: Integrative Medicine Communications; www.drkoop.com Insomnia Source: Prima Communications, Inc.www.personalhealthzone.com Jet Lag Source: Healthnotes, Inc.; www.healthnotes.com Jet Lag Source: Integrative Medicine Communications; www.drkoop.com Lung Cancer Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Integrative Medicine Communications; www.drkoop.com Lupus Source: Integrative Medicine Communications; www.drkoop.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Migraine Headaches Source: Healthnotes, Inc.; www.healthnotes.com Multiple Sclerosis Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Integrative Medicine Communications; www.drkoop.com Prostate Cancer Source: Healthnotes, Inc.; www.healthnotes.com

142 Melatonin

Prostate Cancer Source: Integrative Medicine Communications; www.drkoop.com Psychological Conditions and Disorders Source: Integrative Medicine Communications; www.drkoop.com Radiation Damage Source: Integrative Medicine Communications; www.drkoop.com Sarcoidosis Source: Integrative Medicine Communications; www.drkoop.com Schizophrenia Source: Healthnotes, Inc.; www.healthnotes.com Seasonal Affective Disorder Source: Healthnotes, Inc.; www.healthnotes.com Seasonal Affective Disorder (sad) Source: Integrative Medicine Communications; www.drkoop.com Seizure Disorders Source: Integrative Medicine Communications; www.drkoop.com Sleep Disorders Source: Integrative Medicine Communications; www.drkoop.com Sleeplessness Source: Integrative Medicine Communications; www.drkoop.com Sudden Infant Death Syndrome (SIDS) Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Integrative Medicine Communications; www.drkoop.com Tinnitus Source: Healthnotes, Inc.; www.healthnotes.com •

Alternative Therapy Color Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,683,00.html Light Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,713,00.html

Alternative Medicine 143

•

Herbs and Supplements 5-hydroxytryptophan Source: Healthnotes, Inc.; www.healthnotes.com Aloe Alternative names: Aloe vera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Ava Source: Integrative Medicine Communications; www.drkoop.com Benzodiazepines Source: Prima Communications, Inc.www.personalhealthzone.com Beta-blockers Source: Integrative Medicine Communications; www.drkoop.com Chemotherapy Source: Healthnotes, Inc.; www.healthnotes.com Cyclophosphamide Source: Healthnotes, Inc.; www.healthnotes.com Docetaxel Source: Healthnotes, Inc.; www.healthnotes.com Doxorubicin Source: Healthnotes, Inc.; www.healthnotes.com Fluorouracil Source: Healthnotes, Inc.; www.healthnotes.com Fluvoxamine Source: Healthnotes, Inc.; www.healthnotes.com Gaba Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10027,00.html Hypericum Perforatum Source: Integrative Medicine Communications; www.drkoop.com Kava Kava Alternative names: Piper methysticum, Ava Source: Integrative Medicine Communications; www.drkoop.com Klamathweed Source: Integrative Medicine Communications; www.drkoop.com

144 Melatonin

Melatonin Source: Healthnotes, Inc.; www.healthnotes.com Melatonin Source: Integrative Medicine Communications; www.drkoop.com Melatonin Source: Prima Communications, Inc.www.personalhealthzone.com Melatonin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,804,00.html Methotrexate Source: Healthnotes, Inc.; www.healthnotes.com Mirtazapine Source: Healthnotes, Inc.; www.healthnotes.com Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Source: Integrative Medicine Communications; www.drkoop.com Oral Corticosteroids Source: Healthnotes, Inc.; www.healthnotes.com Paclitaxel Source: Healthnotes, Inc.; www.healthnotes.com Piper Alternative names: Kava; Piper methysticum Forst.f Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Piper Methysticum Source: Integrative Medicine Communications; www.drkoop.com S-Adenosylmethionine (SAMe) Source: Integrative Medicine Communications; www.drkoop.com Sassafras Alternative names: Sassafras albidum (Nuttall) Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Selective Serotonin Reuptake Inhibitors (SSRIS) Source: Integrative Medicine Communications; www.drkoop.com St. John's Wort Alternative names: Hypericum perforatum, Klamathweed Source: Integrative Medicine Communications; www.drkoop.com Tamoxifen Source: Healthnotes, Inc.; www.healthnotes.com

Alternative Medicine 145

Tanacetum Alternative names: Feverfew; Tanacetum parthenium (L.) Schultz-Bip. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Triazolam Source: Healthnotes, Inc.; www.healthnotes.com Valeriana Alternative names: Valerian; Valeriana officinalis Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

147

CHAPTER 4. DISSERTATIONS ON MELATONIN Overview In this chapter, we will give you a bibliography on recent dissertations relating to melatonin. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “melatonin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on melatonin, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Melatonin ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to melatonin. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

A Circadian Rhythm of Melatonin Levels in the Haemolymph of the Insect Rhodnius Prolixus by Gorbet, Diana Judith; MSC from York University (Canada), 2002, 73 pages http://wwwlib.umi.com/dissertations/fullcit/MQ75381

•

A Study of Retinal Oxidation: the Effects of Melatonin and the Roles of Nitric Oxide and Hydroxyl Radicals by Siu, Andrew Wing-Tak; PhD from Hong Kong Polytechnic University (people's Republic of China), 2002, 180 pages http://wwwlib.umi.com/dissertations/fullcit/3064145

•

Dopamine Rhythms in the Mammalian Retina: Regulation by Circadian Oscillators and Melatonin by Doyle, Susan Elizabeth; PhD from University of Virginia, 2002, 101 pages http://wwwlib.umi.com/dissertations/fullcit/3030711

•

Effects of Pinealectomy, Melatonin and Age on Phase-shifting Behavioural Cycles in the Rat by Dawson, Kim A; PhD from University of Waterloo (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL51958

148 Melatonin

•

Immunohistochemical Analysis of Melatonin in Aged Rattus Rattus Pineal Gland and Its Implications in the Aging of Pinealocytes by Ng, Carmen; MS from Baylor University, 2002, 112 pages http://wwwlib.umi.com/dissertations/fullcit/1409848

•

Melatonin-mediated Regulation of Gonadotropin-releasing Hormone (GNRH): Role of Melatonin Receptors and Circadian Rhythms by Gillespie, Julia Margaret Amy; Msc from University of Toronto (Canada), 2002, 117 pages http://wwwlib.umi.com/dissertations/fullcit/MQ74147

•

Protection of Pifithrin-alpha and Melatonin against Doxorubicin-induced Cardiotoxicity by Liu, Xuwan; PhD from East Tennessee State University, 2003, 113 pages http://wwwlib.umi.com/dissertations/fullcit/3083433

•

The Circadian Rhythms of Core Body Temperature, Serum Cortisol and Serum Melatonin Patterns of Disruption in Chronic Insomnia of Chronobiologic Origin by MacFarlane, James Gordon; PhD from McMaster University (Canada), 1990 http://wwwlib.umi.com/dissertations/fullcit/NL57959

•

The Effect of Food Access Schedule and Diet Composition on the Rhythmicity of Serum Melatonin and Pineal N-acetyltransferase Activity in Rats by Oguine, Adaora; MSC from McGill University (Canada), 2002, 75 pages http://wwwlib.umi.com/dissertations/fullcit/MQ78933

•

The Effects of Melatonin on Hippocampal Physiology by El-Sherif, Yasir Nabil; PhD from City University of New York, 2003, 140 pages http://wwwlib.umi.com/dissertations/fullcit/3074649

•

The Influence of Photoperiod and Melatonin on Hormone Levels and Operant Light Demand in the Pig by Deboer, Herman; PhD from University of Guelph (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL48898

•

The Ontogeny of Sleep-wake and Melatonin Rhythmicity in Co-sleeping and Solitary-sleeping Infants by Burnham, Melissa Mae; PhD from University of California, Davis, 2002, 186 pages http://wwwlib.umi.com/dissertations/fullcit/3062194

•

The Role of the Pineal Gland, Melatonin and Brain Monoamines in Endocrine Regulation by Niles, Lennard P; PhD from University of Toronto (Canada), 1978 http://wwwlib.umi.com/dissertations/fullcit/NK38797

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

149

CHAPTER 5. CLINICAL TRIALS AND MELATONIN Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning melatonin.

Recent Trials on Melatonin The following is a list of recent trials dedicated to melatonin.8 Further information on a trial is available at the Web site indicated. •

Melatonin and Radiation Therapy in Treating Patients With Brain Metastases Condition(s): unspecified adult solid tumor, protocol specific; brain metastases; radiation toxicity Study Status: This study is no longer recruiting patients. Sponsor(s): Radiation Therapy Oncology Group; National Cancer Institute (NCI) Purpose - Excerpt: RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs such as melatonin may make tumor cells more sensitive to radiation therapy and may protect normal cells from the side effects of radiation therapy. PURPOSE: Randomized phase II trial to determine the effectiveness of combining melatonin with radiation therapy in treating patients who have brain metastases. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00031967

•

Effects of Season on Melatonin Secretion in Healthy Men and Women and Patients with Seasonal Affective Disorder Condition(s): Seasonal Affective Disorder Study Status: This study is completed.

8

These are listed at www.ClinicalTrials.gov.

150 Melatonin

Sponsor(s): National Institute of Mental Health (NIMH) Purpose - Excerpt: As the seasons change during the course of the year, many animals show major changes in their behavior and physiology. Many of these changes are triggered by changes in the length of time each night that the pineal gland produces the hormone melatonin. Melatonin is produced for a longer time in winter when nights are long, than in summer when nights are short. Some researchers believe that melatonin may play a similar role in how season effects mood of patients with seasonal affective disorder. Seasonal affective disorder (SAD) or mood disorder with seasonal pattern is a condition where the normal biorhythm is disturbed during a season, especially autumnwinter. Patients may begin experiencing or experience worsening of depressive symptoms. Patients complain of being constantly tired, craving sugary foods, overeating, and over sleeping. Researchers have collected some preliminary data showing that the duration of nighttime melatonin secretion increases in winter and decreases in summer in healthy women, but not in healthy men. However, men diagnosed with SAD have shown longer duration of melatonin secretion in the winter, similar to the duration seen in healthy women. If these early findings are confirmed it may explain why SAD is more common in women than in men. The purpose of this study is to continue researching the differences in melatonin secretion over the seasons in healthy men and women, and to determine how these findings may apply to patients with SAD. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001485 •

Study of Melatonin: Sleep Problems in Alzheimer's Disease Condition(s): Alzheimer Disease; Dyssomnias Study Status: This study is completed. Sponsor(s): National Institute on Aging (NIA) Purpose - Excerpt: This protocol is a multicenter clinical trial of melatonin for sleep disturbances associated with Alzheimer's disease (AD). Frequent nocturnal awakening is a common behavioral symptom of AD. Nighttime wandering and agitated behavior may result in injuries and sleep disruption for caregivers. Alternatives are sorely needed to the currently available sleep medications that have marginal efficacy and serious side effects. Melatonin is a naturally occurring hormone secreted by the pineal gland. It has soporific effects with oral administration and is well tolerated. It enhances sleep in normal older people. Melatonin also may help sleep disturbances associated with AD; however, this remains to be proven. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00000171

Clinical Trials 151

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “melatonin” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

•

For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

•

For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

•

For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

•

For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

•

For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

•

For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

•

For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

•

For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

•

For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

•

For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

•

For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

•

For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

152 Melatonin

•

For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

•

For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

153

CHAPTER 6. PATENTS ON MELATONIN Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “melatonin” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on melatonin, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Melatonin By performing a patent search focusing on melatonin, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

154 Melatonin

example of the type of information that you can expect to obtain from a patent search on melatonin: •

Antiarrhythmic and tranquilizer composition and treatment Inventor(s): Patrick; Jay (19631 Pauling, Foothill Ranch, CA 92610) Assignee(s): none reported Patent Number: 6,620,836 Date filed: January 2, 1998 Abstract: A composition employing a small amount of the hormone melatonin combined with a magnesium compound is formed into a lozenge or into a timed release tablet to act as an antiarrhythmic agent. As a lozenge to be dissolved in the mouth, it may incorporate magnesium in several forms such as a citrate, as a niacinate, as an aspartate, or as an orotate. The preferred formulations according to the invention alleviate cardiac arrhythmia, as well as the extreme manifestation of this condition known as atrial fibrillation. Magnesium citrate is not only beneficial to the heart muscle but also contributes to a laxative effect that counters the constipating action of the melatonin. As a time release tablet for daytime use, the same ingredients indicated above may be combined in tablet or capsular form, but are accompanied by the addition of agents which stimulate the mind such as tyrosine and phenylalanine. These stimulants serve to counter the sleep-inducing action of the melatonin. The timed release forms of the composition may also be formulated as a tranquilizer or to reduce mental anxiety. Excerpt(s): The present invention relates to a composition and method of treatment of cardiac arrhythmia. A cardiac condition which has long puzzled heart specialists is atrial fibrillation, which is abbreviated herein and in the medical profession as AF. The condition of AF can be described as an irregular and very rapid heart beat. In extreme cases it may result in sudden death. Persons considered to be medically normal and healthy may experience cardiac arrhythmia, especially during stress or exercise. Cardiac arrhythmia is also typical in cases of acute alcoholism and after surgery. However, although cardiac arrhythmia may be tolerated by a subject for many years, the condition of cardiac arrhythmia usually precedes or is a contributing factor to AF which is a much more dangerous condition. Persistent AF usually occurs in patients with rheumatic heart disease, microvalve disease, hypertension, or thyroidtoxicosis (Taber's Cyclopedic Medical Dictionary). Regarding treatment, Tabor's advises that the patient should be instructed concerning optimum physical function by utilizing frequent rest periods and the need to restrict sodium intake, and also instructed concerning drugs that are prescribed. Web site: http://www.delphion.com/details?pn=US06620836__

Patents 155

•

Aqueous phase dermatological/cosmetic compositions comprising solubilized melatonin values Inventor(s): Bordeaux; Dominique (Saint Michel Sur Orge, FR), Gagnebien; Didier (Westfield, NJ), Simon; Pascal (Vitry Sur Seine, FR) Assignee(s): Societe L'Oreal S.A. (Paris, FR) Patent Number: 5,939,084 Date filed: October 10, 1997 Abstract: Stable, recrystallization-resistant dermatological/cosmetic compositions, well suited for preventing/treating oxidative stress of the skin, comprise a substantially ethanol-free aqueous phase, the aqueous phase containing an active amount of solubilized melatonin values and an amount of at least one glycol effective to dissolve such melatonin values. Excerpt(s): The present invention relates to the formulation of glycols into cosmetic compositions comprising a substantially alcohol-free aqueous phase, to solubilize therein effective amounts of melatonin or analog thereof. The present invention also relates to novel alcohol-free aqueous cosmetic compositions comprising melatonin or analog thereof and a solubilizing amount of at least one glycol. Melatonin, or N-acetyl-5methoxytryptamine, known especially for its bioactivity on the circadian rhythm regulating hormone production, is also known for its antioxidizing activity (Reiter R. J., Verhandung der Deutschen Zoologischen Gesellschaft, 87 (2), 195-204 (1994); Reiter R. J. et al., Neuroendocrinol Letter, 15 (1-3), 103-113 (1993); Reiter R. J. et al., J. Pineal Res., 18 (1), 1-11 (1995), in particular its antiradical activity (Reiter R. J. et al., Brazilian Journal of Medical and Biological Research, 26 (22), 1141-1155 (1993)). The majority of studies on the antioxidant properties of melatonin are concerned with oxidation phenomena related to aging of the brain (Pooggeler B. et al., J. Pineal Res., 14 (4), 151-168 (1993); Cagnoli C. M. et al., J. Pineal Res., 18 (4), 222-226 (1995); Melchiorri D. et al., FASEB J., 9 (12), 1205-1210 (1995); Sewerynek E. et al., Neuroscience Letters, 195 (3), 203-205 (1995)). Web site: http://www.delphion.com/details?pn=US05939084__

•

Arylalkylbenzofuran derivatives as melatonergic agents Inventor(s): Bertenshaw; Stephen R. (Cheshire, CT), Epperson; James R. (Cromwell, CT), Johnson; Graham (Madison, CT), Sun; Li-Quang (Glastonbury, CT), Takaki; Katherine S. (Middletown, CT) Assignee(s): Bristol-Myers Squibb Company (Princeton, NJ) Patent Number: 6,569,894 Date filed: October 3, 2002 Abstract: Novel benzofuran and dihydrobenzofuran derivatives which have a binding affinity for the human melatonin receptor and, therefore, are useful as melatonergic agents. Excerpt(s): The invention pertains to novel arylalkylbenzofuran derivatives having drug and bio-affecting properties, to their preparation, to pharmaceutical formulations containing them and to methods of using them. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders. Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [.sup.125 I]-2-

156 Melatonin

iodomelatonin has led to the identification of high affinity melatonin receptors in the central nervous systems (CNS) of a variety of species. The sequence of one such high affinity melatonin receptor, cloned from frog melanocytes, has been reported. In the mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures. Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discrete nuclei of the hypothalamus. In humans, specific [.sup.125 I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting that melatonin receptors are located within the human biological clock. Web site: http://www.delphion.com/details?pn=US06569894__ •

Compositions and delivery systems for the topical treatment of psoriasis and other conditions of the skin Inventor(s): Neigut; Stanley (10 Red Rowan La., Plymouth Meeting, PA 19462) Assignee(s): none reported Patent Number: 6,048,886 Date filed: September 30, 1999 Abstract: The invention provides compositions and methods for the application of those compositions in order to treat biological surfaces, especially the skin. The compositions contain a ubiquinone, may include other antioxidant agents (including melatonin), and may include an abrasive. The means of application may be by rubbing the composition into the skin, by means of a transdermal patch, or by rubbing the composition into the skin followed by application of a transdermal patch. The compositions and methods are useful for treating a variety of skin conditions, including psoriasis and hyperpigmentation, and may also be used for cosmetic purposes and the prevention of skin damage. Excerpt(s): The invention generally relates to the treatment of skin conditions such as psoriasis. In particular, the invention provides methods for treating skin, which is either damaged or undamaged, using compositions containing a ubiquinone and an abrasive, and for delivering compositions containing a ubiquinone by means of a transdermal patch. The skin provides an essential protective barrier against environmental challenges such as radiation, extremes of temperature, excessive dryness, invasion by infectious organisms, and many others. As such, the maintenance of the health of the skin is of great importance for the overall preservation of well-being. This maintenance includes both preventative skin care and attention to rapid and effective healing of pathological skin conditions. Much effort has been exerted in understanding the factors which promote healthy skin, especially those factors which are "naturally occurring", i.e. biological substances which are the components of the skin's endogenous protective and healing mechanisms. For example, it is known that the skin possesses an elaborate antioxidant defense system to deal with oxidative stress. Evidence for this is suggested by investigations of skin disorders such as Xeroderma pigmentosum, in which biopsies revealed an abnormally low level of activity of the enzyme catalase, which is involved in the defense against oxygen free radicals. Excessive exposure to environmental insults such as UV radiation can overwhelm the cutaneous antioxidant capacity, leading to oxidative damage and ultimately to skin cancer, immunosuppression, and premature skin aging.

Patents 157

Web site: http://www.delphion.com/details?pn=US06048886__ •

Food-based delivery of HGH-stimulating and other nutritional supplements Inventor(s): Marshall; Edward (10932 Savona Rd., Los Angeles, CA 90077) Assignee(s): none reported Patent Number: 6,461,634 Date filed: August 17, 2000 Abstract: A food, or ready-to-drink beverage, delivery system for increasing the production and release of human growth hormone (HGH) for anti-aging effects and/or to improve a condition of HGH deficiency. A food bar, powder, other food forms, or ready-to-drink beverage that contains the full range and optimal dosages of vitamins, minerals, non-prescription hormonal and herbal supplements most desired by individuals who regularly take such supplements from numerous bottles or other packages. HGH stimulation and the above-described supplementation may be delivered for oral ingestion separately or together in the same aliquot, said aliquot providing a pleasant-tasting and convenient snack or mini-meal in addition to the specific HGH stimulation and supplementation. L-glutamine, glycine and melatonin are sufficient to boost HGH up to age 60, and it is preferred to add L-arginine and L-lysine for individuals of age 60 and older. The single food or beverage aliquot makes unnecessary the inconvenient ingestion of numerous pills from numerous bottles, or ill-tasting powders that must be mixed with water. Calories are kept under about 300, and carbohydrate is kept generally below about 5 grams per aliquot in order to permit the stimulation of HGH when the stimulating ingredients are consumed in the form of food or nutritional ready-to-drink beverage. Ingredients are included as needed for optimal flavor and texture choices, and to prevent spoilage. Excerpt(s): The present invention relates to a food-based delivery system for providing (a) the required nutritional supplements for stimulating production and release of human growth hormone (HGH) and/or (b) a full range and desired dosages of vitamins and minerals consumed each day by serious takers of such supplements. In more detail, the present invention relates to combinations of amino acids, vitamins, and other nutrients formulated into a convenient and good-tasting food such as a food bar or ready-to-drink beverage that, when ingested orally, stimulates HGH production and/or release for the purpose of producing anti-aging effects. The same food is formulated to provide the full range of the most commonly desired vitamins and minerals consumed by adults who are serious consumers of vitamin and mineral supplements or the vitamins and minerals can be formulated separately for ingestion without the HGHstimulating amino acids and other nutrients. Either way, the food-based delivery system of the present invention provides a full complement of the vitamins, minerals, and other nutritional supplements in adequate quantity to satisfy most serious consumers of such supplements in a pleasant-tasting form. With regard to the prior art, it is known to those skilled in the art and to many of the public in general, that HGH levels fall with age starting at about age 35, so that HGH levels are reduced by about two-thirds by the age of 60. It is know that when the HGH levels are restored to more youthful levels, by a schedule of either injections of HGH, or the oral consumption of certain combinations of amino acids, over the ensuing 20 to 180 days, anti-aging effects occur, including: boosting of the immune system, restoration of more youthful vigor and libido, increase of the percentage of lean muscle mass, reduction of the percentage of body fat, increase in the thickness of skin with more youthful texture, increased skin turgor and a decrease

158 Melatonin

of brown "aging" spots. The beneficial anti-aging effects of increased levels of growth hormone in humans are well documented. See, for instance, R. Klatz, et al., Grow Young with HGH, New York, HarperCollins Publishers, 1997; see also D. Rudman, et al., Effects of Human Growth Hormone in Men Over 60 Years Old; New England Journal of Medicine, 1990; vol 323; 1:1. In the book by Klatz there are numerous references to published and unpublished studies showing the efficacy of orally ingested amino acids in elevating HGH levels and HGH has long been given by injection. The disadvantages of these prior art methods, however, are several: HGH injections are painful and inconvenient, and the cost usually exceeds $10,000 per year. There can be side effects if the injected dosage is too high for the individual. Injections require careful monitoring of blood laboratory tests and careful physician follow-up. If the person is to take the available pill form of HGH-stimulating amino acids, he/she must take eight to sixteen different pills from four to five different bottles one to four times a day. Some of the pills are quite large, and if one is to take all four of the recommended amino acids in correct dosage, one would have to take is pills from as many as four different bottles at each dosage time, for a total of about 16 pills per dose. Further inconvenience is caused by the fact that the pills of the different bottles run out at different intervals, requiring numerous trips to health food stores. In many locales, some of the ingredients are not available for sale in any store. Typical schedules require taking the pills 6 out of 7 days, with breaks of 2 to 6 weeks every 3 to 6 months, and missing any of the recommended dosages or pills can lessen the desired effects. Web site: http://www.delphion.com/details?pn=US06461634__ •

Genes and genetic markers for improved reproductive traits in animals Inventor(s): Messer; Lori A. (Lincoln, NE), Rothschild; Max F. (Ames, IA), Tuggle; Christopher K. (Ames, IA), Yu; Tun-Ping (Ames, IA) Assignee(s): Iowa State University Research Foundation, Inc. (Ames, IA) Patent Number: 5,939,264 Date filed: July 18, 1997 Abstract: Disclosed herein are genetic markers for favorable reproductive traits in animals such as litter size, and weaning weight. Methods for identifying such markers, and methods of screening animals to determine those more likely to produce favorable reproductive traits and preferably selecting those animals for future breeding purposes. The markers are based upon the presence or absence of certain polymorphisms in the pig reproductive genes, including retinol binding protein 4, retinoic acid receptor gamma, melatonin receptor 1a, and vascular cell adhesion molecule 1 Excerpt(s): This invention relates generally to the detection of genetic differences for reproductive efficiency among animals. More particularly the invention relates to genetic markers which have been identified in several genes indicative of heritable phenotypes associated with improved reproductive traits. Methods and compositions for use of these markers in genotyping of animals and selection are also disclosed. Reproductive efficiency, particularly as it relates to litter size, is the major limiting factor in the efficient production of pork as well as most other livestock animals. Genetic variability exists for several reproductive measures. Average litter size among breeds pigs varies from 4-16 pigs per litter. Mean age at puberty varies from 3 to 7 months of age. This genetic variability within breeds suggests that genetic improvement in reproduction is possible. The number of pigs born alive in the United States averages approximately 9.5 pigs per litter. Heritability for litter size is low (10%-15%), and

Patents 159

standard genetic methods of selecting breeding females on the basis of past litter size have not been effective. Therefore, there is a need for an approach that deals with selection for reproductive traits at the cellular or DNA level. Chinese breeds are known for reaching puberty at an early age and for their large litter size. American breeds are known for their greater growth rates and leanness. Thus, it would be desirable to combine the best characteristics of both types of breeds, thereby improving the efficiency of U.S. pork production. These efforts would be greatly assisted by the discovery of genes or genetic markers that are associated with improved reproductive traits such as increased litter size in pigs. Web site: http://www.delphion.com/details?pn=US05939264__ •

Heterofunctional mucoadhesive pharmaceutical dosage composition Inventor(s): Bromet; Norbert E. (Orleans-la-Source, FR) Assignee(s): Biotec Centre S.A. (Orleans Cedex 2, FR) Patent Number: 5,879,710 Date filed: December 12, 1996 Abstract: A mucoadhesive controlled-release pharmaceutical formulation comprising at least one active principle selected from the group consisting of melatonin and melatonin derivatives, composed of a first layer and a second layer, the first layer being mucoadhesive and permitting a sustained release of the active principle, and the second layer being nonmucoadhesive, and permitting a rapid release of the active principle. Excerpt(s): The present invention relates to a pharmaceutical dosage formulation enabling products such as melatonin or its derivatives to be administered, by combining a loading dose permitting a rapid action and, in the case of melatonin (or its derivatives), a clear chronobiological signal and one or more doses released gradually, enabling products to be made available rapidly, and in a sustained manner, in the body. Generally speaking, the present invention relates to any mucoadhesive formulation combining at least two formulations affording controlled released of different rates, ranging from a rapid form to a sustained-release form. The product is especially advantageous when the formulation is applied to a joint administration via the transmucosal or sublingual route and via the oral route, where the pharmaceutical dosage formulation combines a rapid oral form with a controlled-release oral form and a transmucosal form within a single mucoadhesive buccal tablet. Web site: http://www.delphion.com/details?pn=US05879710__

•

Infant formula Inventor(s): Bindels; Jacob Geert (Zoetermeer, NL), Boehm; Gunther (Echzell, DE), Georgi; Gilda (Friedrichsdorf, DE), Hageman; Robert Johan Joseph (Wageningen, NL), Sawatzki; Gunther (Munzenberg, DE), Wells; John Cowper Kingston (Gloucestershire, GB) Assignee(s): N.V. Nutricia (Zoetermeer, NL) Patent Number: 6,613,367 Date filed: October 24, 2001

160 Melatonin

Abstract: The invention relates to products for complete nutrition of infants. The products are characterized by the type and amount of protein and carbohydrate and the increased levels of folic acid, vitamin B6 and vitamin B12 or their functional equivalents. These products improve feelings of well-being of infants, especially those of young age, and are useful in the treatment and prevention of diseases that are associated with disorders of serotonin- and melatonin metabolism. Excerpt(s): The invention is related to infant formulae, i.e. artificial products for complete nutrition of infants, for improving feelings of well-being, compensation of immaturity and problems in the metabolic capacity of the infant. The nutritional products provide complete nutrition to the infant and their composition is characterised by a selected protein and carbohydrate composition and the increased amounts of folic acid, and vitamin B6 and B12 or their functional analogues. At present a large part of the population of babies in industrialised countries are fed with specialised infant formulae. It has been reported that consumption of these formulae is associated with several medical problems that may occur at young age, such as increased frequency of gastrointestinal problems and decreased immune status, but perhaps also at later age, because infants that are exclusively fed with human breast milk would score better on these parameters. It has also been reported that infants that are exclusively fed with these artificial formulae suffer from longer episodes of crying compared to those that are fed with human breast milk. This suggests a general feeling of discomfort due to perhaps hunger, pain or even medical problems. These problems may delay development of the child and produce concerns and practical problems to the parents. In a first aspect of the invention it is aimed to develop a new infant formula for complete nutrition that decreases the number of crying episodes and promotes sleeping behaviour for the child, especially for infants of young gestational age. Web site: http://www.delphion.com/details?pn=US06613367__ •

Mediation of circadian rhythms Inventor(s): Kennaway; David (South Australia, AU) Assignee(s): Luminis Pty Limited (South Australia, AU) Patent Number: 6,403,651 Date filed: March 6, 2000 Abstract: Method for mediating the effects of light on melatonin rhythmicity in mammals and a method of mediating circadian rhythms, effected by the administration of a compound or compounds effective at a 5-HT2c serotonin receptor site. By administration of selected doses of the 5-HT2c receptor active compound it is possible to advance or delay circadian rhythms as measured by the rate of melatonin production or moderation of core body temperature rhythms. Excerpt(s): This application is a 371 of PCT/AU98/00207, filed Mar. 26, 1998. The present invention relates to a method of mediating the effects of light on melatonin rhythmicity and, accordingly a method of mediation of circadian rhythms. The invention further relates to a method of treatment of conditions associated with dysfunctional or arrhythmic melatonin production. Daily, or circadian, rhythms are common to all eukaryotic biological organisms, including humans. Circadian rhythms help coordinate a number of functions, most notably sleeping patterns. Web site: http://www.delphion.com/details?pn=US06403651__

Patents 161

•

Melatonin 1A receptor gene regulatory regions and uses thereof Inventor(s): Reppert; Steven M. (Newton, MA) Assignee(s): The General Hospital Corporation (Boston, MA) Patent Number: 5,889,177 Date filed: July 17, 1997 Abstract: Disclosed are DNAs encoding melatonin 1a receptor gene promoter regions, recombinant polypeptides expressed from such DNAs, and methods of using such expression constructs to screen for promoter activators or inhibitors. Transcriptional activators are useful as therapeutics to reentrain endogenous melatonin rhythms as a means of treating circadian rhythm disorders in humans and control reproductive cycles in seasonally breeding animals. Transcriptional inhibitors are useful as therapeutics to control the initiation or timing of puberty in humans. Excerpt(s): This application claims priority from provisional application 60/022,185, filed on Jul. 18, 1996. The invention relates to nucleic acids encoding transcriptional regulatory sequences of a high-affinity melatonin receptor gene. The high-affinity melatonin receptor is a membrane protein that is coupled to guanine nucleotide binding proteins (G proteins). G proteins, in turn, communicate ligand-activated receptor signals to the appropriate intracellular effector system(s). The hormone, melatonin, inhibits adenylyl cyclase causing a decrease in intracellular cyclic AMP (cAMP) concentration. Web site: http://www.delphion.com/details?pn=US05889177__

•

Melatonin derivative dermocosmetic compositions for whitening/depigmenting the skin Inventor(s): Nadaud; Jean-Fran.cedilla.ois (Clamart, FR), Nguyen; Quang Lan (Antony, FR) Assignee(s): Societe L'Oreal S.A. (Paris, FR) Patent Number: 5,932,608 Date filed: July 25, 1997 Abstract: Topically applicable dermocosmetic compositions for whitening/depigmenting human skin, comprise a skin-whitening/depigmenting effective amount of at least one melatonin derivative having the structural formula (I): in which R.sub.1 is a lower alkyl radical, R.sub.2 is a hydrogen atom or a lower alkyl radical, and R.sub.3 is a hydrogen atom or a lower acyl radical, with the proviso that the hydroxyl radical is in the 4-, 6- or 7-position on the indole ring system, or a physiologically acceptable salt, solvate or bioprecursor/prodrug thereof, formulated into a topically applicable, cosmetically/dermatologically acceptable vehicle, carrier or diluent therefor. Excerpt(s): The present invention relates to novel topically applicable dermocosmetic compositions comprising certain melatonin derivative depigmenting agents, for treating the skin of the face and/or the body, for the purpose of whitening the skin or for treating pigmentation blemishes. At different periods in their lifetimes, certain individuals develop dark and/or colored blemishes on the skin and, more especially, on the hands, imparting to the skin a heterogeneous appearance. These blemishes are due to a considerable concentration of melanin in the keratinocytes located at the skin surface. The reason for this is that the melanocytes located deep in the epidermis

162 Melatonin

produce melanin and deliver such melanin to the surrounding kertinocytes, which then rise to the surface of the epidermis, loaded with melanin. Tyrosinase is the essential enzyme involved in this reaction sequence. In particular, it catalyzes the reaction for the conversion of tyrosine into dopa (dihydroxyphenylalanine) and the reaction for the conversion of dopa into dopaquinone. This tyrosinase acts only when it is in a mature state, under the influence of certain biological factors. Web site: http://www.delphion.com/details?pn=US05932608__ •

Melatonin derivatives for use in treating desynchronization disorders Inventor(s): Flaugh; Michael E. (Indianapolis, IN) Assignee(s): Eli Lilly and Company (Indianapolis, IN) Patent Number: 6,180,657 Date filed: November 18, 1993 Abstract: The present invention provides a method of treating desynchronization disorders using various melatonin analogs. Excerpt(s): is named systematically as N-[2-(5-methoxy-3-indolyl)ethyl]-acetamide. Trivial names for the compound include N-acetyl-5-methoxytryptamine and N-acetylO-methylserotonin. Melatonin is a pineal gland hormone which has ovulation inhibitory activity, Chu et al., Endocrinology, 75, 238 (1964), as well as some activity against MCF-7 human breast cancer cells, Blask et al. J. Neural. Transm. [Supp.], 21, 433 (1986) and for the treatment of mammalian breast carcinoma, Blask et al., Neuroendocrinol. Lett., 9(2), 63 (1987). Furthermore, melatonin has been known to expedite recovery from "jet lag syndrome", Arendt et al., Ergonomics, 30, 1379 (1987), to cause sleep, Waldhauser et al., Psychopharmacology, 100, 222 (1990) and to minimize disturbances in circadian rhythms of bodily performance and function, U.S. Pat. Nos. 4,600,723 and 5,242,941. provided that when R.sup.2 is hydrogen, at least one of R.sup.5 and R.sup.6 is halo, have also been prepared and shown to possess ovulation inhibition activity (see U.S. Pat. Nos. 4,997,845 and 4,614,807). Such analogues are also stated to be active in treating hormonally dependent breast carcinomas in U.S. Pat. No. 5,196,435. However, none of these analogues were previously shown to possess activity in treating desynchronization disorders. wherein R.sup.1 and R.sup.2 are the same or different and are hydrogen or halogen can be used in treating sleep disorders and in pre-anesthetic medication. Again, such disclosure does not teach or suggest the use of melatonin analogues for treating desychronization disorders. Web site: http://www.delphion.com/details?pn=US06180657__

•

Melatonin for the production of a peroral pulsatile form of medication Inventor(s): Dittgen; Michael (Apolda, DE), Fricke; Sabine (Jena, DE), Graser; Thomas (Erfurt, DE), Lippert; Theodor Hermann (Tu bingen, DE), Oettel; Michael (Jena, DE), Osterwald; Hermann (Bovenden, DE) Assignee(s): Jenapharm GmbH (Jena, DE) Patent Number: 6,214,377 Date filed: December 5, 1995

Patents 163

Abstract: The use of melatonin for the production of peroral pulsatile forms of medications assures the safeguard of an effective level of the medical substance of melatonin in the blood, and which realize a relatively short invasion phase with a controlled delivery in comparison to conventional forms of medication containing melatonin, and which simultaneously exclude the known side effects. A control of the delivery of the melatonin is effected which is associated with the precise adaptation to the illness episodes or the pain attacks of certain illnesses, which can be treated prophylactically and therapeutically with the active agent melatonin. Excerpt(s): The invention relates to a method of using melatonin for the production of peroral pulsatile forms of medication for safeguarding an effective blood level of the medical substance melatonin, which pulsatile forms realize a controlled delivery within a relatively short invasion phase in contrast to conventional forms of medication containing melatonin and which pulsatile forms exclude at the same time the known side effects. The term "pulsatile forms of medication" is synonymous with the term "regulated or modulated delivery systems" and designates according to Peppas (N. A. Peppas, Preface in R. Gurny; H. E. Junginger; N. A. Peppas (Eds.) Pulsatile Drug Delivery, Current Applications and Future Trends, 1 Ed., page 5-5, Wiss. Verlagsges., Stuttgart 1993) a delivery system for medication which is capable of delivering the contained medical agent in prescribed intervals in response to the situation in the surrounding liquid or based on an external stimulus. The preferred field of application of pulsatile forms of medication are illnesses such as ischaemia, asthma, arthritis, sleep disorders, Parkinson's Syndrome, incontinence, aids, and states of pain (H. E. Junginger, Oral Applications of Pulsatile Drug Delivery in R. Gurny; H. E. Junginger; N. A. Peppas (Eds.) Pulsatile Drug Delivery, Current Applications and Future Trends, Ed. 1, pages 113-134, Wiss. Verlagsges., Stuttgart 1993). These illnesses or states of pain are subjected to time variations such that they can be treated best with forms of medication, which are adapted with the intermittent (pulsatile) release of the medical agents to the occurrence of episodes of the illness or of attacks of the pain. Web site: http://www.delphion.com/details?pn=US06214377__ •

Melatonin receptor-deficient mice and uses thereof Inventor(s): Gribkoff; Valentin K. (Wallingford, CT), Reppert; Steven M. (Newtown, MA) Assignee(s): Bristol-Myers Squibb Company (Princeton, NJ), The General Hospital Corporation (Boston, MA) Patent Number: 6,326,526 Date filed: January 7, 2000 Abstract: Disclosed are mice containing a targeted disruption of various melatonin receptor subtypes, and methods of using the mice to identify agonists and antagonists of melatonin. Excerpt(s): The field of the invention is melatonin and its receptors. Melatonin, the principal hormone of the pineal gland, influences the timing of mammalian circadian rhythms and regulates the reproductive alterations that occur in response to changes in day length in seasonally breeding mammals (Reppert, S. M. and Weaver, D. T., Cell 83:1059-1062, 1995). In humans, melatonin administration has been shown to alleviate the symptoms of jet lag after air travel across several time zones. The hormone also has potent sedative effects in humans and may be a useful hypnotic agent. Melatonin exerts

164 Melatonin

these effects through specific guanine nucleotide binding protein,(G protein)-coupled receptors. A family of these G protein-coupled melatonin receptors has been cloned from Xenopus laevis, chicken and various mammals (U.S. applications Ser. Nos. 08/261,857, filed Jun. 17, 1994; 08/319,887, filed Oct. 7, 1994; and 08/466,103, filed Jun. 6, 1995; Ebisawa, T., et al. Proc. Natl. Acad. Sci. USA 91:6133-6137, 1994; Reppert, S. M. et al., Neuron 13:1177-1185, 1994; Reppert, S. M. et al. Proc. Natl. Acad. Sci. USA 92:87348738, 1995; Reppert, S. M. et al., Neuron 15:1003-1015, 1995). These cloned receptors exhibit affinity and pharmacological characteristics similar to each other and to endogenous receptors, as defined by the melatonin agonist 2- [.sup.125 I]iodomelatonin (.sup.125,-Mel). Two mammalian melatonin receptor subtypes have been identified by molecular cloning studies. The mammalian receptor Mel.sub.1a is expressed in the hypothalamic suprachiasmatic nuclei (SCN) and hypophyseal pars tuberalis, which are presumed sites of the circadian and some of the reproductive actions of melatonin, respectively (Reppert, S. M. et al., Neuron 13:1177-1185, 1994). The mammalian Mel.sub.1b receptor is expressed in retina and brain and may mediate the reported effects of melatonin on retinal physiology in mammals (Reppert, S. M. et al. Proc. Natl. Acad. Sci. USA 92:8734-8738, 1995). A third receptor subtype, the Mel.sub.1c melatonin receptor, has been cloned from zebrafish, Xenopus, and chicken, but not from mammals (Reppert, S. M. et al., Neuron 15:1003-1015, 1995). Web site: http://www.delphion.com/details?pn=US06326526__ •

Melatonin-antagonist.beta.-carboline derivatives and analogues thereof containing naphthalenic structure, process for their preparation and their use as medicinal products Inventor(s): Fourtillan; J-Bernard (Migne-Auxances, FR), Fourtillan; Marianne (MigneAuxances, FR), Jacquesy; Jean-Claude (Bruxerolles, FR), Jouannetaud; Marie-Paule (Poitiers, FR), Karam; Omar (Poitiers, FR), Violeau; Bruno (Marcay, FR) Assignee(s): Cemaf (Migne-Auxances, FR), Laboratories Besins Iscovesco (Paris, FR) Patent Number: 6,048,868 Date filed: March 17, 1998 Abstract: The present invention provides.beta.-carboline derivatives useful as components of cosmetic, medicinal, and pharmaceutical compositions. The medicinal and pharmaceutical compositions can be used to induce hypnotic activity in a subject. Methods of producing the.beta.-carboline derivatives are provided as well. Excerpt(s): The present invention relates to novel.beta.-carboline derivatives, which are melatonin agonists, and to analogues of naphthalenic structure, to a process for their preparation and to their use as medicinal products. Melatonin, N-acetyl-5methoxytryptamine, is a hormone from the pineal gland, isolated by Lerner & al. (J. Am. Chem. Soc., 80, 1958, 2587), which has formed the subject of numerous studies for its circadian activity, in the rhythm of sleep, for its effects on the production of testosterone, for its activity on the hypothalamus and in psychiatric disorders. It has thus been envisaged to employ melatonin and analogues thereof especially for the treatment of depression and psychiatric disorders, in particular stress, anxiety, depression, insomnia, schizophrenia, psychoses and epilepsy, and also for the treatment of sleeping disorders associated with travelling ("jet lag"), neurodegenerative diseases of the central nervous system such as Parkinson's disease or Alzheimer's disease, for the treatment of cancers or, alternatively, as a contraceptive or as an analgesic.

Patents 165

Web site: http://www.delphion.com/details?pn=US06048868__ •

Method and compositions for enhancing pregnancy success in an animal Inventor(s): Cleaver; Brian D. (Gainesville, FL), Sharp; Dan (Gainesville, FL) Assignee(s): Equitech Laboratories, Inc. (Alachua, FL) Patent Number: 6,403,631 Date filed: January 14, 2000 Abstract: Enhancement of pregnancy success in an animal is achieved by a method of treatment which includes administration of a single dose of melatonin during follicular development. An additional dose of melatonin can be administered during pregnancy to modulate accessory follicle formation. Novel compositions, which include a mixture of melatonin isomers or analogs, are also useful for enhancing pregnancy success. Excerpt(s): The subject invention concerns a novel use for melatonin to regulate the uterine environment in an animal for enhanced pregnancy success. Melatonin has been administered in the past to treat a variety of ailments and is currently in common use in humans for regulation of biorhythms, including light-dark cycle regulation in treating depression and for treating disrupted sleep patterns, or "jet-lag," which can result from long-distance travel across time zones. Melatonin, or a derivative thereof, has also been described as being useful as a treatment for breast or other cancers. It has been recognized that progesterone levels increase following administration of melatonin to certain animals, including sheep and marmosets. For example, Wallace et al. ([1988] J Endocr. 119:5-523-530) stated that melatonin orally administered to ewes increased plasma progesterone concentrations. However, the conclusion as to the effect of melatonin on the corpus luteum and improvements in conception rates were "equivocal." See Wallace et al., supra, at 529, col. 2. This reference also reveals that a 1987 paper by Webley and Hearn (J Endocrin. 112:449-457) reported that in vivo perfusion of melatonin to marmosets stimulated progesterone production by the marmoset corpus luteum. A 1986 Webley and Luck paper ([1986] J Reprod. Fert. 78:711-717) described in vitro melatonin-enhanced production of progesterone in human and bovine granulosa cells. This is in direct contrast to the results found for in vitro administration of melatonin to corpora lutea tissue according to the subject invention. Web site: http://www.delphion.com/details?pn=US06403631__

•

Method and pharmaceutical formulation for treating benign prostatic hyperplasia Inventor(s): Zisapel; Nava (Tel Aviv, IL) Assignee(s): Neurim Pharamaceuticals (1991) Ltd. (Tel-Aviv, IL) Patent Number: 6,048,888 Date filed: November 24, 1997 Abstract: Benign prostatic hyperplasia (BPH) in male humans is treated by administering to a male patient in which such condition has been diagnosed, an effective BPH treating amount within the range of from 1 ng to 80 mg of melatonin, which may be in the form of a pharmaceutical formulation for use in treating BPH, which comprises, in combination a carrier, diluent or adjuvant, (1) an effective BPH treating amount of melatonin; and optionally (2) antiandrogens, antiestrogens, growth

166 Melatonin

hormones and/or inhibitors of prostatal testosterone reductase; and/or (3) oxazepam or other melatonin receptor profile modifier. Excerpt(s): The present invention relates to a method for treating benign prostatic hyperplasia (BPH) and to a pharmaceutical formulation for this purpose. Melatonin is the principal hormone secreted by the pineal gland in all vertebrates. In all mammals studied to date, including humans, a nocturnal rise in the production of melatonin by the pineal gland is evident, regardless of whether the mammals are nocturnal or diurnal, and conversely, melatonin production by the body is acutely suppressed by light. Melatonin is involved in the coordination of photoperiod and physiological processes, e.g. in animals which use changes in the photoperiod to time their thermoregulation and reproduction, temporal signals to the thermoregulatory and reproductive systems are controlled by the daily rhythm in the duration of melatonin during the dark phase. Numerous studies have shown that melatonin has a potent influence on gonadal activity. The timing of melatonin administration has been shown to be crucial for its biological activities. E.g., while in the case of rats whose circadian rhythms are disrupted or arrhythmic in constant light, as well as in the case of rats free running in constant darkness, their rhythms are synchronized by daily melatonin injections, by contrast it has been found that continuous availability of melatonin in circulation, or injection of melatonin in the morning, sometimes prevents gonodal responses to melatonin in the afternoon. The inventor has shown, e.g. in Zisapel et al, Neuroendocrinology 40: 102 (1985), that the inhibition by melatonin of the stimulated release of dopamine from rat hypothalamus, was highest in the early photophase and lowest in the early afternoon. Web site: http://www.delphion.com/details?pn=US06048888__ •

Method for delaying the onset of alheimer's disease and for treatment or delaying the onset of other amyloidosis-related diseases/disorders Inventor(s): Frangione; Blas (New York, NY), Ghiso; Jorge (Elmhurst, NY), Pappolla; Miguel A. (Mobile, AL) Assignee(s): New York University (New York City, NY), South Alabama Medical Science Foundation (Mobile, AL) Patent Number: 6,274,615 Date filed: March 25, 1999 Abstract: The present invention relates to a method of using melatonin to reduce, inhibit or reverse the formation of amyloid fibrils and amyloid or amyloid-like deposits. The present invention also relates to a method for delaying the onset of Alzheimer's Disease or other amyloidosis-related diseases/disorders or for treating such diseases/disorders by administering an effective amount of melatonin to a subject in need thereof. Excerpt(s): The present invention relates to a method for delaying the onset of Alzheimer's Disease and for treating or delaying the onset of other amyloidosis-related diseases/disorders. It is estimated that ten percent of persons older than 65 years of age have mild to severe dementia. Alzheimer's Disease (AD) is the most common cause of chronic dementia with approximately two million people in the United States having the disease. Although once considered a condition of middle age, it is now known that the histopathologic lesions of Alzheimer's disease (i.e., neuritic amyloid plaques, neurofibrillary degeneration, and granulovascular neuronal degeneration) are also found in the brains of elderly people with dementia. The number of such lesions correlates with the degree of intellectual deterioration. This high prevalence, combined

Patents 167

with the rate of growth of the elderly segment of the population, make dementia (and particularly AD) one of the most important current public health problems. Deposition of cerebral amyloid is a primary neuropathologic marker of Alzheimer's disease. This amyloid is composed of a 40-42 amino acid peptide called the amyloid beta protein (A.beta.) (Glenner et al., 1984). Amyloid deposits in AD are found mainly as components of senile plaques, and in the walls of cerebral and meningeal blood vessels (Robakis et al., 1994). Web site: http://www.delphion.com/details?pn=US06274615__ •

Method for treating patients suffering from drug dependencies which lead to plasma melationin deficiencies Inventor(s): Zisapel; Nava (Tel Aviv, IL) Assignee(s): Neurim Pharmaceuticals (1991) Ltd. (Tel Aviv, IL) Patent Number: 6,469,044 Date filed: February 1, 1995 Abstract: A method of treating a patient suffering from a dependence on, tolerance of, or addiction to at least one benzodiazepine comprises administering melatonin to said patient on a daily basis in an amount sufficient to treat said dependence on, tolerance of, or addiction to said benzodiazepine. Excerpt(s): The present invention relates to a method for treating a patient who is suffering from a dependence on, tolerance of, or addiction to at least one benzodiazepine or is at risk of becoming dependent upon, tolerant of, or addicted to such a drug. More specifically, the invention relates to such a method which comprises administering an amount of melatonin effective to treat or prevent the dependence, tolerance or addiction. Insomnia is a frequently encountered problem in modern society: it is estimated that almost one third of the U.S. population suffers from this condition to some extent. The problem is particularly troublesome among the elderly. Benzodiazepine hypnotics are among the most commonly used drugs in the therapeutic treatment of insomnia. Although the precise mechanism of action of these drugs on sleep induction has not been completely elucidated, it is assumed that they exert their activity through a benzodiazepine/GABA-A (gamma amino butyric acid) receptor complex. As insomnia is thought to be associated with derangement of the normal sleep-wake cycle, it is possible that the effects of these drugs on sleep induction may be accomplished by phase-shifting the internal biological clock in the brain. Indiscriminate and/or prolonged use of benzodiazepine hypnotics often results in the development of tolerance to the drugs, and rebound or withdrawal phenomena can appear following abrupt cessation of the drugs. The extent of these phenomena depends upon both the compound and its dosage. Web site: http://www.delphion.com/details?pn=US06469044__

168 Melatonin

•

Method of treatment using deuterium compounds Inventor(s): Bell; Rupert Charles (Box A, Palmer Unit, K.P.H. 1312 Oakland Dr., Kalamazoo, MI 49008) Assignee(s): none reported Patent Number: 6,376,531 Date filed: November 12, 1999 Abstract: The present invention provides organic deuterium compounds which can be therapeutic compounds to treat manic depression. In particular, the present invention relates to deuterated methionine, norepinephrine, pyridoxine-5-phosphate, tryptophan, 5-hydroxytryptophan, serotonin, N-acetyl serotonin and melatonin, which can be used as therapeutic agents. Excerpt(s): None. The present invention relates to deuterated therapeutic compounds for the treatment of psychiatric disorders. In particular, the present invention relates to the use of deuterated tryptophan, tryptamine, serotonin, melatonin, norepinephrine, vanilmandelic acid, vanitiolide, methionine, pyridoxine-5-phosphate, and derivatives therefrom as therapeutic agents. Deuterium oxide, otherwise known as heavy water, has been to shown to have a chronomutagenic effect on the period and entrainment of the light-dark (LD) cycle of mice (Hayes and Palmer, Int. J. Chromobiol 4:63-69 (1976); and, Biol. Bull 143 513-524 (1972)). In particular, it has been shown that deuterium oxide suppressed the spontaneous locomotor activity of the mouse (Hayes and Palmer, Experientia, 4: 469-470 (1976)) Other references are Rutger Wever, In The Circadian System of Man, Springer Verlag; and, Mohammud & Sharon Shaffi, In Phototherapy, Biological Rhythms, Mood Disorders, and the Pineal Gland, American Psychiatric Press (1990). These cycles are also related to the manic depressive state in humans. Web site: http://www.delphion.com/details?pn=US06376531__

•

Methods useful for the treatment of neurological and mental disorders related to deficient serotonin neurotransmission and impaired pineal melatonin functions Inventor(s): Sandyk; Reuven (7 Piper Ct., Roslyn, NY 11576) Assignee(s): none reported Patent Number: 5,885,976 Date filed: November 25, 1997 Abstract: A composition is described which is useful for treating neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in humans the composition being administered in combination with a sufficient amount of an AC pulsed magnetic field alone or in conjunction with a DC magnetic field and a sufficient amount of random noise to the brain of a human in need of such treatment which composition comprises an effective amount of a composition which increases serotonin transmission to the human to be treated. A method of treating neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in humans is described which comprises administering to a human in need thereof an effective amount of a composition which increases serotonin transmission to the human to be treated followed by the application to the brain of the human of a sufficient amount of

Patents 169

AC pulsed magnetic field alone, or in combination with a DC magnetic field and low frequency random noise, of proper intensity, frequency, waveform, wave symmetry and phase shift of the wave to treat the disorder. Excerpt(s): The present invention relates to a method of treating neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in humans. The pineal gland serves as a magnetoreceptor organ in the brain of humans and other mammals and its stimulation with an AC pulsed magnetic field has shown beneficial effects in the treatment of neurological and mental disorders which are associated with or related pathogenetically to impairment of pineal melatonin functions including multiple sclerosis, Parkinson's disease, juvenile Parkinsonism, progressive supranuclear palsy. Huntington's chorea, Shy-Drager syndrome, essential tremor, AIDS dementia complex, motor neuron disease, traumatic spinal cord injuries, ischemic stroke, diabetic neuropathy, dystonia, myoclonus, tardive dyskinesia, Tourette's syndrome, epilepsy, narcolepsy, Restless-legs syndrome, akathisia, chronic pain syndromes, migraine, Alzheimer's disease, depression (including seasonal affective disorder and premenstrual depression), autism, Attention Deficit hyperactivity disorder, schizophrenia, alcohol and substance abuse, obsessive-compulsive disorder, anxiety and panic disorder, posttraumatic stress disorder, trichotillomania, impulsive and aggressive behavior, chronic insomnia, sleep paralysis, and bulimia. For many years physiologists considered the pineal gland, lodged deep within the brain, a vestigial organ which is merely an anatomical remnant of a primary sensory system. To the clinician the pineal gland, by virtue of its midline position and calcification, was of interest as a radiological landmark to identify intracranial space occupying processes. The pineal gland attracted scientific attention in 1963, when its primary secretion, melatonin, was first recognized as a hormone. Wurtman and Axelrod (1965) "The pineal gland." Scientific American, 231, 5060) considered the pineal gland a "neuroendocrine transducer," an organ which converts neural signals from the external environment such as photic, acoustic, thermic, and magnetic cues into neuroendocrine output which acts on the nervous system largely via the secretion of its principal hormone melatonin. The pineal gland is unique among endocrine organs for a number of reasons: (1) it is one of the few unpaired endocrine organs: (2) on a weight basis, it receives one of the richest blood supplies of any organ; (3) it lies outside the blood brain barrier, but has direct access to the cerebrospinal fluid (CSF) via the third ventricle; (4) it produces and/or contains high concentrations of a number of different indoleamines and low molecular weight peptides of probable endocrine importance; and (5) it is responsive to changes in magnetic field strength and to external electrical stimuli (Foley et al., (1986) "Pineal indoles: significance and measurement." Neuroscience & Biobehavioral Reviews, 10, 273-293). Web site: http://www.delphion.com/details?pn=US05885976__ •

Nasal melatonin composition Inventor(s): Merkus; Franciscus W. H. M. (Kasterlee, BE) Assignee(s): Merkus, Franciscus W.H.M. (Kasterlee, BE) Patent Number: 6,007,834 Date filed: March 26, 1998 Abstract: A pharmaceutical composition for intranasal administration, comprising melatonin and a pharmaceutically acceptable excipient, which is effective to cause the blood plasma melatonin concentration in a human adult, receiving an amount of

170 Melatonin

melatonin in the range of 50-1000.mu.g and in a single or simultaneous intranasal administration of said composition, to reach at least X pg/ml, within 30 minutes of said administration, wherein X is equal to 5 times the amount of melatonin, expressed in.mu.g, in said single or simultaneous administration. Excerpt(s): This invention relates to a pharmaceutical composition for intranasal administration of melatonin. The invention further relates to doses or dosage units for intranasal administration, and the use of the same for the preparation of an intranasal dosage form. Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone secreted from the pineal gland. It has been disclosed in numerous references that melatonin induces sleep when administered to a patient. The sleep-inducing effects of melatonin have advantages over conventional hypnotics, since not being a hypnotic drug itself, it only induces a state of sleepiness without having the adverse side-effects of conventional hypnotics. Melatonin is usually administered orally but, as with most oral preparations, it takes over an hour after administration for the blood plasma concentration of the active agent (melatonin) to reach its peak. Other routes of administration, in particular nasal administration have been considered. However, because of inherent problems, inter alia due to the low solubility of melatonin in water, melatonin compositions suitable for nasal administration have yet to be prepared. In an early attempt to develop such a composition, Vollrath et ala, Adv. Bioscience, 29 (1981), pp. 327-329 described the nasal administration of 1.7 mg of melatonin in ethanol. Due to serious local irritation and painful administration, this composition was found to be unsuitable for use in man. In 1980, intranasal compositions containing reduced quantities of ethanol were disclosed in Japanese patent application J55057563 (Hoechst AG). A composition of 100 mg of melatonin in 10 ml of a 5% solution of ethanol in water was proposed, but even this still causes an unacceptable degree of adverse sideeffects. This patent application also disclosed a composition in which propylene glycol was used in place of ethanol. Web site: http://www.delphion.com/details?pn=US06007834__ •

Screening method using the RZR receptor family Inventor(s): Missbach; Martin (Rheinfelden, CH), Wiesenberg; Irmgard (Weil am Rhein, DE) Assignee(s): Novartis Corporation (Summit, NJ) Patent Number: 5,958,683 Date filed: August 22, 1996 Abstract: The current invention concerns the use of a receptor from the RZR/ROR receptor family or a functional fragment thereof in a test of a compound for antiautoimmune, anti-arthritic, anti-tumor, melatonin-like and or melatonin-antagonistic activity and the production of a receptor ligand complex comprising the receptor or a functional fragment thereof and a ligand of the receptor. Also described is a method for testing compounds for said activity (screening for ligands) and the active compounds identified therewith. Excerpt(s): The current invention concerns the use of a receptor from the RZR/ROR receptor family or of a functional fragment thereof in a test of a compound for antiautoimmune, anti-arthritic, anti-tumor, melatonin-like and/or melatonin-antagonistic activity and the production of a receptor ligand complex comprising said receptor or a functional fragment thereof and a ligand of said receptor. Described is also a method for

Patents 171

testing compounds for said agonists or antagonists (screening for ligands) and the active compounds identified therewith. Small lipophilic substances like retinoic acid (RA), 1,25-dihydroxyvitaminD.sub.3 (VD), thyroid hormone (T3) and steroid hormones regulate a number of developmental and physiological processes in vertebrates and in invertebrates by binding to specific receptors that function directly as transcription factors. These ligand-dependent transcription factors are members of the nuclear receptor superfamily. The nuclear receptor superfamily also includes structurally related proteins for which no ligand has been identified yet and therefore are referred to as orphan receptors (O'Malley et al., Mol. Endocrinol. (1992), 6, 1259-1361). Examples of such orphan receptors are peroxisome-proliferator activated receptors (PPARs) and chicken ovalbumin upstream promoter transcription factor (COUP-TFs). Despite large diversity in function, two conserved zinc-finger motifs which are involved in binding to DNA appear in all members of this superfamily. Web site: http://www.delphion.com/details?pn=US05958683__ •

Therapeutic uses of melatonin Inventor(s): Laudon; Moshe (Kfar Saba, IL), Zisapel; Nava (Tel Aviv, IL) Assignee(s): Neurim Pharmaceuticals (1991) Ltd. (Tel Aviv, IL) Patent Number: 6,566,389 Date filed: November 26, 2001 Abstract: A method for treating or preventing symptoms of tardive dyskensia comprises administering melatonin to patient exhibiting or liable to develop such symptoms. The melatonin is administered in an amount effective to ameliorate or prevent symptoms of tardive dyskensia developing in the patient. Excerpt(s): This is a 371 of PCT UK 00/00296 filed May 24, 2000. Tardive dyskinesia (TD) is an involuntary movement disorder, which develops in a high percentage of patients who have been treated with neuroleptic drugs. A number of articles have appeared in the literature suggesting an inverse relationship between melatonin secretion and the incidence of TD symptoms. However, to the best of our knowledge, in only one instance has administration of exogenous melatonin been attempted in this connection, in which it was found that whereas treatment with haloperidol of pinealectomized rats resulted, in significantly more severe movement disorder than in unoperated control rats, subsequent administration of melatonin (4 mg, i.p.) was associated with a non-significant reduction of the severity of movements within one hour (Sabdyk, R., et al., Int. J. Neurosci., 1989, 48 (3-4): 303-8). The amount of melatonin used in this non-significant result was equivalent to more than 1000 mg for a 70 kg human, so that it is not surprising that subsequent attempts at TD therapy have avoided the use of exogenous melatonin. In U.S. Pat. No. 5,691,324 to Sandyk, R., for example, TD is one of a number of conditions, related to deficient serotonin transmission and impaired melatonin function, which is treated by administering to a patient a composition which increases serotonin neurotransmission, followed by applying a magnetic field to the brain. The entire contents of U.S. Pat. No. 5,691,324 are incorporated herein by reference. It has now surprisingly been found, in relation to tardive dyskinesia, that exogenous melatonin produces a significant therapeutic effect in humans, at a dosage rate which is at least one order of magnitude lower (taking into account the average weight of humans in relation to laboratory animals) than that used in the report in Int. J. Neurosci., mentioned above.

172 Melatonin

Web site: http://www.delphion.com/details?pn=US06566389__ •

Unit dosage forms for treatment of vasoconstriction and related conditions Inventor(s): Pearson; Don C. (Tacoma, WA), Richardson; Kenneth T. (Anchorage, AK) Assignee(s): ChronoRX, LLC (Anchorage, AK) Patent Number: 6,042,849 Date filed: July 7, 1998 Abstract: Magnesium is formulated in combination with vitamin E, vitamin C, folate, selenium, and optionally melatonin a unit dosage form for oral administration, for the treatment of vasoconstriction and the physiological and pathological conditions giving rise to vasoconstriction. These active agents complement each other in suppressing these conditions, using a variety of mechanisms operating in conjunction with one another. The inclusion of magnesium in a plurality of forms provides additional advantages in terms of controlling and sustaining the release of magnesium in locations along the digestive tract where the magnesium will have its greatest effectiveness as a therapeutic agent, thus improving control over the clinical bioavailability of magnesium and in improving the selection of appropriate therapeutic ranges. Excerpt(s): This invention is in the field of pharmacology, and relates specifically to the pharmacological treatment of conditions associated with the constriction of small blood vessels. Vasoconstriction, or the reduction in the cross-sectional area of the lumen of small blood vessels, is a potentially lethal condition arising in a variety of pathologies, and is due either to vasospasm, inadequate vasodilatation, thickening of the vessel wall, or the accumulation of flow-restricting materials on the internal wall surfaces or within the wall itself. Vasoconstriction is a major factor in various diseases, including progressive generalized atherogenesis, heart attack, stroke, hypertension, glaucoma, migraine, hypertension of pregnancy, and diabetes mellitus, among others. Vasoconstriction originates in a variety of ways. One example is the local conversion by dysfunctional endothelium of circulating low density lipoproteins (LDL) into oxidatively activated low density lipoproteins ((ox)LDL). (ox)LDL is internalized via cellular macrophage scavenger receptors creating lipid-engorged macrophages, called "foam cells." These cells are bound to the vascular endothelium and subendothelium, release a variety of growth factors and cytokines that stimulate vascular smooth muscle cell proliferation and trigger the increase of the local endothelial expression of leukocyte adhesion molecules and leukocyte chemotaxants; all precursors of progressive vascular atherosclerosis and its subsequent reduction of vascular cross-sectional area. Web site: http://www.delphion.com/details?pn=US06042849__

•

Use of melatonin for the treatment of androgenetic alopecia Inventor(s): Elsner; Peter (Meilen, CH) Assignee(s): ASAT AG Applied Science and Technology (Zug, CH) Patent Number: 6,281,241 Date filed: February 18, 2000 Excerpt(s): The invention relates to the use of melatonin and melatonin-containing preparations for the treatment of androgenetic alopecia of the female type. Melatonin

Patents 173

(N-acetyl-5-methoxytryptamine) is a hormone with a broad spectrum of action [1,2], produced and secreted from the pineal gland under the influence of.beta.-adrenergic receptors having a circadian rhythm. Although the mechanisms of the action of melatonin are still not comprehensively clarified in detail, melatonin appears to control the adaptation of the organism to environmental stimuli, in particular light and temperature. The toxicity of melatonin is not detectable, even on oral administration of several grams per day [3]. In the case of topical application in a nanocolloid preparation, and of alcoholic solutions, no local or systemic side effects were seen in over 60 subjects. Animal experimental studies indicate that the systemic administration of melatonin improves the thickness and structure of coat hair [4,5 ]. The influence of the duration of daylight exposure to the seasonal change of coat has been described for the sheep [6], the Kashmir goat and some other species of goat [7], red deer [8] and mink [9]. The mitotic activity of the secondary follicles and the hair growth resulting therefrom increases from the beginning of summer until the winter, to stop in the spring. After a resting stage, in which the hairs of the primary and secondary follicles fall out, a new growth cycle begins with induction of a new anagenic phase. Web site: http://www.delphion.com/details?pn=US06281241__ •

Use of melatonin in a composition for stabilizing hydrophilic gelling polymers Inventor(s): Lebreton; Fran.cedilla.oise (Bures-Sur-Yvette, FR), Louvet-Plaisant; Nathalie (Chevilly Larue, FR) Assignee(s): Societe L'Oreal S.A. (Paris, FR) Patent Number: 5,891,903 Date filed: December 8, 1997 Abstract: The present invention relates to the use of melatonin or analogues thereof in a composition as an agent for stabilizing hydrophilic gelling polymers. The invention relates more particularly to cosmetic or pharmaceutical compositions for topical use. Excerpt(s): The present invention relates to the use of melatonin or analoges thereof for stabilizing compositions comprising hydrophilic gelling polymers, in particular in topical pharmaceutical or cosmetic compositions. Hydrophilic gelling agents are very widely used in topical pharmaceutical or cosmetic compositions. These are, in particular, gelling agents such as polymers of natural and/or synthetic origin, among which mention may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkyl acrylate copolymers, polyacrylamides or optionally modified polysaccharides such as hydroxypropyl cellulose. It is known that these hydrophilic gelling polymers lose their viscosity under the effect of light, more particularly under the effect of UV radiation, and UVA and/or UVB screening agents are generally added to preparations containing them in order to overcome this problem. However, such screening agents are generally hydrophobic and are often considered to be responsible in intolerance phenomena such as photoallergy and/or phototoxicity, thus greatly limiting their use in topical pharmaceutical or cosmetic compositions. Web site: http://www.delphion.com/details?pn=US05891903__

174 Melatonin

•

Use of phospholipids of animal origin in therapy and/or dietetics Inventor(s): Ponroy; Yves (4A quai Ernest Ansermet, Montreux, CH-1820, CH) Assignee(s): none reported Patent Number: 6,069,138 Date filed: January 21, 1999 Abstract: The invention concerns a novel use of phospholipids of animal origin in therapy and/or dietetics, more particularly the use of phospholipids rich in long-chain polyunsaturated fatty acids derived from animal brains or hen's eggs, to produce a pharmaceutical and/or dietetic composition to regulate melatonin secretion. Excerpt(s): The present invention relates to a novel therapeutic and/or dietetic use of animal-derived phospholipids. The present invention is more specifically directed to the use of phospholipids rich in polyunsaturated fatty acids for providing a pharmaceutical and/or dietetic composition which has an effect on melatonin secretion. Previous studies have suggested that melatonin, a neurohormone produced by the pineal gland, acts as an endogenous timing mechanism in humans (Armstrong--Melatonin: The internal Zeitgeber of Mammals. Pineal Res. Rev., 7: 157-202, 1989). Known pharmacological properties ascribed to melatonin mainly include its myorelaxant activity, sedative, hypnotic and tranquillizing effect (Sugden, D., Psychoparmacological effects of melatonin in mouse and rat--J. Pharmacol. Exp. Ther., 227, 587-591, 1983). Web site: http://www.delphion.com/details?pn=US06069138__

Patent Applications on Melatonin As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to melatonin: •

Benzoxazole derivatives as novel melatonergic agents Inventor(s): Bertenshaw, Stephen R.; (Cheshire, CT), Chen, Jie; (Madison, CT), Denhart, Derek; (Durham, CT), Johnson, Graham; (Madison, CT), Sun, Li-Qiang; (Glastonbury, CT), Takaki, Katherine S.; (Middletown, CT) Correspondence: Stephen B. Davis; Bristol-myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20030216456 Date filed: March 6, 2003 Abstract: Novel benzoxazole derivatives which have a binding affinity for the human melatonin receptor and, therefore, are useful as melatonergic agents. Excerpt(s): The invention pertains to novel benzoxazole derivatives having drug and bio-affecting properties, to their preparation, to pharmaceutical formulations containing them and to methods of using them. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders. Recent evidence

10

This has been a common practice outside the United States prior to December 2000.

Patents 175

demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [.sup.125I]-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the central nervous systems (CNS) of a variety of species. The sequence of one such high affinity melatonin receptor, cloned from frog melanocytes, has been reported. In the mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures. Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discrete nuclei of the hypothalamus. In humans, specific [.sup.125I]-2iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting that melatonin receptors are located within the human biological clock. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions normalizing circadian rhythm Inventor(s): Kiso, Yoshinobu; (Osaka, JP), Nagai, Katsuya; (Osaka, JP), Ono, Yoshiko; (Osaka, JP) Correspondence: Manelli Denison & Selter; 2000 M Street NW Suite 700; Washington; DC; 20036-3307; US Patent Application Number: 20030091614 Date filed: January 14, 2002 Abstract: The present invention provides a circadian rhythm normalizing composition containing astaxanthin and/or its ester as an active ingredient, and a composition having the action of enhancing the circadian rhythm normalizing action of melatonin by protecting melatonin. The composition can be in the form of a drug, a functional food, a food or a beverage.This composition has a circadian rhythm normalizing action, and has the action of preventing or alleviating sleep disorder and various diseases due to disturbance of the circadian rhythm. Excerpt(s): This invention relates to a circadian rhythm normalizing composition containing astaxanthin and/or its ester as an active ingredient, and a composition having astaxanthin and/or its ester incorporated in or combined with melatonin in order to enhance the somniferous action of melatonin. The invention also relates to a composition incorporating astaxanthin and/or its ester in order to enhance the somniferous action of melatonin already present in vivo. Living beings on the Earth have a mechanism, called a biological clock, for a circadian rhythm tuned to a 24-hour environmental cycle from the daytime to the nighttime, such as a light-dark cycle, occurring as the Earth revolves on its own axis. The biological clock is controlled by the hypothalamic suprachiasmatic nucleus of the brain. We have the circadian rhythm of sleep-wakefulness and eating behavior attributed to the biological clock. The circadian rhythm is observed not only in sleep and diet, but also in most of the body temperature, blood pressure, heart beat, and internal secretion. Understanding the circadian rhythms of the autonomic nervous system, endocrine system, hemodynamics, etc and keeping them normal are considered important to the treatment and prevention of cardiovascular diseases. In modern society, artificial and irregular lives due to work shifts, long distance jet flights, aging of the society, diverse life styles, and so on are becoming routine. In this modern society, there are rapid increases in various diseases attributed to biorhythm disorders, including circadian rhythm-associated sleep disorder. Effective therapeutic action against such diseases is urgently needed. A patient

176 Melatonin

with desynchronosis syndrome (time zone fatigue) due to disturbance of the circadian rhythm falls into insomnia at night, and suffers from a sleep attack during the daytime. The patient is also annoyed by headache, tinnitus, palpitation, nausea, abdominal pain, or diarrhea, and presents with symptoms of decline in judgment and decrease in concentration. Draw-back sleep phase syndrome (DSPS) shows the highest morbidity rate during puberty (Diagnostic Classification Steering Committee, Thorpy M. J.: International Classification of Sleep Disorders: Diagnostic and Coding Manual., American Sleep Disorders Association, Rochester. 1990). Such circadian rhythmassociated sleep disorder among young people makes social adaptation difficult, and hinders the patients from exhibiting their abilities (Kajimura et al.: The Japanese Journal of Clinical Medicine, Vol. 56, No. 2, p. 404, 1998). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

GROWTH INHIBITION AND ERADICATION OF SOLID TUMORS USING NEUROENDOCRINE RESETTING THERAPY AND PHOTODYNAMIC THERAPY Inventor(s): CINCOTTA, ANTHONY H.; (CHARLESTOWN, MA), CINCOTTA, LOUIS; (ANDOVER, MA) Correspondence: Darby & Darby; 805 Third Avenue; New York; NY; 10022 Patent Application Number: 20010049350 Date filed: November 6, 1998 Abstract: A method of ablating the growth of or eradicating tumors in mammals having prolactin, growth hormone, and melatonin daily rhythms by adjusting one or more of the prolactin, growth hormone, and melatonin profiles of the mammal to conform to or approach the corresponding normal profile for healthy members of the same species and sex as said mammal, contacting the cells of the tumor with a photoactive photosensitizer, and, exposing the photosensitizer-contacted tumor cells to light of a predetermined wavelength, power density, and energy level. Excerpt(s): (c) exposing the contacted tumor cells to light of a predetermined wavelength, power density, and energy level. It is well known in the art to inhibit the growth of tumors by using cytotoxic compositions or ionizing radiation. A major drawback of ionizing radiation as a therapeutic modality is that it often results in injury or damage to healthy tissue in the vicinity of, or in contact with, the malignant tumor cells. Cytotoxic compositions have the even greater drawback of often causing systemic toxicity, i.e. damaging tissues at loci distal to the tumor. (iii) prolonged retention of these photosensitizers in the skin leads to dermal photosensitization that can persist for months. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Melatonin derivatives and medicine containing same Inventor(s): Blanchard, Beatric; (Rueil-Malmaison, FR), Ducrocq, Claire; (Orsay, FR) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20020198253 Date filed: July 3, 2002

Patents 177

Abstract: The invention concerns melatonin derivatives of formula (I) wherein: R.sub.1 represents H, a C.sub.1-C.sub.4 alkyl group or a C.sub.1-C.sub.4 alkoxy group; R.sub.2 represents H or a C.sub.1-C.sub.4 alkyl group; R.sub.3 represents H, methyl or a halogen atom; R.sub.4, R.sub.5 represent individually H or a halogen atom; R.sub.6 represents H or a C.sub.1-C.sub.4 alkyl group, or a pharmaceutically acceptable salt thereof. The invention also concerns a medicine comprising said derivatives. Excerpt(s): The present invention relates to novel melatonin derivatives capable of releasing nitrogen monoxide (NO) and melatonin under physiological conditions. Another subject matter of the invention is these melatonin derivatives for their application as therapeutically active substances. Nitrogen monoxide is a product of NOsynthetases in all animal organs, where it plays varied roles in maintaining the physiological functions, but especially in pathological situations, where it is synthesized in much greater amounts. It is a vasodilator and an antiaggregant for platelets and leukocytes with other cell types. It is involved in nerve transmissions, neither cholinergic nor adrenergic, but also in excitotoxicity processes of glutamate in the nervous system. In neurodegenerative processes, it is still difficult to take into consideration the involvement of NO and/or of oxygen derivatives. According to several authors, NO would rather have a protective role with regard to the neurons and would have an antioxidizing role by combining with oxygenated radicals. However, when it binds to superoxide, it generates peroxynitrite, which, in turn, modifies macromolecules and very particularly DNA. The fragmentation of DNA constitutes a phase in the apoptosis process. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Melatonin-receptor expression cells and thier uses Inventor(s): Koga, Jun-Ichi; (Kobe, JP), Shirono, Hiroyuki; (Kobe, JP), Yokoyama, Tetsuo; (Kobe, JP) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20030044909 Date filed: March 29, 2002 Abstract: The present invention provides materials capable of screening human melatonin which comprise an animal cell containing an expression plasmid for the gene encoding a human melatonin receptor protein and having said protein expressed therein, as well as a method for screening the same, thus permitting not only human melatonin but also hormones showing affinity for the same, and their agonists or antagonists to be screened with an enhanced degree of precision. Excerpt(s): The present invention relates to preparation of animal cells capable of expressing a gene encoding a human melatonin receptor protein, to a method for screening a hormone compound showing affinity for the said protein and its agonist or antagonist, and to uses of a recombinant human melatonin receptor protein produced according to the present invention. Melatonin, a hormone secreted by the pineal gland of the brain, occurs in body fluids, such as cerebrospinal fluid and blood, and its production is known to undergo marked circadian changes [L. Wetterberg et. al., Journal of Neural Transmission. Suppl. 13, 289-310 (1978)]. The mean blood level of melatonin is about 63 pg/ml for males and about 100 pg/ml for females, respectively, and increases by 50 to 100 fold during night than in the daytime. Melatonin is

178 Melatonin

biosynthesized from tryptophan as a lead compound by enzymatic modification through N-acetylserotonin via serotonin. Biosynthesis of melatonin shows a circadian rhythm, since M-acetyltransferase acting to catalyze acetylation of serotonin exhibits a circadian rhythm. In the brain tissues, there exist a variety of bioamines, such as catecholamine, adrenalin and serotonin, which are produced through modification of the corresponding amino acids and act as a neurotransmitter. It has been clarified that melatonin, when administered to humans, causes phase changes in circadian rhythm, and actually, the reports were published that melatonin is effecive for the treatment of circadian rhythm disorders inclusive of jet lag syndrome. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for controlling the alertness of a human subject and a light source for use in this method Inventor(s): Arendt, Josephine; (Guildford, GB), Skene, Debra J.; (Guildford, GB), Thapan, Kavita; (Guildford, GB), Van Den Beld, Gerrit Jan; (Eindhoven, NL), Van Der Burgt, Petrus Johannes Mathijs; (Eindhoven, NL) Correspondence: Philips Electronics North America Corporation; Corporate Intellectual Property; 580 White Plains Road; Tarrytown; NY; 10591; US Patent Application Number: 20030069616 Date filed: September 16, 2002 Abstract: The invention relates to a method for controlling the alertness of a human subject and a light source for use in this method and use of a light source for this method. The method comprises exposure of a human subject during an exposure period to suitable light radiation without substantially influencing the phase of a melatonin cycle. Melatonin is a sleep-hormone that can be used to control the alertness of a human subject. The suitable light radiation being specified by an output fraction of melatonin suppressive radiation (Melatonin Watt/Watt) and light output (lumen/Watt), the output fraction and light output being adjusted to obtain the desired effect on the phase of said cycle. Excerpt(s): The invention relates to a method for controlling the alertness of a human subject via suitable light radiation. The invention further relates to a method of adjustment of the circadian pacemaker and to a light source for use in these methods. In the last decade the knowledge of human photobiology is increased tremendously and has made clear that light radiation that is administered to the human subject through the eye--in addition to vision--is of major importance in controlling a variety of biological rhythms. Consequently light radiation has influence not only on many physical body functions but also on mental performance and mood. All scientific evidence is for the major part based on administering `white light radiation` of various intensities to the eye, this is generally known and for example described in U.S. Pat. No. 5,545,192. Findings show a sensitivity of melatonin suppression for light radiation administered through the eye, the melatonin suppression being dependent on dose and spectral composition of the light radiation, see Annals New York Academy of Sciences 453 (1985), p.376-378. Melatonin is a hormone which shows a daily cycle and is considered as a marker of the phase of the biological rhythms. Melatonin is generally known as a sleeping hormone that influences the alertness of the human subject. Hence, when the melatonin cycle is controlled, the risk on making mistakes because of lack of alertness is decreased. A relatively low melatonin level stimulates alertness, a relatively high melatonin level increases sleepiness. Annals New York Academy of Sciences 453 (1985),

Patents 179

p.376-378, states that the suppression of melatonin shows a highest sensitivity at a wavelength of about 509 nm. Suppressing melatonin is in the natural daily cycle possible in the `dark` hours, so where there is only artificial illumination available. During daytime the melatonin level is relatively low, the level increases in the evening, and reaches a maximum at night and decreases gradually to the level during daytime, in the wake up period. In a 24-hour society many people have to work and drive at night and be alert to perform well and safe, and to sleep well at abnormal hours. Under these conditions many people run an enhanced risk on making mistakes, for example causing car accidents, and/or are likely to suffer from a distorted sleeping behavior. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for reducing intraocular pressure using indole derivatives Inventor(s): Brown, Edward G.; (Apex, NC), Peral, Maria A.; (Madrid, ES), Peterson, Ward M.; (Durham, NC), Pintor, Jesus J.; (Madrid, ES), Plourde, Robert JR.; (Chapel Hill, NC), Yerxa, Benjamin R.; (Raleigh, NC) Correspondence: Howrey Simon Arnold & White, Llp; Box 34; 301 Ravenswood AVE.; Menlo Park; CA; 94025; US Patent Application Number: 20020037887 Date filed: July 25, 2001 Abstract: The present invention provides a method of reducing intraocular pressure by administering pharmaceutical compositions comprising indole derivatives. The pharmaceutical compositions useful in this invention comprise indole derivatives and melatonin analogs of Formulae I-IV. A preferred embodiment is a method of lowering intraocular pressure using 5-(methoxycarbonylamino)-N-acetyltryptamine (5-MCANAT), also known as GR 135531, which has a prolonged duration of action and greater efficacy in lowering intraocular pressure compared to melatonin. The present invention further provides a method of treating disorders associated with ocular hypertension, and a method of treating various forms of glaucoma; the method comprises administering an effective dose of a pharmacuetical composition comprising an indole derivative with or without agents commonly used to treat such disorders. 1 Excerpt(s): This application claims the benefit of Spanish Application No. P200001916, filed Jul. 28, 2000. This application also claims the benefit of U.S. Provisional Application Ser. No. 60/276,885, filed Mar. 16, 2001. This invention relates to a method for lowering intraocular pressure, treating ocular hypertension, and treating glaucoma, by administering indole analogues and pharmaceutical compositions. Glaucoma is a slowly progressive blinding disease usually associated with chronic elevation of intraocular pressure (TOP). Sufficiently high and persistent intraocular pressure is believed to result in damage to the optic disc at the juncture of the optic nerve and retina, resulting in degeneration of retinal ganglion cells and blindness characteristic of glaucoma. However, the mechanism whereby TOP elevation (also known as ocular hypertension) leads to glaucoma is not well understood. Additionally, a fraction of patients with typical visual field loss associated with glaucoma do not show abnormal elevated TOP levels (known as low-tension or normal-tension glaucoma). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

180 Melatonin

•

Method for the treatment of neurological or neuropsychiatric disorders Inventor(s): Willis, Gregory Lynn; (Woodend, AU) Correspondence: Rothwell, Figg, Ernst & Manbeck, P.C.; 555 13th Street, N.W.; Suite 701, East Tower; Washington; DC; 20004; US Patent Application Number: 20020068692 Date filed: October 9, 2001 Abstract: A method for the treatment and/or prophylaxis of a neurological or neuropsychiatric disorder associated with altered dopamine function which comprises subjecting a patient in need thereof to therapy which blocks and/or inhibits melatonin, precursors thereof and/or metabolic products thereof Excerpt(s): This is a continuation-in-part application of U.S. Ser. No. 09/285,859, filed Apr. 2, 1999 which is a continuation-in-part application of International Patent Application No. PCT/AU97/00661, filed on Oct. 3, 1997. The present invention relates generally to a method for the treatment and/or prophylaxis of neurological or neuropsychiatric disorders, in particular neurological or neuropsychiatric disorders associated with altered dopamine function. The pineal body, situated in the epithalarmus at the center of the brain, synthesises and releases melatonin into the general circulation only during nocturnal darkness, irrespective of whether a species is nocturnal or diurnal in its behavioral activity pattern. In mammals, the rhythm of pineal nocturnal melatonin secretion is generated by a biological clock located at the suprachiasmatic nuclei (hereinafter referred to as "SCN") of the anterior hypothalamus. After following a circuitous route through the brain, afferent pathways of the conarian nerves originating from the superior cervical ganglia end in sympathetic innervation on pinealocytes. In humans, the only natural phenomenon presently known to inhibit melatonin release is bright light. Melatonin release appears to be robust and resistant to change by a variety of potent stimuli. The stability of the melatonin rhythm makes melatonin an ideal candidate as a biological timing hormone, a role which is indisputable for rhythms in photo-sensitive seasonal breeding mammals and has been postulated for daily rhythms in non-seasonal breeders. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Method of hormone treatment for patients with symptoms consistent with multiple sclerosis Inventor(s): Chein, Edmund Y.M.; (Beverly Hills, CA) Correspondence: Blakely Sokoloff Taylor & Zafman; 12400 Wilshire Boulevard, Seventh Floor; Los Angeles; CA; 90025; US Patent Application Number: 20010012832 Date filed: February 12, 2001 Abstract: A method for patients having symptoms consistent with multiple sclerosis comprising administering a regimen of doses of human growth hormone of less than 0.5 mg/day. In one aspect, the method includes replenishing one or more of melatonin, thymus, thyroid, adrenal and sex hormones to predetermined levels in conjunction with the human growth hormone. Excerpt(s): The invention relates to hormone therapy as a treatment for patients with symptoms consistent with multiple sclerosis. It is known that the levels of a variety of

Patents 181

hormones drop substantially with age. These include human growth hormone, sex hormones, pineal, adrenal, thyroid, and thymus hormones. Hormonal replenishment methods employed as anti-aging treatments have been developed. An example of such method is described in U.S. Pat. No. 8,855,920. The utility of this method in connection with certain degenerative diseases, often associated with hormonal deficiencies due to aging, is also known in the art. In contrast, Multiple Sclerosis (MS) is not a disease associated with degenerative conditions associated with old age. Rather, MS strikes mainly young adults and is the most common neurologic cause of disability in that age group. Overall, MS affects approximately 300,000 Americans. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method of treating paralysis of the extremities caused by cerebral infarction Inventor(s): Borlongan, Cesario V.; (Silver Spring, MD), Nishino, Hitoo; (Nagoya-shi, JP), Uneyama, Hisayuki; (Kawasaki-shi, JP) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20010051652 Date filed: January 5, 2001 Abstract: The administration of a therapeutically effective amount of melatonin is an effective method for treating paralysis of the extremities caused by cerebral infarction. Excerpt(s): The present invention relates to a method for the treatment of paralysis of the extremities induced by cerebral infarction. More specifically, it relates to a method comprising administering melatonin for the treatment of such paralysis of the extremities. Cerebral infarction is a severe cerebral dysfunction induced by cerebral ischemia or hypoxemia. With the increase of the aged population, the incidence of diseases or conditions, which may cause cerebral ischemia such as cerebral thrombosis and cerebral embolism, is increasing. Indeed, the number of patients suffering from cerebral infarction and having cerebral dysfunctions is continuously increasing. One of the cerebral dysfunctions caused by cerebral infarction is paralysis of the extremities. When the hands and legs cannot perform their functions, the quality of life of such affected patients is significantly lowered and many burdens are placed on them and their families. For such patients, complete daily care is necessary. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Methods for treating circadian rhythm phase disturbances Inventor(s): Lewy, Alfred J.; (Portland, OR), Sack, Robert L.; (Portland, OR) Correspondence: Mcdonnell Boehnen Hulbert & Berghoff; 300 South Wacker Drive; Suite 3200; Chicago; IL; 60606; US Patent Application Number: 20030008912 Date filed: July 23, 2002 Abstract: A method for treating circadian rhythm phase disorders is described. The invention provides methods to specifically advance or delay the phase of certain circadian rhythms in humans. The disclosed methods relate to the administration of melatonin at times determined with relation to the time of dim light endogenous

182 Melatonin

melatonin onset. Embodiments capable of alleviating the effects of jet lag, winter depression and shift-work sleep disturbance are provided. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 07/842,723, filed Feb. 25, 1992, now U.S. Pat. No. 5,242,941, issued Sep. 7, 1993, which is a continuation of U.S. patent application Ser. No. 07/621,866, filed Dec. 4, 1990. The field of the invention disclosed in this application relates to circadian rhythms in humans, and particularly to the synchronization of such human circadian rhythms with the external environment. Specifically, this invention describes methods for achieving a chronobiologic (circadian phase-shifting) effect in humans. The invention provides methods to specifically advance or delay the phase of certain circadian rhythms in humans. Specific embodiments of the invention comprise methods for alleviating the effects of transmeridional travel (i.e., jet lag); methods for alleviating circadian phase disturbance-based psychological disorders (such as winter depression or seasonal affective disorder); and methods for achieving synchrony between a human's wake/sleep cycle or other circadian rhythms and the human's occupational and other human activity schedules. Such re-synchrony enabled by the methods of this invention is achieved by the administration of effective amounts of melatonin at specific and predictable times based upon an individual human's circadian rhythm phase response curve (PRC). The phenomenon of circadian rhythms in biology is well known, and circadian rhythms are exhibited by all eukaryotic plants and animals, including man. Biological rhythms are periodic fluctuations in biological properties over time; these include circadian as well as seasonal variations. Circadian, or approximately 24-hour, rhythms include the production of biological molecules such as hormones, the regulation of body temperature, and behaviors such as wakefulness, sleep and periods of activity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods for treating patients suffering from drug dependencies which leads to plasma melatonin deficiencies Inventor(s): Zisapel, Nava; (Tel Aviv, IL) Correspondence: Rothwell, Figg, Ernst & Manbeck, P.C.; 1425 K Street, N.W.; Suite 800; Washington; DC; 20005; US Patent Application Number: 20020156121 Date filed: April 8, 2002 Abstract: A method of treating a patient suffering from a dependence on, tolerance of, or addiction to at least one benzodiazepine comprises administering melatonin to said patient on a daily basis in an amount sufficient to treat said dependence on, tolerance of, or addiction to said benzodiazepine. Excerpt(s): This application is a Continuation of Ser. No. 08/381,535, filed Feb. 1, 1995. The present invention relates to a method for treating a patient who is suffering from a dependence on, tolerance of, or addiction to at least one benzodiazepine or is at risk of becoming dependent upon, tolerant of, or addicted to such a drug. More specifically, the invention relates to such a method which comprises administering an amount of melatonin effective to treat or prevent the dependence, tolerance or addiction. Insomnia is a frequently encountered problem in modern society: it is estimated that almost one third of the U.S. population suffers from this condition to some extent. The problem is particularly troublesome among the elderly. Benzodiazepine hypnotics are among the

Patents 183

most commonly used drugs in the therapeutic treatment of insomnia. Although the precise mechanism of action of these drugs on sleep induction has not been completely elucidated, it is assumed that they exert their activity through a benzodiazepine/GABAA (gamma amino butyric acid) receptor complex. As insomnia is thought to be associated with derangement of the normal sleep-wake cycle, it is possible that the effects of these drugs on sleep induction may be accomplished by phase-shifting the internal biological clock in the brain. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pharmaceutical or food composition for treatment or prevention of brain edema Inventor(s): Nishino, Hitoo; (Nagoya-shi, JP), Torii, Kunio; (Kawasaki-shi, JP), Uneyama, Hisayuki; (Kawasaki-shi, JP) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20020119191 Date filed: April 24, 2000 Abstract: Melatonin has an activity of treating or preventing brain edema. Thus, the invention relates to a pharmaceutical composition comprising melatonin as an active ingredient. And, the invention relates to use of melatonin in the preparation of a pharmaceutical composition comprising melatonin as an active ingredient. Excerpt(s): The present invention relates to compositions for the treatment or prevention of brain edema. More particularly, it relates to pharmaceutical or food compositions for the treatment or prevention of brain edema comprising melatonin as an active ingredient. And, it relates to the use of melatonin in the preparation of the above composition. It relates also to a method for the treatment or prevention of brain edema with the above composition. Brain edema refers to a condition where fluid is excessively accumulated in brain parenchyma (in intercellular spaces or in cells) resulting in swell of brain tissue. The swell of tissue in the limited cranial space increases intracranial pressure. Thus, the brain edema generally associates with increased intracranial pressure. Brain edema can be etiologically classified into "vasogenic brain edema" and "cytotoxic brain edema" (I. Klatzo, J. Neuropatho. Exp. Neurol., 25: 1-14, 1967). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Photoreceptor system for melatonin regulation and phototherapy Inventor(s): Brainard, George; (Haddonfield, NJ) Correspondence: Thomas Jefferson University; Intellectual Property Division; 1020 Walnut Street; Suite 620; Philadelphia; PA; 19107; US Patent Application Number: 20010056293 Date filed: May 10, 2001 Abstract: The present invention involves a light system for stimulating or regulating neuroendocrine, circadian, and photoneural systems in mammals based upon the discovery of peak sensitivity ranging from 425-505 nm; a light meter system for quantifying light which stimulates or regulates mammalian circadian, photoneural, and neuroendocrine systems. The present invention also relates to translucent and

184 Melatonin

transparent materials, and lamps or other light sources with or without filters capable of stimulating or regulating neuroendocrine, circadian, and photoneural systems in mammals. Additionally, the present invention involves treatment of mammals with a wide variety of disorders or deficits, including light responsive disorders, eating disorders, menstrual cycle disorders, non-specific alerting and performance deficits, hormone-sensitive cancers, and cardiovascular disorders. Excerpt(s): This application claims priority under 35 U.S.C.sctn. 119 based upon U.S. Provisional Patent Application No. 60/203,308 filed May 10, 2000 and upon U.S. Provisional Patent Application No.60/228,493 filed Aug. 28, 2000. The present invention generally relates to the fields of neurology, neuroscience, and endocrinology and to light systems, light meters, lamps, filters, transparent and translucent materials, and methods of treating a variety of mammalian disorders and, more particularly to a light system for stimulating or regulating neuroendocrine, circadian, and photoneural systems in mammals based upon the discovery of peak sensitivity ranging from 425-505 nm; a light meter system for quantifying light which stimulates mammalian circadian, photoneural, and neuroendocrine systems; translucent and transparent materials, and lamps or other light sources with or without filters stimulating or regulating neuroendocrine, circadian, and photoneural systems in mammals; and treatment of mammals with a wide variety of disorders or deficits, including light responsive disorders, eating disorders, menstrual cycle disorders, non-specific alerting and performance deficit, hormone-sensitive cancers, and cardiovascular disorders. Light is the primary stimulus for regulating circadian rhythms, seasonal cycles, and neuroendocrine responses in many species including humans (Klein et al., 1991; Wehr, 1991). Further, clinical studies have demonstrated that light therapy is effective for treating selected affective disorders, sleep problems, and circadian disruptions (Wetterberg, 1993; Lam, 1998). Previously, the ocular photoreceptors which transduce light stimuli for circadian regulation and the clinical benefits of light therapy have been unknown. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Subtype selective melatonergics Inventor(s): Jones, Robert M.; (Salt Lake City, UT) Correspondence: Rothwell, Figg, Ernst & Manbeck, P.C.; 555 13th Street, N.W.; Suite 701, East Tower; Washington; DC; 20004; US Patent Application Number: 20020040018 Date filed: June 22, 2001 Abstract: The invention relates to the use of MT.sub.2 selective melatonergics as anticonvulsant agents and as analgesic agents. More specifically, the invention relates to the use of 6H-isoindolo[2,1-a]indoles or 5,6-dihydroindolo[2,1-a]isoquinolines as described herein which have melatonin agonist activity and which are selective for the MT.sub.2 receptor as anticonvulsant agents or analgesic agents. The invention further relates to the use of 5,6-dihydroindolo[2,1-a]isoquinolines and 6,7-dihydro-5Hbenzo[c]azepino[2,1-a]indoles as described herein which have melatonin antagonist activity and which are selective for the MT.sub.2 receptor as pharmacological tools for delineation of physiological responses governed by MT.sub.2 receptor activation either by melatonin or selective agonists disclosed herein and for treatment of disorders associated with overproduction of melatonin such as seasonal affective disorder (SAD) and shift work syndrome. Such melatonin antagonists are also useful for treating Parkinson's Disease.

Patents 185

Excerpt(s): The present application is related to U.S. provisional patent application No. 60/______ filed on Jun. 23, 2000 (attorney docket number 2314-183) and to U.S. provisional patent application No. 60/264,695 filed on Jan. 30, 2001, each incorporated by reference herein. The present application further claims priority to each of these applications. The invention relates to the use of MT.sub.2 selective melatonergics as anticonvulsant agents and as analgesic agents. More specifically, the invention relates to the use of 6H-isoindolo[2,1-a]indo- les or 5,6-dihydroindolo[2,1-a]isoquinolines as described herein having melatonin agonist activity and which are selective for the MT.sub.2 receptor as anticonvulsant agents or analgesic agents. The invention further relates to the use of 5,6-dihydroindolo[2,1-a]isoquinolines and 6,7-dihydro-5Hbenzo[c]azepino[2,1-a]indoles as described herein having have melatonin antagonist activity and which are selective for the MT.sub.2 receptor as pharmacological tools for delineation of physiological responses governed by MT.sub.2 receptor activation either by melatonin or selective agonists disclosed herein and for treatment of disorders associated with overproduction of melatonin such as seasonal affective disorder (SAD) and shift work syndrome. Such melatonin antagonists are also useful for treating Parkinson's Disease. The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Topical testosterone formulations and associated methods Inventor(s): Kryger, Abraham H.; (Monterey, CA) Correspondence: Thorpe North Western; 8180 South 700 East, Suite 200; P.O. Box 1219; Sandy; UT; 84070; US Patent Application Number: 20020150625 Date filed: December 11, 2001 Abstract: A topical testosterone formulation is disclosed. In one aspect, the formulation may include a therapeutically effective amount of micronized testosterone, an arginine ingredient, and a tocopherol ingredient admixed with a poloxamer lecithin organogel. Additional ingredients may be included, such as melatonin, oxytocin, DHEA, and progesterone. Excerpt(s): This application claims priority to United States Provisional Patent Application Serial No. 60/254,713, filed on Dec. 11, 2000, which is hereby incorporated by reference. The present invention relates to topical testosterone formulations, including methods for making and using such formulations. Accordingly, this invention covers the fields of pharmaceutical sciences and medicine. Hormone replacement therapy has been used in the past to treat patients who have lost the ability to make the hormones or who have reduced hormone levels. Further, testosterone replacement therapy has been used to treat patients with abnormally low testosterone levels. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

186 Melatonin

•

Use of melatonin for induction of general anesthesia Inventor(s): Attala, Mohamed Naguib; (Coralville, IA) Correspondence: Mckee, Voorhees & Sease, P.L.C.; 801 Grand Avenue; Suite 3200; Des Moines; IA; 50309-2721; US Patent Application Number: 20020035141 Date filed: August 10, 2001 Abstract: Melatonin (N-acetyl-5-methoxytryptamine), analogues, are used to induce anesthesia.

or

its

biologically

active

Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 60/233,785 filed Sep. 19, 2000 and claims the benefit of that filing date. In the medical field there is a continuing need for new compounds having demonstrated use for inducing anesthesia. It is not only important to induce beneficial anesthesia, but it must be done in a manner that limits toxicity to patients, and as well, minimizes what is known as "anesthesia hangover". The pineal hormone melatonin (N-acetyl-5-methoxytryptamine) has several putative functions, including regulation of circadian rhythms, regulation of the reproductive axis and antioxidant activity. Autoradiographic studies and receptor assays have demonstrated the presence of melatonin receptors in various regions of the central nervous system and in other tissues in humans. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of resveratrol for the treatment of exfoliative eczema, acne and psoriasis Inventor(s): Giannella, Attilio; (Codogno, IT), Giannella, Jenny; (Codogno, IT), Pelliccia, Maria Teresa; (Avellino, IT) Correspondence: Young & Thompson; 745 South 23rd Street 2nd Floor; Arlington; VA; 22202 Patent Application Number: 20010056071 Date filed: March 22, 2001 Abstract: The use of resveratrol (3,4',5-trihydroxy-trans-stilbene) and derivatives thereof, for the preparation of medicaments for the treatment of exfoliative eczema, acne and psoriasis, topical pharmaceutical formulations containing resveratrol or derivatives thereof in combination with other active principles. Treatment consists in topical administrations of resveratrol at concentrations of 0.01 to 20%, in the form of lotions, creams or ointments, optionally in combination with other active principles such as melatonin, vitamins D, E and A and derivatives thereof, hormones, vegetable and/or animal extracts. Contrary to current therapies, the use of resveratrol has neither systemic nor topical effects during and after therapy. Excerpt(s): The present invention relates to the use of resveratrol (3,4',5-trihydroxytrans-stilbene) and derivatives thereof (esters, glycosides, 3'-oxyresveratrol), for the preparation of medicaments for the treatment of exfoliative eczema, acne and psoriasis. Resveratrol (3,4',5-trihydroxy-trans-stilbene), a phytoalexin produced by a number of vegetables under stress conditions, is one of the natural substances of vegetable origin at present arousing great interest in the pharmaceutical, cosmetic and nutritional fields, due to the important, established effects this molecule exerts in humans. In vitro and in vivo studies on resveratrol proved that the molecule: a) exerts protective action on the cardiovascular system, (Clin. Chim. Acta, 235:207, 1995) and decreases arteriosclerosis

Patents 187

risks (Clin. Chim. Acta, 246:163, 1996); b) has vasal relaxing effect on the arteries (Gen. Pharm. 27:363, 1996); c) has antioxidant action which inhibits LDL cholesterol peroxidation (The Lancet, 341:1103, 1993); reduces oxidative stress (Neuroreport 8:1499, 1997); protects from the radical damage in cerebral ischemia (Chin. Pharm. Bull. 12:128, 1996); prevents the propagation of free radicals responsible for the molecular damage of the biological systems and for cell aging; d) modulates lipid synthesis, preventing the accumulation of cholesterol and fats in the liver, decreases the concentrations of blood triglycerids and of cholesterol in low-density LDL lipoproteins and reduces the atherogenic index (Chem Pharm. Bull. 30:1766, 1982); e) inhibits platelet aggregation, preventing the formation of thrombi (Int. J. Tiss. Reac. XVIII, 1, 1995; Thrombosis and Haemostasis, 76:818, 1996); f) inhibits the production of proatherogenic eicosanoids by platelets and neutrophils, exerting anti-inflammatory action (Biochem. Biophys. Acta, 834:275, 1985); g) inhibits protein-tyrosine kinase which modulates cell proliferation and differentiation and the signaling processes in the immune system cells, biological processes involved in the inflammatory response and in severe pathologies such as cancer, arteriosclerosis and psoriasis (J. Natural Products, 56:1805, 1993, Science 267:1782, 1995); h) has marked antimutagenic action, inhibiting the cell events connected with the initiation, promotion and progression of the tumor (Science 275:218, 1997, Anal. Biochem, 169:328, 1988, Proc. Natl. Acad. Sci USA, 91:3147, 1994, Proc. Natl. Acad. USA, 72:1848, 1975, Carcinogenesis, 8:541, 1987). The presence of resveratrol traces in red wines is believed to be the main cause of the beneficial nutritional effects thereof (Am, J. Enol. Vitic. 46:159, 1996, Clin. Chim. Acta, 246:183, 1996, Amer. J. Clin. Nutr., 55:1012, 1992). The poor concentrations of resveratrol in wine and in wine industry by-products have, until some time ago, remarkably restricted a wide use of this molecule in the pharmaceutical and nutritional fields. Recently, rhizomes of the Chinese plant Poligonum cuspidatum have been found to contain high amounts of resveratrol (more than about 400 times those in wine) thus inducing a strong commercial development of this molecule as alimentary supplement, in particular on the U.S. market. Lately, the actions of resveratrol for pharmacological or cosmetic use have been claimed (WO9959561; WO9958119; EP0773020; FR2766176; WO9904747). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with melatonin, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “melatonin” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on melatonin. You can also use this procedure to view pending patent applications concerning melatonin. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

189

CHAPTER 7. BOOKS ON MELATONIN Overview This chapter provides bibliographic book references relating to melatonin. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on melatonin include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “melatonin” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on melatonin: •

101 Tips for Staying Healthy with Diabetes (and Avoiding Complications). 2nd ed Source: Alexandria, VA: American Diabetes Association. 1999. 127 p. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $14.95 plus shipping and handling. ISBN: 1580400078. Summary: This book presents a collection of tips, techniques, and strategies for preventing and treating diabetes complications. One question appears on each page, with the answer immediately below. Questions in chapter one provide general information about diabetes and diabetes complications. Chapter two focuses on glucose control. The third chapter answers questions about various foods and nutrients, including chromium, fiber, fructose, ginseng, folic acid, magnesium, and melatonin. Questions in chapter four provide general information about nutrition, meal planning,

190 Melatonin

and weight management. This is followed by a chapter that describes small blood vessel complications, including eye and kidney disease, diabetic gastroparesis, and foot problems. Chapter six answers questions about large blood vessel complications, including heart disease, erectile dysfunction, and bladder problems. The next two chapters answer miscellaneous questions and offer new tips. The final chapter lists the name, address, and telephone number of helpful organizations. The book also includes an index.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “melatonin” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “melatonin” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “melatonin” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

Boost Your Vitality With Melatonin: Programming Your Internal Clock For Health & Well-Being by Ingeborg Cernaj (1998); ISBN: 0806942177; http://www.amazon.com/exec/obidos/ASIN/0806942177/icongroupinterna

•

Chronobiology and Chronic Rheumatism: Effects of Radon-Balneotherapy and Melatonin Treatment Within Chronic Arthrosis (Berichte (Forschungsinstitut (Badgastein, Austria)),Bd. 4.) by Bernd Minnich, et al (2001); ISBN: 0820453552; http://www.amazon.com/exec/obidos/ASIN/0820453552/icongroupinterna

•

Melatonin by Jo Robinson (Author), Russel J. Reiter (Author) (1996); ISBN: 0553574841; http://www.amazon.com/exec/obidos/ASIN/0553574841/icongroupinterna

•

Melatonin by Walji Hasnain, Hasnain Walji; ISBN: 0722532253; http://www.amazon.com/exec/obidos/ASIN/0722532253/icongroupinterna

•

Melatonin - Current Status and Perspectives by N. Birau, W. Schloot; ISBN: 008026400X; http://www.amazon.com/exec/obidos/ASIN/008026400X/icongroupinterna

•

Melatonin (Woodland Health Ser) by Deanne Tenney, Woodland Publishing (1999); ISBN: 1885670222; http://www.amazon.com/exec/obidos/ASIN/1885670222/icongroupinterna

•

Melatonin After Four Decades: An Assessment of Its Potential (Advances in Experimental Medicine and Biology, 460) by James Olcese (Editor), Hanseatic Endocrine Conference on Melatonin After Four Decades; ISBN: 030646134X; http://www.amazon.com/exec/obidos/ASIN/030646134X/icongroupinterna

•

Melatonin and Its Analogs, from Molecular Biology to Clinical Application: Erice Italy, June 1998 by F. Fraschini (Editor), et al (1999); ISBN: 3805568401; http://www.amazon.com/exec/obidos/ASIN/3805568401/icongroupinterna

•

Melatonin and the Biological Clock by Alan E. Lewis, et al; ISBN: 0879837349; http://www.amazon.com/exec/obidos/ASIN/0879837349/icongroupinterna

Books

191

•

Melatonin and the Mammalian Pineal Gland by J. Arendt (1994); ISBN: 0412536005; http://www.amazon.com/exec/obidos/ASIN/0412536005/icongroupinterna

•

Melatonin and the Pineal Gland: From Basic Science to Clinical Application by Y. Touitou, et al; ISBN: 0444895833; http://www.amazon.com/exec/obidos/ASIN/0444895833/icongroupinterna

•

Melatonin Binding Sites in Endocrine and Immune Systems: Journal: Biological Signals, Vol 3, No 2, 1994 by G. M. Brown (Editor), et al (1994); ISBN: 3805560079; http://www.amazon.com/exec/obidos/ASIN/3805560079/icongroupinterna

•

Melatonin in Health Promotion by Ronald R. Watson (Editor); ISBN: 0849385644; http://www.amazon.com/exec/obidos/ASIN/0849385644/icongroupinterna

•

Melatonin in Humans: Proceedings of the First International Conference on Melatonin in Humans (Journal of Neural Transmission, Supplementum 21) by J.R. Wurtman, et al; ISBN: 0387819274; http://www.amazon.com/exec/obidos/ASIN/0387819274/icongroupinterna

•

Melatonin in Humans: Proceedings of the First International Conference on Melatonin in Humans, Vienna, Austria, November 7-9, 1985; ISBN: 3211819274; http://www.amazon.com/exec/obidos/ASIN/3211819274/icongroupinterna

•

Melatonin in Psychiatric and Neoplastic Disorders by Mohammad, Md. Shafii (Editor), et al; ISBN: 0880489197; http://www.amazon.com/exec/obidos/ASIN/0880489197/icongroupinterna

•

Melatonin Rhythm Generating System: Developmental Aspects by D. C. Klein (Editor) (1983); ISBN: 3805534604; http://www.amazon.com/exec/obidos/ASIN/3805534604/icongroupinterna

•

Melatonin: A Universal Photoperiodic Signal With Diverse Actions (Frontiers of Hormone Research, Vol. 21) by P. L. Tang (Editor), et al (1997); ISBN: 3805563442; http://www.amazon.com/exec/obidos/ASIN/3805563442/icongroupinterna

•

Melatonin: Biological Basis of Its Function in Health and Disease by S. R. PandiPerumal (2003); ISBN: 1587062445; http://www.amazon.com/exec/obidos/ASIN/1587062445/icongroupinterna

•

Melatonin: Biosynthesis, Physiological Effects, and Clinical Applications by HingSing, Ph.D. Yu, Russel J., Ph.D. Reiter (Editor); ISBN: 0849369002; http://www.amazon.com/exec/obidos/ASIN/0849369002/icongroupinterna

•

Melatonin: Clinical Perspectives by Andrew Miles (Editor), et al (1993); ISBN: 0192616528; http://www.amazon.com/exec/obidos/ASIN/0192616528/icongroupinterna

•

Melatonin: From Contraception to Breast Cancer Prevention by Michael Cohen (1996); ISBN: 1880613107; http://www.amazon.com/exec/obidos/ASIN/1880613107/icongroupinterna

•

Melatonin: Natures Sleeping Pill by Ray Sahelian; ISBN: 0963975579; http://www.amazon.com/exec/obidos/ASIN/0963975579/icongroupinterna

•

Melatonin: The Anti-Aging Hormone by Suzanne LeVert; ISBN: 0380807181; http://www.amazon.com/exec/obidos/ASIN/0380807181/icongroupinterna

•

Photoperiodism, melatonin and the pineal; ISBN: 0272798215; http://www.amazon.com/exec/obidos/ASIN/0272798215/icongroupinterna

192 Melatonin

•

Photoperiodism, Melatonin and the Pineal - Symposium No. 117 by CIBA Foundation Symposium (Author); ISBN: 0471910864; http://www.amazon.com/exec/obidos/ASIN/0471910864/icongroupinterna

•

Putative Melatonin Receptors in Peripheral Tissues (Biological Signals, Vol 2, No 4) by S. F. Pang (Editor), et al (1994); ISBN: 380555947X; http://www.amazon.com/exec/obidos/ASIN/380555947X/icongroupinterna

•

Recent Progress of Pineal Research - 40 Years After Discovery of Melatonin (Biological Signals, 4-6) by Y. Morita (Editor) (1998); ISBN: 3805566387; http://www.amazon.com/exec/obidos/ASIN/3805566387/icongroupinterna

•

Receptor and Non-Receptor Mediated Actions of Melatonin: Selected Papers from the International Symposium Held in Hong Kong, China, November 6-8, 1999 by S. Y. W. Shiu (Editor), S. F. Pang (Editor) (2000); ISBN: 3805571259; http://www.amazon.com/exec/obidos/ASIN/3805571259/icongroupinterna

•

Role of Melatonin and Pineal Peptides in Neuroimmunomodulation (NATO Asi Series A, Life Sciences, Vol 204) by NATO Advanced Research Workshop on the Role of Melatonin and Pineal Pe, et al (1991); ISBN: 0306439212; http://www.amazon.com/exec/obidos/ASIN/0306439212/icongroupinterna

•

Stay Young : The Melatonin Way by Dr. Stephen J. Bock (Author); ISBN: 0091809967; http://www.amazon.com/exec/obidos/ASIN/0091809967/icongroupinterna

•

The Melatonin and Aging Sourcebook by Roman Rozencwaig, et al (1997); ISBN: 0934252769; http://www.amazon.com/exec/obidos/ASIN/0934252769/icongroupinterna

•

The Melatonin Hypothesis: Breast Cancer and Use of Electric Power by Richard G. Stevens (Editor), et al (1997); ISBN: 1574770209; http://www.amazon.com/exec/obidos/ASIN/1574770209/icongroupinterna

•

The Melatonin Miracle: Nature's Age-Reversing, Disease-Fighting, Sex-Enhancing Hormone by Walter, Md Pierpaoli, et al; ISBN: 0671534351; http://www.amazon.com/exec/obidos/ASIN/0671534351/icongroupinterna

•

The Melatonin Miracle: Nature's Age-Reversing, Disease-Fighting, Sex-Enhancing Hormone/Cassette by Walter Pierpaoli, William Regelson; ISBN: 0671535390; http://www.amazon.com/exec/obidos/ASIN/0671535390/icongroupinterna

•

The Melatonin Report by Billie Jay Sahley (1996); ISBN: 0962591467; http://www.amazon.com/exec/obidos/ASIN/0962591467/icongroupinterna

•

The Pineal Organ, Its Hormone Melatonin, and the Photoneuroendocrine System by C. Schomerus, et al; ISBN: 3540641351; http://www.amazon.com/exec/obidos/ASIN/3540641351/icongroupinterna

•

Therapeutic Potential of Melatonin: 2nd Locarno Meeting on Neuroendocrinoimmunology, Locarno, May 5-8, 1996 (Frontiers of Hormone Research, Vol. 23) by Georges J. M. Maestroni (Editor), et al (1997); ISBN: 3805564392; http://www.amazon.com/exec/obidos/ASIN/3805564392/icongroupinterna

•

Treatise on Pineal Gland and Melatonin by Chandana Haldar (Editor), et al (2002); ISBN: 1578082250; http://www.amazon.com/exec/obidos/ASIN/1578082250/icongroupinterna

•

Tryptophan, Serotonin, and Melatonin: Basic Aspects and Applications (Advances in Experimental Medicine and Biology, 467) by Gerald Huether (Editor), et al; ISBN:

Books

193

0306462044; http://www.amazon.com/exec/obidos/ASIN/0306462044/icongroupinterna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “melatonin” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:11 •

Melatonin in human and animal tissues: an analytical physiological study Author: Vakkuri, Olli.; Year: 1986; Oulu: University of Oulu, 1986; ISBN: 951422244X

•

The melatonin and aging sourcebook Author: Rozencwaig, Roman,; Year: 1998; Prescott, Ariz.: Hohm Press, c1997; ISBN: 0934252734 http://www.amazon.com/exec/obidos/ASIN/0934252734/icongroupinterna

•

The melatonin miracle: nature's age-reversing, disease-fighting, sex-enhancing hormone Author: Pierpaoli, Walter.; Year: 1996; New York: Simon; Schuster, c1995; ISBN: 0684813351 http://www.amazon.com/exec/obidos/ASIN/0684813351/icongroupinterna

Chapters on Melatonin In order to find chapters that specifically relate to melatonin, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and melatonin using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “melatonin” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on melatonin: •

Cognitive Enhancement Source: In Chapter 1 of: Oldham, J.M. and Riba, M.B. eds. Complementary and Alternative Medicine and Psychiatry. Washington, DC: American Psychiatric Press. 2000. p. 38-46. Contact: Available from American Psychiatric Press, Inc. 1400 K Street, N.W., Washington, DC 20005. (202) 682-6262. Toll-free: 1-800-368- 5777. FAX: (202) 789-2648. Website: www.appi.org. PRICE: $34.95. ISBN: 0-88048-174-9. APPI Item 8174.

11

In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

194 Melatonin

Summary: This book section reviews some of the herbs that have been used to enhance cognitive function. Ginkgo has been used to treat Alzheimer's disease (AD) and cerebrovascular-related problems, but memory improvements are modest and are dose related. Acetyl L- carnitine appears to slow the progression of AD and help inhibit neural degeneration. Selegiline has been used as a treatment for Parkinson's disease and to improve cognitive function in early AD. Choline has been used as a cognitive enhancer and a treatment for depression, but the research is preliminary. Several nootropic compounds have been promoted as 'smart drugs,' but there is no evidence of memory improvement in human studies. Alpha-lipoic acid and coenzyme Q-10 appear to be beneficial after stroke and for ischemic heart disease. Several studies have failed to support claims that Asian ginseng promotes memory. Phosphatidyl serine has shown positive results in both age-associated memory impairment and AD. Omega-3 fatty acids, particularly DHA, have shown promise in delaying the onset of AD and improving symptoms. Melatonin and dehydroepiandrosterone (DHEA) are popular as anti-aging hormones, but concerns have been raised in the medical literature.

Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to melatonin have been published that consolidate information across various sources. The Combined Health Information Database lists the following, which you may wish to consult in your local medical library:12 •

Dietary Supplements Resource List Source: Beltsville, MD: Food and Nutrition Information Center. 2000. 10 p. Contact: Available from Food and Nutrition Information Center. National Agricultural Library, U.S. Department of Agriculture, 10301 Baltimore Avenue, Room 304, Beltsville, MD 20705-2351. INTERNATIONAL: (301) 504-5719; TTY: (301) 504-6856; FAX: (301) 5046409; E-MAIL: [email protected]. PRICE: Free. Summary: This resource list, compiled by the National Agriculture Library, contains sources of information on the uses and risks of dietary supplements. The resources selected cover nutrition information on phytochemicals, vitamins, minerals, herbs, botanicals, and other plant-derived substances; melatonin; amino acids; fatty acids; concentrates; and metabolites. Resources are listed in alphabetical order under the following headings: books, magazines/newsletters, and resources including web sites on the Internet. Contact information is provided for web sites and organizations.

12

You will need to limit your search to “Directory” and “melatonin” using the "Detailed Search" option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Select your preferred language and the format option “Directory.” Type “melatonin” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months.

195

CHAPTER 8. MULTIMEDIA ON MELATONIN Overview In this chapter, we show you how to keep current on multimedia sources of information on melatonin. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Bibliography: Multimedia on Melatonin The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in melatonin (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on melatonin: •

Melatonin [videorecording]. Year: 1996; Format: Videorecording; [Atlanta, Ga.: CNN, 1996?]

197

CHAPTER 9. PERIODICALS AND NEWS ON MELATONIN Overview In this chapter, we suggest a number of news sources and present various periodicals that cover melatonin.

News Services and Press Releases One of the simplest ways of tracking press releases on melatonin is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “melatonin” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to melatonin. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “melatonin” (or synonyms). The following was recently listed in this archive for melatonin: •

Elevated melatonin levels may worsen nocturnal asthma Source: Reuters Medical News Date: September 08, 2003

•

Asthma patients: avoid melatonin supplements Source: Reuters Health eLine Date: September 08, 2003

198 Melatonin

•

Melatonin may protect brain after stroke: rat study Source: Reuters Health eLine Date: March 25, 2003

•

More research needed on melatonin, say scientists Source: Reuters Health eLine Date: February 07, 2003

•

More research needed on melatonin Source: Reuters Medical News Date: February 06, 2003

•

Many melatonin supplements meet label claims Source: Reuters Health eLine Date: December 30, 2002

•

Melatonin ineffective for cluster headache patients who fail conventional therapy Source: Reuters Industry Breifing Date: November 22, 2002

•

Melatonin may exacerbate asthma symptoms Source: Reuters Industry Breifing Date: November 21, 2002

•

Asthmatics may be more sensitive to melatonin Source: Reuters Health eLine Date: October 16, 2002

•

Melatonin, exercise conquer jet lag in athletes Source: Reuters Health eLine Date: February 22, 2002

•

Melatonin supplements may not help older people Source: Reuters Health eLine Date: February 12, 2002

•

Chronic cluster headache may resolve with melatonin treatment Source: Reuters Industry Breifing Date: February 04, 2002

•

Winter depression linked with melatonin cycle Source: Reuters Health eLine Date: December 19, 2001

•

Melatonin may reduce tardive dyskinesia symptoms Source: Reuters Industry Breifing Date: November 23, 2001

•

Melatonin may treat side effects of antipsychotics Source: Reuters Health eLine Date: November 21, 2001

•

Magnetic fields depress nocturnal rise in melatonin in some women Source: Reuters Medical News Date: September 28, 2001

•

Melatonin reduces sleep latency in children with developmental disabilities Source: Reuters Industry Breifing Date: September 03, 2001

Periodicals and News

•

Melatonin helps sleep quality in diabetics, facilitates withdrawal from benzodiazepines Source: Reuters Medical News Date: July 06, 2001

•

Melatonin prevents oxidative stress from iron and erythropoietin use Source: Reuters Industry Breifing Date: May 11, 2001

•

Low melatonin associated with uncontrolled seizures Source: Reuters Health eLine Date: January 01, 2001

•

Melatonin no cure for jet lag, but may fight insomnia Source: Reuters Health eLine Date: November 08, 2000

•

Melatonin sparks sexual desire Source: Reuters Health eLine Date: October 17, 2000

•

Phase-shifting effect of melatonin helps blind people sleep Source: Reuters Medical News Date: October 11, 2000

•

Melatonin corrects sleep problems in the blind Source: Reuters Health eLine Date: October 11, 2000

•

Melatonin helps patients discontinue benzodiazepine treatment for insomnia Source: Reuters Medical News Date: November 16, 1999

•

Melatonin decline is not characteristic of normal aging Source: Reuters Medical News Date: November 08, 1999

•

Melatonin levels do not fall with age Source: Reuters Health eLine Date: November 05, 1999

•

Melatonin linked to bone formation Source: Reuters Medical News Date: October 05, 1999

•

Melatonin has no effect on symptoms of jet lag Source: Reuters Medical News Date: September 02, 1999

•

Melatonin as a jet lag remedy needs more study Source: Reuters Health eLine Date: September 02, 1999

•

Melatonin supplements may affect mood Source: Reuters Health eLine Date: June 11, 1999

•

Abnormal melatonin metabolism found in schizophrenics Source: Reuters Medical News Date: May 10, 1999

199

200 Melatonin

•

Beta-blocker insomnia may be influenced by melatonin. Source: Reuters Medical News Date: April 02, 1999

•

Melatonin may not help rotating shift workers Source: Reuters Health eLine Date: September 24, 1998

•

Melatonin does not appear to improve sleep patterns and quality in night-shift workers. Source: Reuters Medical News Date: September 23, 1998

•

Melatonin deficiency may explain increased breast cancer risk in flight attendants Source: Reuters Medical News Date: August 21, 1998

•

Melatonin may influence nocturnal asthma symptoms Source: Reuters Medical News Date: June 05, 1998

•

Melatonin Relieves Headache Related To Delayed Sleep Phase Syndrome Source: Reuters Medical News Date: May 05, 1998

•

Melatonin Use Linked To Increased Seizure Frequency In Neurologically Disabled Children Source: Reuters Medical News Date: April 27, 1998

•

Melatonin Linked To Child Seizures Source: Reuters Health eLine Date: April 24, 1998

•

Nighttime Magnetic Field Reduces Melatonin Source: Reuters Health eLine Date: March 27, 1998

•

Nighttime Magnetic Field Exposure Linked To Reduction In Melatonin Source: Reuters Medical News Date: March 26, 1998

•

Proteasome Switches Melatonin Production On And Off Source: Reuters Medical News Date: February 27, 1998

•

Experts Debate Melatonin's Value Source: Reuters Health eLine Date: December 24, 1997

•

Abnormal Melatonin Secretion Seen In Status Migrainosus Source: Reuters Medical News Date: July 31, 1997

•

Family Physicians Believe Melatonin More Useful Than Rx Drugs For Insomnia Source: Reuters Medical News Date: October 07, 1996

Periodicals and News

•

Melatonin May Disturb Sleep Patterns Source: Reuters Medical News Date: August 27, 1996

•

NIH Panel Seeks To Curb Melatonin Use Source: Reuters Medical News Date: August 14, 1996

•

Experts Urge Caution On Melatonin Use Source: Reuters Health eLine Date: August 14, 1996

•

Melatonin Facilitates Changing Of Endogenous Circadian Clock Source: Reuters Medical News Date: May 07, 1996

201

The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “melatonin” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “melatonin” (or synonyms). If you know the name of a company that is relevant to melatonin, you can go to any stock trading Web site (such as http://www.etrade.com/) and

202 Melatonin

search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “melatonin” (or synonyms).

Academic Periodicals covering Melatonin Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to melatonin. In addition to these sources, you can search for articles covering melatonin that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

203

APPENDICES

205

APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute13: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

13

These publications are typically written by one or more of the various NIH Institutes.

206 Melatonin

•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

Physician Resources

207

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.14 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:15 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

14

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 15 See http://www.nlm.nih.gov/databases/databases.html.

208 Melatonin

•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

The NLM Gateway16 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.17 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “melatonin” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 10702 89 100 4 0 10895

HSTAT18 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.19 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.20 Simply search by “melatonin” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

16

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

17

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 18 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 19 20

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

Physician Resources

209

Coffee Break: Tutorials for Biologists21 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.22 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.23 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Melatonin In the following section, we will discuss databases and references which relate to the Genome Project and melatonin. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).24 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 21 Adapted 22

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 23 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 24 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

210 Melatonin

To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “melatonin” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for melatonin: •

Melatonin Receptor 1a Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600665

•

Melatonin Receptor 1b Web site: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600804 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

•

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

•

Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

•

Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease,

Physician Resources

211

Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html •

Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

•

Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez

Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

•

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

212 Melatonin

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “melatonin” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database25 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database26 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “melatonin” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

25

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 26 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

213

APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on melatonin can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to melatonin. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to melatonin. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “melatonin”:

214 Melatonin

•

Other guides Dietary Supplements http://www.nlm.nih.gov/medlineplus/dietarysupplements.html Herbal Medicine http://www.nlm.nih.gov/medlineplus/herbalmedicine.html Seasonal Affective Disorder http://www.nlm.nih.gov/medlineplus/seasonalaffectivedisorder.html Sleep Disorders http://www.nlm.nih.gov/medlineplus/sleepdisorders.html Traveler's Health http://www.nlm.nih.gov/medlineplus/travelershealth.html

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on melatonin. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

A Practical Guide to Complementary Therapies for People Living With HIV Contact: Community AIDS Treatment Information Exchange, PO Box 1104, Toronto, (416) 203-7122, http://www.catie.ca. Summary: This brochure discusses the use of complementary therapies for persons with the human immunodeficiency virus (HIV). It discusses research and complementary therapies; the regulation of practitioners; several therapeutic systems including Ayurvedic medicine, homeopathy, North American Aboriginal healing traditions, naturopathy, and traditional Chinese medicine (TCM); several wellness systems including aromatherapy, color therapy, and juicing; unconventional therapies using melatonin and oxygen; and how to find a practicioner and avoid health fraud.

•

Pills, Patches, and Shots: Can Hormones Prevent Aging? Source: Bethesda, MD: National Institute on Aging. 2001. 6 p. Contact: Available from National Institute on Aging Information Center. PO Box 8057, Gaithersburg, MD 20898-8057. (800) 222-2225. Internet: http://www.nih.gov/nia. PRICE: Free.

Patient Resources

215

Summary: This fact sheet examines what is known about the role of hormones in reducing frailty and improving functioning in older people. Hormones are powerful chemicals that help keep the body working normally. For more than a decade, the National Institute on Aging (NIA) has conducted research on hormones that are known to decline with age. To date, there is no proof that hormone supplements can prevent frailty or add years to a person's life. The NIA discourages people from self-medicating with hormone-like products that are available over the counter. Hormone supplements may adversely affect the body. Hormones known to decline in older age include dehydroepiandrosterone (DHEA), growth hormone, melatonin, testosterone, and estrogen. Estrogen has been studied significantly more than the other hormones, and researchers know much more about its helpful and harmful effects. •

Products That Consumers Inquire About Source: College Park, MD: Center for Food Safety and Applied Nutrition, Food and Drug Administration. 2001. 4 p. Contact: Available from CFSAN Outreach and Information Center. Center for Food Safety and Applied Nutrition, Food and Drug Administration, 200 C Street, SW (HFS555), Washington, DC 20204. (888) 723-3366. PRICE: Single copy free. Summary: This Food and Drug Administration fact sheet provides information on several supplements about which consumers frequently have questions. The supplements discussed include ephedra or ephedrine, dehydroepiandrosterone (DHEA), melatonin, dieter's teas, L-tryptophan, folic acid, gamma hydroxybutyric acid (GHB), gamma butyrolactone (GBL), and 1,4-butanediol (BD). The fact sheet also provides information about where consumers can go for more information on each supplement is also provided. The NIH Search Utility

The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to melatonin. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

216 Melatonin

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMDHealth: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to melatonin. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with melatonin. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about melatonin. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “melatonin” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “melatonin”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For

Patient Resources

217

publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “melatonin” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “melatonin” (or a synonym) into the search box, and click “Submit Query.”

219

APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.27

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

27

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

220 Melatonin

libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)28: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

28

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries

221

•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

222 Melatonin

•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

Finding Medical Libraries

223

•

Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

224 Melatonin

•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

225

ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

227

MELATONIN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 5-Hydroxytryptophan: Precursor of serotonin used as antiepileptic and antidepressant. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Ablation: The removal of an organ by surgery. [NIH] Acatalasia: A rare autosomal recessive disorder resulting from the absence of catalase activity. Though usually asymptomatic, a syndrome of oral ulcerations and gangrene may be present. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Accommodation: Adjustment, especially that of the eye for various distances. [EU] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Acoustic: Having to do with sound or hearing. [NIH] Actin: Essential component of the cell skeleton. [NIH] Action Potentials: The electric response of a nerve or muscle to its stimulation. [NIH] Activities of Daily Living: The performance of the basic activities of self care, such as dressing, ambulation, eating, etc., in rehabilitation. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine

228 Melatonin

derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adjunctive Therapy: Another treatment used together with the primary treatment. Its purpose is to assist the primary treatment. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenalin: A hormone of the adrenal medulla. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenergic Antagonists: Drugs that bind to but do not activate adrenergic receptors. Adrenergic antagonists block the actions of the endogenous adrenergic transmitters epinephrine and norepinephrine. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aetiology: Study of the causes of disease. [EU] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring

Dictionary 229

substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Airway Obstruction: Any hindrance to the passage of air into and out of the lungs. [NIH] Akathisia: 1. A condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. 2. An inability to sit down because of intense anxiety at the thought of doing so. [EU] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]

Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Aloe: A genus of the family Liliaceae containing anthraquinone glycosides such as aloinemodin or aloe-emodin (emodin). [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Alveolar Process: The thickest and spongiest part of the maxilla and mandible hollowed out into deep cavities for the teeth. [NIH]

230 Melatonin

Amblyopia: A nonspecific term referring to impaired vision. Major subcategories include stimulus deprivation-induced amblyopia and toxic amblyopia. Stimulus deprivationinduced amblopia is a developmental disorder of the visual cortex. A discrepancy between visual information received by the visual cortex from each eye results in abnormal cortical development. Strabismus and refractive errors may cause this condition. Toxic amblyopia is a disorder of the optic nerve which is associated with alcoholism, tobacco smoking, and other toxins and as an adverse effect of the use of some medications. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnestic: Nominal aphasia; a difficulty in finding the right name for an object. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel, Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but

Dictionary 231

shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Anestrus: Period of sexual inactivity between estrus periods in animals. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Anginal: Pertaining to or characteristic of angina. [EU] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Annealing: The spontaneous alignment of two single DNA strands to form a double helix. [NIH]

Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Anterior chamber: The space in front of the iris and behind the cornea. [NIH] Antiandrogens: Drugs used to block the production or interfere with the action of male sex hormones. [NIH] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on

232 Melatonin

the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Antibody-Dependent Cell Cytotoxicity: The phenomenon of antibody-mediated target cell destruction by non-sensitized effector cells. The identity of the target cell varies, but it must possess surface IgG whose Fc portion is intact. The effector cell is a "killer" cell possessing Fc receptors. It may be a lymphocyte lacking conventional B- or T-cell markers, or a monocyte, macrophage, or polynuclear leukocyte, depending on the identity of the target cell. The reaction is complement-independent. [NIH] Anticarcinogenic: Pertaining to something that prevents or delays the development of cancer. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antidepressant: A drug used to treat depression. [NIH] Antidote: A remedy for counteracting a poison. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]

Antiepileptic: An agent that combats epilepsy. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the movement disorders associated with Huntington's chorea, Gilles de la Tourette's syndrome, and ballismus; and to treat intractable hiccups and severe nausea and vomiting. Antipsychotic agents bind to dopamine, histamine, muscarinic cholinergic, a-adrenergic, and serotonin receptors. Blockade of dopaminergic transmission in various areas is thought to be responsible for their major effects : antipsychotic action by blockade in the mesolimbic

Dictionary 233

and mesocortical areas; extrapyramidal side effects (dystonia, akathisia, parkinsonism, and tardive dyskinesia) by blockade in the basal ganglia; and antiemetic effects by blockade in the chemoreceptor trigger zone of the medulla. Sedation and autonomic side effects (orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation) are caused by blockade of histamine, cholinergic, and adrenergic receptors. [EU] Antitussive: An agent that relieves or prevents cough. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiety Disorders: Disorders in which anxiety (persistent feelings of apprehension, tension, or uneasiness) is the predominant disturbance. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Apathy: Lack of feeling or emotion; indifference. [EU] Aperture: A natural hole of perforation, especially one in a bone. [NIH] Apomorphine: A derivative of morphine that is a dopamine D2 agonist. It is a powerful emetic and has been used for that effect in acute poisoning. It has also been used in the diagnosis and treatment of parkinsonism, but its adverse effects limit its use. [NIH] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Aqueous humor: Clear, watery fluid that flows between and nourishes the lens and the cornea; secreted by the ciliary processes. [NIH] Arachidonate 12-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in platelets. EC 1.13.11.31. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal

234 Melatonin

phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arcuate Nucleus: A nucleus located in the middle hypothalamus in the most ventral part of the third ventricle near the entrance of the infundibular recess. Its small cells are in close contact with the ependyma. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatic: Having a spicy odour. [EU] Arrestin: A 48-Kd protein of the outer segment of the retinal rods and a component of the phototransduction cascade. Arrestin quenches G-protein activation by binding to phosphorylated photolyzed rhodopsin. Arrestin causes experimental autoimmune uveitis when injected into laboratory animals. [NIH] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Articular: Of or pertaining to a joint. [EU] Aspartate: A synthetic amino acid. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astigmatism: A condition in which the surface of the cornea is not spherical; causes a blurred image to be received at the retina. [NIH] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH]

Dictionary 235

Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] Atrial: Pertaining to an atrium. [EU] Atrial Fibrillation: Disorder of cardiac rhythm characterized by rapid, irregular atrial impulses and ineffective atrial contractions. [NIH] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Auricular: Pertaining to an auricle or to the ear, and, formerly, to an atrium of the heart. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [NIH] Avian: A plasmodial infection in birds. [NIH] Avulsion: The forcible separation, or tearing away, of a part of an organ. [NIH] Axonal: Condition associated with metabolic derangement of the entire neuron and is manifest by degeneration of the distal portion of the nerve fiber. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH]

236 Melatonin

Axotomy: Transection or severing of an axon. This type of denervation is used often in experimental studies on neuronal physiology and neuronal death or survival, toward an understanding of nervous system disease. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Barbiturates: A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are medically important as sedatives and hypnotics (sedatives, barbiturate), as anesthetics, or as anticonvulsants. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign prostatic hyperplasia: A benign (noncancerous) condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder, blocking the flow of urine. Also called benign prostatic hypertrophy or BPH. [NIH] Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Beta-Endorphin: A peptide consisting of amino acid sequence 61-91 of the endogenous pituitary hormone beta-lipotropin. The first four amino acids show a common tetrapeptide sequence with methionine- and leucine enkephalin. The compound shows opiate-like activity. Injection of beta-endorphin induces a profound analgesia of the whole body for several hours. This action is reversed after administration of naloxone. [NIH] Beta-pleated: Particular three-dimensional pattern of amyloidoses. [NIH]

Dictionary 237

Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biological Clocks: The physiological mechanisms that govern the rhythmic occurrence of certain biochemical, physiological, and behavioral phenomena in plants and animals. [NIH] Biological Factors: Compounds made by living organisms that contribute to or influence a phenomenon or process. They have biological or physiological activities. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH]

238 Melatonin

Biotinylation: Incorporation of biotinyl groups into molecules. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity, enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood Volume: Volume of circulating blood. It is the sum of the plasma volume and erythrocyte volume. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]

Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH]

Dictionary 239

Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Injuries: Acute and chronic injuries to the brain, including the cerebral hemispheres, cerebellum, and brain stem. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with diffuse axonal injury or coma, posttraumatic. Localized injuries may be associated with neurobehavioral manifestations; hemiparesis, or other focal neurologic deficits. [NIH] Brain metastases: Cancer that has spread from the original (primary) tumor to the brain. [NIH]

Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Butyric Acid: A four carbon acid, CH3CH2CH2COOH, with an unpleasant odor that occurs in butter and animal fat as the glycerol ester. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcitonin Gene-Related Peptide: Calcitonin gene-related peptide. A 37-amino acid peptide derived from the calcitonin gene. It occurs as a result of alternative processing of mRNA from the calcitonin gene. The neuropeptide is widely distributed in neural tissue of the brain, gut, perivascular nerves, and other tissue. The peptide produces multiple biological effects and has both circulatory and neurotransmitter modes of action. In particular, it is a

240 Melatonin

potent endogenous vasodilator. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsular: Cataract which is initiated by an opacification at the surface of the lens. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiac arrest: A sudden stop of heart function. [NIH] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Resuscitation: The artificial substitution of heart and lung action as indicated for heart arrest resulting from electric shock, drowning, respiratory arrest, or other causes. The two major components of cardiopulmonary resuscitation are artificial ventilation and closed-chest cardiac massage. [NIH] Cardiopulmonary Resuscitation: The artificial substitution of heart and lung action as

Dictionary 241

indicated for heart arrest resulting from electric shock, drowning, respiratory arrest, or other causes. The two major components of cardiopulmonary resuscitation are artificial ventilation and closed-chest cardiac massage. [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Caspases: A family of intracellular cysteine endopeptidases. They play a key role in inflammation and mammalian apoptosis. They are specific for aspartic acid at the P1 position. They are divided into two classes based on the lengths of their N-terminal prodomains. Caspases-1,-2,-4,-5,-8, and -10 have long prodomains and -3,-6,-7,-9 have short prodomains. EC 3.4.22.-. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalase: An oxidoreductase that catalyzes the conversion of hydrogen peroxide to water and oxygen. It is present in many animal cells. A deficiency of this enzyme results in acatalasia. EC 1.11.1.6. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH]

242 Melatonin

Cell Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Count: A count of the number of cells of a specific kind, usually measured per unit volume of sample. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Physiology: Characteristics and physiological processes of cells from cell division to cell death. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Aqueduct: Narrow channel in the mesencephalon that connects the third and

Dictionary 243

fourth ventricles. [NIH] Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Ceroid: A naturally occurring lipid pigment with histochemical characteristics similar to lipofuscin. It accumulates in various tissues in certain experimental and pathological conditions. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH] Chlorpyrifos: An organothiophosphate cholinesterase inhibitor that is used as an insecticide and as an acaricide. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular

244 Melatonin

reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Choreatic Disorders: Acquired and hereditary conditions which feature chorea as a primary manifestation of the disease process. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromaffin System: The cells of the body which stain with chromium salts. They occur along the sympathetic nerves, in the adrenal gland, and in various other organs. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Fatigue Syndrome: Fatigue caused by the combined effects of different types of prolonged fatigue. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chronobiology: The study of biological systems as affected by time. Aging, biological rhythms, and cyclic phenomena are included. Statistical, computer-aided mathematical procedures are used to describe, in mathematical terminology, various biological functions over time. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary Body: A ring of tissue extending from the scleral spur to the ora serrata of the retina. It consists of the uveal portion and the epithelial portion. The ciliary muscle is in the uveal portion and the ciliary processes are in the epithelial portion. [NIH] Ciliary processes: The extensions or projections of the ciliary body that secrete aqueous humor. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Circadian Rhythm: The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs and stimuli, hormone secretion, sleeping, feeding, etc. This rhythm seems to be set by a 'biological clock' which seems to be set by recurring daylight and darkness. [NIH] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis,

Dictionary 245

it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Citalopram: A selective neuronal serotonin reuptake inhibitor and a clinically effective antidepressant with tolerable side effects. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia (TD) in preference to tricyclic antidepressants, which aggravate this condition. [NIH]

Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cochlear: Of or pertaining to the cochlea. [EU] Cochlear Diseases: Diseases of the cochlea, the part of the inner ear that is concerned with hearing. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup

246 Melatonin

characteristics. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Color Therapy: A form of phototherapy using color to influence health and to treat various physical or mental disorders. The color rays may be in the visible or invisible spectrum and can be administered through colored lights or applied mentally through suggestion. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy,

Dictionary 247

spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete response. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Cone: One of the special retinal receptor elements which are presumed to be primarily concerned with perception of light and color stimuli when the eye is adapted to light. [NIH] Cone cells: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Constrict: Tighten; narrow. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

248 Melatonin

Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Callosum: Broad plate of dense myelinated fibers that reciprocally interconnect regions of the cortex in all lobes with corresponding regions of the opposite hemisphere. The corpus callosum is located deep in the longitudinal fissure. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the

Dictionary 249

internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Coturnix: A genus of birds (family Phasianidae) containing the common European and other Old World quails. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Cribriform: Pierced with small holes as in a sieve. Refers to the appearance of a tumor when viewed under a microscope. The tumor appears to have open spaces or small holes inside. [NIH]

Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Cues: Signals for an action; that specific portion of a perceptual field or pattern of stimuli to which a subject has learned to respond. [NIH] Cultured cell line: Cells of a single type that have been grown in the laboratory for several generations (cell divisions). [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curettage: Removal of tissue with a curette, a spoon-shaped instrument with a sharp edge. [NIH]

Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteine Endopeptidases: Endopeptidases which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by sulfhydryl reagents. EC 3.4.22. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as

250 Melatonin

cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Dacarbazine: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Dark Adaptation: Adjustment of the eyes under conditions of low light. The sensitivity of the eye to light is increased during dark adaptation. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decidua: The epithelial lining of the endometrium that is formed before the fertilized ovum reaches the uterus. The fertilized ovum embeds in the decidua. If the ovum is not fertilized, the decidua is shed during menstruation. [NIH] Decubitus: An act of lying down; also the position assumed in lying down. [EU] Decubitus Ulcer: An ulceration caused by prolonged pressure in patients permitted to lie too still for a long period of time. The bony prominences of the body are the most frequently affected sites. The ulcer is caused by ischemia of the underlying structures of the skin, fat, and muscles as a result of the sustained and constant pressure. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delirium: (DSM III-R) an acute, reversible organic mental disorder characterized by reduced ability to maintain attention to external stimuli and disorganized thinking as manifested by rambling, irrelevant, or incoherent speech; there are also a reduced level of consciousness,

Dictionary 251

sensory misperceptions, disturbance of the sleep-wakefulness cycle and level of psychomotor activity, disorientation to time, place, or person, and memory impairment. Delirium may be caused by a large number of conditions resulting in derangement of cerebral metabolism, including systemic infection, poisoning, drug intoxication or withdrawal, seizures or head trauma, and metabolic disturbances such as hypoxia, hypoglycaemia, fluid, electrolyte, or acid-base imbalances, or hepatic or renal failure. Called also acute confusional state and acute brain syndrome. [EU] Delusions: A false belief regarding the self or persons or objects outside the self that persists despite the facts, and is not considered tenable by one's associates. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dentate Gyrus: Gray matter situated above the gyrus hippocampi. It is composed of three layers. The molecular layer is continuous with the hippocampus in the hippocampal fissure. The granular layer consists of closely arranged spherical or oval neurons, called granule cells, whose axons pass through the polymorphic layer ending on the dendrites of pyramidal cells in the hippocampus. [NIH] Depersonalization: Alteration in the perception of the self so that the usual sense of one's own reality is lost, manifested in a sense of unreality or self-estrangement, in changes of body image, or in a feeling that one does not control his own actions and speech; seen in depersonalization disorder, schizophrenic disorders, and schizotypal personality disorder. Some do not draw a distinction between depersonalization and derealization, using depersonalization to include both. [EU] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Derealization: Is characterized by the loss of the sense of reality concerning one's surroundings. [NIH] Dermal: Pertaining to or coming from the skin. [NIH] Dermatitis: Any inflammation of the skin. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH]

252 Melatonin

Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detergents: Purifying or cleansing agents, usually salts of long-chain aliphatic bases or acids, that exert cleansing (oil-dissolving) and antimicrobial effects through a surface action that depends on possessing both hydrophilic and hydrophobic properties. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Deuterium Oxide: The isotopic compound of hydrogen of mass 2 (deuterium) with oxygen. (From Grant & Hackh's Chemical Dictionary, 5th ed) It is used to study mechanisms and rates of chemical or nuclear reactions, as well as biological processes. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Dietetics: The study and regulation of the diet. [NIH] Diffuse Axonal Injury: A relatively common sequela of blunt head injury, characterized by a global disruption of axons throughout the brain. Associated clinical features may include neurobehavioral manifestations; persistent vegetative state; dementia; and other disorders. [NIH]

Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] Diltiazem: A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of the calcium ion in membrane functions. It is also teratogenic. [NIH] Diphenhydramine: A histamine H1 antagonist used as an antiemetic, antitussive, for dermatoses and pruritus, for hypersensitivity reactions, as a hypnotic, an antiparkinson, and as an ingredient in common cold preparations. It has some undesired antimuscarinic and

Dictionary 253

sedative effects. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disabled Children: Children with mental or physical disabilities that interfere with usual activities of daily living and that may require accommodation or intervention. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuresis: Increased excretion of urine. [EU] Diurnal: Occurring during the day. [EU] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and homozygotes. [EU] Dopa: The racemic or DL form of DOPA, an amino acid found in various legumes. The dextro form has little physiologic activity but the levo form (levodopa) is a very important physiologic mediator and precursor and pharmacological agent. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH]

254 Melatonin

Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Dosimetry: All the methods either of measuring directly, or of measuring indirectly and computing, absorbed dose, absorbed dose rate, exposure, exposure rate, dose equivalent, and the science associated with these methods. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] Dysphoria: Disquiet; restlessness; malaise. [EU] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystonia: Disordered tonicity of muscle. [EU] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] Eczema: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents (Dorland, 27th ed). [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active

Dictionary 255

second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that act near the site of synthesis without altering functions throughout the body. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Electric shock: A dangerous patho-physiological effect resulting from an electric current passing through the body of a human or animal. [NIH] Electroacupuncture: A form of acupuncture using low frequency electrically stimulated needles to produce analgesia and anesthesia and to treat disease. [NIH] Electrocardiogram: Measurement of electrical activity during heartbeats. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electromagnetic Fields: Fields representing the joint interplay of electric and magnetic forces. [NIH] Electron microscope: A microscope (device used to magnify small objects) that uses electrons (instead of light) to produce an enlarged image. An electron microscopes shows tiny details better than any other type of microscope. [NIH] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emetic: An agent that causes vomiting. [EU] Emodin: Purgative anthraquinone found in several plants, especially Rhamnus frangula. It was formerly used as a laxative, but is now used mainly as tool in toxicity studies. [NIH] Emollient: Softening or soothing; called also malactic. [EU]

256 Melatonin

Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Endocrine Glands: Ductless glands that secrete substances which are released directly into the circulation and which influence metabolism and other body functions. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH]

Dictionary 257

Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enkephalin: A natural opiate painkiller, in the hypothalamus. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] Ependyma: A thin membrane that lines the ventricles of the brain and the central canal of the spinal cord. [NIH] Ephedrine: An alpha- and beta-adrenergic agonist that may also enhance release of norepinephrine. It has been used in the treatment of several disorders including asthma, heart failure, rhinitis, and urinary incontinence, and for its central nervous system stimulatory effects in the treatment of narcolepsy and depression. It has become less extensively used with the advent of more selective agonists. [NIH] Epidemiologic Studies: Studies designed to examine associations, commonly, hypothesized causal relations. They are usually concerned with identifying or measuring the effects of risk factors or exposures. The common types of analytic study are case-control studies, cohort studies, and cross-sectional studies. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH]

258 Melatonin

Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Esophagectomy: An operation to remove a portion of the esophagus. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Esotropia: A form of ocular misalignment characterized by an excessive convergence of the visual axes, resulting in a "cross-eye" appearance. An example of this condition occurs when paralysis of the lateral rectus muscle causes an abnormal inward deviation of one eye on attempted gaze. [NIH] Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethinyl Estradiol: A semisynthetic estrogen with high oral estrogenic potency. It is often used as the estrogenic component in oral contraceptives. [NIH] Ethmoid: An unpaired cranial bone which helps form the medial walls of the orbits and contains the themoidal air cells which drain into the nose. [NIH] Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a

Dictionary 259

suitable consistency or form to the drug; a vehicle. [EU] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excitotoxicity: Excessive exposure to glutamate or related compounds can kill brain neurons, presumably by overstimulating them. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exotropia: A form of ocular misalignment where the visual axes diverge inappropriately. For example, medial rectus muscle weakness may produce this condition as the affected eye will deviate laterally upon attempted forward gaze. An exotropia occurs due to the relatively unopposed force exerted on the eye by the lateral rectus muscle, which pulls the eye in an outward direction. [NIH] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]

External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extraocular: External to or outside of the eye. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Eye Movements: Voluntary or reflex-controlled movements of the eye. [NIH] Eyecup: Vessel which may be filled with fluid and fitted to the orbital aperture to bathe or treat the area of the conjunctival sac. [NIH] Fallopian Tubes: Two long muscular tubes that transport ova from the ovaries to the uterus. They extend from the horn of the uterus to the ovaries and consist of an ampulla, an infundibulum, an isthmus, two ostia, and a pars uterina. The walls of the tubes are composed of three layers: mucosal, muscular, and serosal. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Feeding Behavior: Behavioral responses or sequences associated with eating including modes of feeding, rhythmic patterns of eating, and time intervals. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds.

260 Melatonin

Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fibula: The bone of the lower leg lateral to and smaller than the tibia. In proportion to its length, it is the most slender of the long bones. [NIH] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Flatus: Gas passed through the rectum. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Fluoxetine: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. [NIH] Foam Cells: Lipid-laden macrophages originating from monocytes or from smooth muscle cells. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH]

Dictionary 261

Follicles: Shafts through which hair grows. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fourth Ventricle: An irregularly shaped cavity in the rhombencephalon, between the medulla oblongata, the pons, and the isthmus in front, and the cerebellum behind. It is continuous with the central canal of the cord below and with the cerebral aqueduct above, and through its lateral and median apertures it communicates with the subarachnoid space. [NIH]

Fraud: Exploitation through misrepresentation of the facts or concealment of the purposes of the exploiter. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Gallate: Antioxidant present in tea. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gastroparesis: Nerve or muscle damage in the stomach. Causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as

262 Melatonin

a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational Age: Age of the conceptus. In humans, this may be assessed by medical history, physical examination, early immunologic pregnancy tests, radiography, ultrasonography, and amniotic fluid analysis. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Gliosis: The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion. [NIH] Glomeruli: Plural of glomerulus. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH]

Dictionary 263

Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Glyceraldehyde 3-Phosphate: An aldotriose which is an important intermediate in glycolysis and in tryptophan biosynthesis. [NIH] Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycols: A generic grouping for dihydric alcohols with the hydroxy groups (-OH) located on different carbon atoms. They are viscous liquids with high boiling points for their molecular weights. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with

264 Melatonin

formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granulocyte-Macrophage Colony-Stimulating Factor: An acidic glycoprotein of MW 23 kDa with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Granulosa Cells: Cells of the membrana granulosa lining the vesicular ovarian follicle which become luteal cells after ovulation. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Haloperidol: Butyrophenone derivative. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH]

Dictionary 265

Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Heart Arrest: Sudden and usually momentary cessation of the heart beat. This sudden cessation may, but not usually, lead to death, sudden, cardiac. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemiparesis: The weakness or paralysis affecting one side of the body. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Hepatic: Refers to the liver. [NIH] Hepatobiliary: Pertaining to the liver and the bile or the biliary ducts. [EU] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Heterotropia: One in which the angle of squint remains relatively unaltered on conjugate movement of the eyes. [NIH]

266 Melatonin

Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Hippocampus: A curved elevation of gray matter extending the entire length of the floor of the temporal horn of the lateral ventricle (Dorland, 28th ed). The hippocampus, subiculum, and dentate gyrus constitute the hippocampal formation. Sometimes authors include the entorhinal cortex in the hippocampal formation. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histiocytosis: General term for the abnormal appearance of histiocytes in the blood. Based on the pathological features of the cells involved rather than on clinical findings, the histiocytic diseases are subdivided into three groups: Langerhans cell histiocytosis, nonLangerhans cell histiocytosis, and malignant histiocytic disorders. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homotypic: Adhesion between neutrophils. [NIH] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Human growth hormone: A protein hormone, secreted by the anterior lobe of the pituitary, which promotes growth of the whole body by stimulating protein synthesis. The human gene has already been cloned and successfully expressed in bacteria. [NIH] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time

Dictionary 267

unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxides: Inorganic compounds that contain the OH- group. [NIH] Hydroxyl Radical: The univalent radical OH that is present in hydroxides, alcohols, phenols, glycols. [NIH] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hygienic: Pertaining to hygiene, or conducive to health. [EU] Hyperbaric: Characterized by greater than normal pressure or weight; applied to gases under greater than atmospheric pressure, as hyperbaric oxygen, or to a solution of greater specific gravity than another taken as a standard of reference. [EU] Hyperbaric oxygen: Oxygen that is at an atmospheric pressure higher than the pressure at sea level. Breathing hyperbaric oxygen to enhance the effectiveness of radiation therapy is being studied. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperopia: Farsightedness; ability to see distant objects more clearly than close objects; may be corrected with glasses or contact lenses. [NIH] Hyperphagia: Ingestion of a greater than optimal quantity of food. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglossal Nerve: The 12th cranial nerve. The hypoglossal nerve originates in the hypoglossal nucleus of the medulla and supplies motor innervation to all of the muscles of the tongue except the palatoglossus (which is supplied by the vagus). This nerve also contains proprioceptive afferents from the tongue muscles. [NIH] Hypoglycaemia: An abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache, accompanied by irritability, confusion, hallucinations, bizarre behaviour, and ultimately, convulsions and coma. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]

268 Melatonin

Hypophyseal: Hypophysial. [EU] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxemia: Deficient oxygenation of the blood; hypoxia. [EU] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Immaturity: The state or quality of being unripe or not fully developed. [EU] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to

Dictionary 269

prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and

270 Melatonin

then cemented into the cavity. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inositol Phosphates: Phosphoric acid esters of inositol. They include mono- and polyphosphoric acid esters, with the exception of inositol hexaphosphate which is phytic acid. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]

Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy,

Dictionary 271

implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intracranial Pressure: Pressure within the cranial cavity. It is influenced by brain mass, the circulatory system, CSF dynamics, and skull rigidity. [NIH] Intraocular: Within the eye. [EU] Intraocular pressure: Pressure of the fluid inside the eye; normal IOP varies among individuals. [NIH] Intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs). [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intrinsic Factor: A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12. Deficiency of intrinsic factor results in pernicious anemia. [NIH]

Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH]

272 Melatonin

Irradiance: At a point of a surface, the quotient of the radiant flux incident on an element of the surface containing the point, by the area of that element. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Ischemic stroke: A condition in which the blood supply to part of the brain is cut off. Also called "plug-type" strokes. Blocked arteries starve areas of the brain controlling sight, speech, sensation, and movement so that these functions are partially or completely lost. Ischemic stroke is the most common type of stroke, accounting for 80 percent of all strokes. Most ischemic strokes are caused by a blood clot called a thrombus, which blocks blood flow in the arteries feeding the brain, usually the carotid artery in the neck, the major vessel bringing blood to the brain. When it becomes blocked, the risk of stroke is very high. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Jet lag: Symptoms produced in human beings by fast travel through large meridian difference. [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kainate: Glutamate receptor. [NIH] Kava: Dried rhizome and roots of Piper methysticum, a shrub native to Oceania and known for its anti-anxiety and sedative properties. Heavy usage results in some adverse effects. It contains alkaloids, lactones, kawain, methysticin, mucilage, starch, and yangonin. Kava is also the name of the pungent beverage prepared from the plant's roots. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually

Dictionary 273

by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] Killer Cells: Lymphocyte-like effector cells which mediate antibody-dependent cell cytotoxicity. They kill antibody-coated target cells which they bind with their Fc receptors. [NIH]

Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Laceration: 1. The act of tearing. 2. A torn, ragged, mangled wound. [EU] Lactation: The period of the secretion of milk. [EU] Lag: The time elapsing between application of a stimulus and the resulting reaction. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Larva: Wormlike or grublike stage, following the egg in the life cycle of insects, worms, and other metamorphosing animals. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Latency: The period of apparent inactivity between the time when a stimulus is presented and the moment a response occurs. [NIH] Lateral Ventricles: Cavity in each of the cerebral hemispheres derived from the cavity of the embryonic neural tube. They are separated from each other by the septum pellucidum, and each communicates with the third ventricle by the foramen of Monro, through which also the choroid plexuses of the lateral ventricles become continuous with that of the third ventricle. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils,

274 Melatonin

and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Levo: It is an experimental treatment for heroin addiction that was developed by German scientists around 1948 as an analgesic. Like methadone, it binds with opioid receptors, but it is longer acting. [NIH] Levodopa: The naturally occurring form of dopa and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonism and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipectomy: Removal of localized subcutaneous fat deposits by suction curettage or blunt cannulization in the cosmetic correction of obesity and other esthetic contour defects. [NIH] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipofuscin: A naturally occurring lipid pigment with histochemical characteristics similar to ceroid. It accumulates in various normal tissues and apparently increases in quantity with age. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC

Dictionary 275

1.13.11.12. [NIH] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]

Litter: Appliance consisting of an oblong frame over which is stretched a canvas or other material, used for carrying an injured or disabled person. [NIH] Litter Size: The number of offspring produced at one birth by an animal. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Loading dose: A quantity higher than the average or maintenance dose, used at the initiation of therapy to rapidly establish a desired level of the drug [EU] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Luciferase: Any one of several enzymes that catalyze the bioluminescent reaction in certain marine crustaceans, fish, bacteria, and insects. The enzyme is a flavoprotein; it oxidizes luciferins to an electronically excited compound that emits energy in the form of light. The color of light emitted varies with the organism. The firefly enzyme is a valuable reagent for measurement of ATP concentration. (Dorland, 27th ed) EC 1.13.12.-. [NIH] Lumen: The cavity or channel within a tube or tubular organ. [EU] Luteal Phase: The period of the menstrual cycle that begins with ovulation and ends with menstruation. [NIH] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH]

276 Melatonin

Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malaise: A vague feeling of bodily discomfort. [EU] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Malondialdehyde: The dialdehyde of malonic acid. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Mandible: The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. [NIH] Mania: Excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behaviour, and elevation of mood. [EU] Manic: Affected with mania. [EU] Manic-depressive psychosis: One of a group of psychotic reactions, fundamentally marked by severe mood swings and a tendency to remission and recurrence. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Meatus: A canal running from the internal auditory foramen through the petrous portion of the temporal bone. It gives passage to the facial and auditory nerves together with the auditory branch of the basilar artery and the internal auditory veins. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH]

Dictionary 277

Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanophores: Chromatophores (large pigment cells of fish, amphibia, reptiles and many invertebrates) which contain melanin. Short term color changes are brought about by an active redistribution of the melanophores pigment containing organelles (melanosomes). Mammals do not have melanophores; however they have retained smaller pigment cells known as melanocytes. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [NIH]

Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meningeal: Refers to the meninges, the tissue covering the brain and spinal cord. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Fatigue: Fatigue arising in consequence of mental effort. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH]

278 Melatonin

Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metamorphosis: The ontogeny of insects, i. e. the series of changes undergone from egg, through larva and pupa, or through nymph, to adult. [NIH] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methyltransferase: A drug-metabolizing enzyme. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU] Midazolam: A short-acting compound, water-soluble at pH less than 4 and lipid-soluble at physiological pH. It is a hypnotic-sedative drug with anxiolytic and amnestic properties. It is used for sedation in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. Because of its short duration and cardiorespiratory stability, it is particularly useful in poor-risk, elderly, and cardiac patients. [NIH]

Middle Cerebral Artery: The largest and most complex of the cerebral arteries. Branches of the middle cerebral artery supply the insular region, motor and premotor areas, and large regions of the association cortex. [NIH] Migration: The systematic movement of genes between populations of the same species,

Dictionary 279

geographic race, or variety. [NIH] Mineralization: The action of mineralizing; the state of being mineralized. [EU] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Mood Disorders: Those disorders that have a disturbance in mood as their predominant feature. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]

Morphological: Relating to the configuration or the structure of live organs. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Motor Neurons: Neurons which activate muscle cells. [NIH] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucosal Ulceration: Skin ulceration in workers who work with lime and lime solutions. [NIH]

Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells,

280 Melatonin

water, inorganic salts, and exfoliated cells. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mycotoxins: Toxins derived from bacteria or fungi. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH]

Dictionary 281

Myoclonus: Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous systems diseases (e.g., epilepsy, myoclonic). Nocturnal myoclonus may represent a normal physiologic event or occur as the principal feature of the nocturnal myoclonus syndrome. (From Adams et al., Principles of Neurology, 6th ed, pp102-3). [NIH] Myometrium: The smooth muscle coat of the uterus, which forms the main mass of the organ. [NIH] Myopia: That error of refraction in which rays of light entering the eye parallel to the optic axis are brought to a focus in front of the retina, as a result of the eyeball being too long from front to back (axial m.) or of an increased strength in refractive power of the media of the eye (index m.). Called also nearsightedness, because the near point is less distant than it is in emmetropia with an equal amplitude of accommodation. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Naltrexone: Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of naloxone. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence. [NIH] Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Narcosis: A general and nonspecific reversible depression of neuronal excitability, produced by a number of physical and chemical aspects, usually resulting in stupor. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Nearsightedness: The common term for myopia. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH]

282 Melatonin

Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Nervousness: Excessive excitability and irritability, with mental and physical unrest. [EU] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neurobehavioral Manifestations: Signs and symptoms of higher cortical dysfunction caused by organic conditions. These include certain behavioral alterations and impairments of skills involved in the acquisition, processing, and utilization of knowledge or information. [NIH]

Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neuroglia: The non-neuronal cells of the nervous system. They are divided into macroglia (astrocytes, oligodendroglia, and schwann cells) and microglia. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the blood-brain and blood-retina barriers, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Neuroglia have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitters, but their role in signaling (as in many other functions) is unclear. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU]

Dictionary 283

Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurosecretory Systems: A system of neurons that has the specialized function to produce and secrete hormones, and that constitutes, in whole or in part, an endocrine organ or system. [NIH] Neurotic: 1. Pertaining to or characterized by neurosis. 2. A person affected with a neurosis. [EU]

Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful antianginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] Nimodipine: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14.

284 Melatonin

Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] NSAIDs: Nonsteroidal anti-inflammatory drugs. A group of drugs that decrease fever, swelling, pain, and redness. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nymph: The immature stage in the life cycle of those orders of insects characterized by gradual metamorphosis, in which the young resemble the imago in general form of body, including compound eyes and external wings; also the 8-legged stage of mites and ticks that follows the first moult. [NIH] Octreotide: A potent, long-acting somatostatin octapeptide analog which has a wide range of physiological actions. It inhibits growth hormone secretion, is effective in the treatment of hormone-secreting tumors from various organs, and has beneficial effects in the management of many pathological states including diabetes mellitus, orthostatic hypertension, hyperinsulinism, hypergastrinemia, and small bowel fistula. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Ocular Hypertension: A condition in which the intraocular pressure is elevated above normal and which may lead to glaucoma. [NIH] Odour: A volatile emanation that is perceived by the sense of smell. [EU] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Olfactory Bulb: Ovoid body resting on the cribriform plate of the ethmoid bone where the olfactory nerve terminates. The olfactory bulb contains several types of nerve cells including the mitral cells, on whose dendrites the olfactory nerve synapses, forming the olfactory glomeruli. The accessory olfactory bulb, which receives the projection from the vomeronasal organ via the vomeronasal nerve, is also included here. [NIH] Oligodendroglial: A cell that lays down myelin. [NIH] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or

Dictionary 285

allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oncology: The study of cancer. [NIH] On-line: A sexually-reproducing population derived from a common parentage. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Ophthalmic: Pertaining to the eye. [EU] Ophthalmologic: Pertaining to ophthalmology (= the branch of medicine dealing with the eye). [EU] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opsin: A visual pigment protein found in the retinal rods. It combines with retinaldehyde to form rhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic disc: The circular area (disc) where the optic nerve connects to the retina. [NIH] Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU] Orderly: A male hospital attendant. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoarthritis: Degeneration of articular cartilage. Primary osteoarthritis is very common in older persons, especially affecting weight-bearing joints. Articular cartilage becomes soft, frayed and thinned. [NIH]

286 Melatonin

Osteomalacia: A condition marked by softening of the bones (due to impaired mineralization, with excess accumulation of osteoid), with pain, tenderness, muscular weakness, anorexia, and loss of weight, resulting from deficiency of vitamin D and calcium. [EU]

Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovalbumin: An albumin obtained from the white of eggs. It is a member of the serpin superfamily. [NIH] Ovarian Follicle: Spheroidal cell aggregation in the ovary containing an ovum. It consists of an external fibro-vascular coat, an internal coat of nucleated cells, and a transparent, albuminous fluid in which the ovum is suspended. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxazepam: A benzodiazepine used in the treatment of anxiety, alcohol withdrawal, and insomnia. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] Oxytocin: A nonapeptide posterior pituitary hormone that causes uterine contractions and stimulates lactation. [NIH] Pacemaker: An object or substance that influences the rate at which a certain phenomenon occurs; often used alone to indicate the natural cardiac pacemaker or an artificial cardiac

Dictionary 287

pacemaker. In biochemistry, a substance whose rate of reaction sets the pace for a series of interrelated reactions. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palpitation: A subjective sensation of an unduly rapid or irregular heart beat. [EU] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it may be inherited as an autosomal dominant trait. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Paresthesias: Abnormal touch sensations, such as burning or prickling, that occur without an outside stimulus. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH]

288 Melatonin

Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Periodicity: The tendency of a phenomenon to recur at regular intervals; in biological systems, the recurrence of certain activities (including hormonal, cellular, neural) may be annual, seasonal, monthly, daily, or more frequently (ultradian). [NIH] Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral vision: Side vision; ability to see objects and movement outside of the direct line of vision. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Perivascular: Situated around a vessel. [EU] Pernicious: Tending to a fatal issue. [EU] Pernicious anemia: A type of anemia (low red blood cell count) caused by the body's inability to absorb vitamin B12. [NIH] Peroral: Performed through or administered through the mouth. [EU] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Peroxide: Chemical compound which contains an atom group with two oxygen atoms tied to each other. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that

Dictionary 289

of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharynx: The hollow tube about 5 inches long that starts behind the nose and ends at the top of the trachea (windpipe) and esophagus (the tube that goes to the stomach). [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylates: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photobiology: The branch of biology dealing with the effect of light on organisms. [NIH]

290 Melatonin

Photodynamic therapy: Treatment with drugs that become active when exposed to light. These drugs kill cancer cells. [NIH] Photoperiod: The time period of daily exposure that an organism receives from daylight or artificial light. It is believed that photoperiodic responses may affect the control of energy balance and thermoregulation. [NIH] Photoreceptor: Receptor capable of being activated by light stimuli, as a rod or cone cell of the eye. [NIH] Photosensitivity: An abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280400 mm. There are two main types : photoallergy and photoxicity. [EU] Photosensitization: The development of abnormally heightened reactivity of the skin to sunlight. [EU] Photosensitizer: A drug used in photodynamic therapy. When absorbed by cancer cells and exposed to light, the drug becomes active and kills the cancer cells. [NIH] Phototherapy: Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. [NIH] Phototransduction: The transducing of light energy to afferent nerve impulses, such as takes place in the retinal rods and cones. After light photons are absorbed by the photopigments, the signal is transmitted to the outer segment membrane by the cyclic GMP second messenger system, where it closes the sodium channels. This channel gating ultimately generates an action potential in the inner retina. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Phytic Acid: Complexing agent for removal of traces of heavy metal ions. It acts also as a hypocalcemic agent. [NIH] Picrotoxin: A noncompetitive antagonist at GABA-A receptors and thus a convulsant. Picrotoxin blocks the GABA-activated chloride ionophore. Although it is most often used as a research tool, it has been used as a CNS stimulant and an antidote in poisoning by CNS depressants, especially the barbiturates. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Pilot Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pineal Body: A small conical midline body attached to the posterior part of the third ventricle and lying between the superior colliculi, below the splenium of the corpus callosum. [NIH] Pineal gland: A tiny organ located in the cerebrum that produces melatonin. Also called pineal body or pineal organ. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected

Dictionary 291

to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasmid: An autonomously replicating, extra-chromosomal DNA molecule found in many bacteria. Plasmids are widely used as carriers of cloned genes. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation

292 Melatonin

of, or exposure to a deleterious agent. [NIH] Polychromatic: Erythrocyte that, on staining, shows various shades of blue combined with tinges of pink. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymerase Chain Reaction: In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Popliteal: Compression of the nerve at the neck of the fibula. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Postural: Pertaining to posture or position. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH]

Dictionary 293

Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Pregnancy Tests: Tests to determine whether or not an individual is pregnant. [NIH] Pregnenolone: Steroid hormone. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Premenstrual: Occurring before menstruation. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH]

294 Melatonin

Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Pro-Opiomelanocortin: A precursor protein, MW 30,000, synthesized mainly in the anterior pituitary gland but also found in the hypothalamus, brain, and several peripheral tissues. It incorporates the amino acid sequences of ACTH and beta-lipotropin. These two hormones, in turn, contain the biologically active peptides MSH, corticotropin-like intermediate lobe peptide, alpha-lipotropin, endorphins, and methionine enkephalin. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propofol: A widely used anesthetic. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Propylene Glycol: A clear, colorless, viscous organic solvent and diluent used in pharmaceutical preparations. [NIH] Prosencephalon: The part of the brain developed from the most rostral of the three primary vesicles of the embryonic neural tube and consisting of the diencephalon and telencephalon. [NIH]

Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prostate gland: A gland in the male reproductive system just below the bladder. It surrounds part of the urethra, the canal that empties the bladder, and produces a fluid that forms part of semen. [NIH] Prostatic Hyperplasia: Enlargement or overgrowth of the prostate gland as a result of an increase in the number of its constituent cells. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine

Dictionary 295

residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pruritic: Pertaining to or characterized by pruritus. [EU] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [NIH] Pseudarthrosis: A new false joint arising at the site of an ununited fracture; may be caused by vibrating hand tools. [NIH] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychosis: A mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and

296 Melatonin

editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupa: An inactive stage between the larval and adult stages in the life cycle of insects. [NIH] Pupil: The aperture in the iris through which light passes. [NIH] Purgative: 1. Cathartic (def. 1); causing evacuation of the bowels. 2. A cathartic, particularly one that stimulates peristaltic action. [EU] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Pyridoxal: 3-Hydroxy-5-(hydroxymethyl)-2-methyl-4- pyridinecarboxaldehyde. [NIH] Pyridoxal Phosphate: 3-Hydroxy-2-methyl-5-((phosphonooxy)methyl)-4pyridinecarboxaldehyde. An enzyme co-factor vitamin. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH]

Dictionary 297

Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Reaction Time: The time from the onset of a stimulus until the organism responds. [NIH] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego function. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recur: To occur again. Recurrence is the return of cancer, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH]

298 Melatonin

Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractive Errors: Deviations from the average or standard indices of refraction of the eye through its dioptric or refractive apparatus. [NIH] Refractive Power: The ability of an object, such as the eye, to bend light as light passes through it. [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Reproductive system: In women, this system includes the ovaries, the fallopian tubes, the uterus (womb), the cervix, and the vagina (birth canal). The reproductive system in men includes the prostate, the testes, and the penis. [NIH] Resection: Removal of tissue or part or all of an organ by surgery. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Resuscitation: The restoration to life or consciousness of one apparently dead; it includes

Dictionary 299

such measures as artificial respiration and cardiac massage. [EU] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] Retinal pigment epithelium: The pigment cell layer that nourishes the retinal cells; located just outside the retina and attached to the choroid. [NIH] Retinaldehyde: A carotenoid constituent of visual pigments. It is the oxidized form of retinol which functions as the active component of the visual cycle. It is bound to the protein opsin forming the complex rhodopsin. When stimulated by visible light, the retinal component of the rhodopsin complex undergoes isomerization at the 11-position of the double bond to the cis-form; this is reversed in "dark" reactions to return to the native transconfiguration. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retreatment: The therapy of the same disease in a patient, with the same agent or procedure repeated after initial treatment, or with an additional or alternate measure or follow-up. It does not include therapy which requires more than one administration of a therapeutic agent or regimen. Retreatment is often used with reference to a different modality when the original one was inadequate, harmful, or unsuccessful. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retrovirus: A member of a group of RNA viruses, the RNA of which is copied during viral replication into DNA by reverse transcriptase. The viral DNA is then able to be integrated into the host chromosomal DNA. [NIH] Rheumatic Heart Disease: Disease of the heart resulting from rheumatic fever and characterized by inflammatory changes in the myocardium or scarring of the valves. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH]

300 Melatonin

Rhythmicity: Regular periodicity. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risperidone: A selective blocker of dopamine D2 and serotonin-5-HT-2 receptors that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative symptoms in the treatment of schizophrenia. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rod cells: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide side vision and the ability to see objects in dim light (night vision). [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Scoliosis: A lateral curvature of the spine. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Seasonal Affective Disorder: A syndrome characterized by depressions that recur annually at the same time each year, usually during the winter months. Other symptoms include anxiety, irritability, decreased energy, increased appetite (carbohydrate cravings), increased duration of sleep, and weight gain. SAD (seasonal affective disorder) can be treated by daily exposure to bright artificial lights (phototherapy), during the season of recurrence. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in

Dictionary 301

response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Senile Plaques: Spherical masses consisting of amyloid fibrils and neuronal processes. [NIH] Sensibility: The ability to receive, feel and appreciate sensations and impressions; the quality of being sensitive; the extend to which a method gives results that are free from false negatives. [NIH] Sepsis: The presence of bacteria in the bloodstream. [NIH] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH]

302 Melatonin

Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin Aging: The process of aging due to changes in the structure and elasticity of the skin over time. It may be a part of physiological aging or it may be due to the effects of ultraviolet radiation, usually through exposure to sunlight. [NIH] Skin Care: Maintenance of the hygienic state of the skin under optimal conditions of cleanliness and comfort. Effective in skin care are proper washing, bathing, cleansing, and the use of soaps, detergents, oils, etc. In various disease states, therapeutic and protective solutions and ointments are useful. The care of the skin is particularly important in various occupations, in exposure to sunlight, in neonates, and in decubitus ulcer. [NIH]

Dictionary 303

Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep Deprivation: The state of being deprived of sleep under experimental conditions, due to life events, or from a wide variety of pathophysiologic causes such as medication effect, chronic illness, psychiatric illness, or sleep disorder. [NIH] Sleep Paralysis: A state experienced by a person while going to sleep or on waking: consciousness is present but muscular movement is lost as well as the ability to speak. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Soaps: Sodium or potassium salts of long chain fatty acids. These detergent substances are obtained by boiling natural oils or fats with caustic alkali. Sodium soaps are harder and are used as topical anti-infectives and vehicles in pills and liniments; potassium soaps are soft, used as vehicles for ointments and also as topical antimicrobials. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a

304 Melatonin

neurotransmitter in the central and peripheral nervous systems. [NIH] Soporific: 1. Causing or inducing profound sleep. 2. A drug or other agent which induces sleep. [EU] Soybean Oil: Oil from soybean or soybean plant. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spinal Cord Injuries: Penetrating and non-penetrating injuries to the spinal cord resulting from traumatic external forces (e.g., wounds, gunshot; whiplash injuries; etc.). [NIH] Spinous: Like a spine or thorn in shape; having spines. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stellate: Star shaped. [NIH] Stellate Ganglion: A paravertebral sympathetic ganglion formed by the fusion of the inferior cervical and first thoracic ganglia. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become

Dictionary 305

specialized and take the place of those that die or are lost. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strabismus: Deviation of the eye which the patient cannot overcome. The visual axes assume a position relative to each other different from that required by the physiological conditions. The various forms of strabismus are spoken of as tropias, their direction being indicated by the appropriate prefix, as cyclo tropia, esotropia, exotropia, hypertropia, and hypotropia. Called also cast, heterotropia, manifest deviation, and squint. [EU] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Sublingual: Located beneath the tongue. [EU] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally

306 Melatonin

conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Sudden death: Cardiac arrest caused by an irregular heartbeat. The term "death" is somewhat misleading, because some patients survive. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sumatriptan: A serotonin agonist that acts selectively at 5HT1 receptors. It is used in the treatment of migraines. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Suprachiasmatic Nucleus: An ovoid densely packed collection of small cells of the anterior hypothalamus lying close to the midline in a shallow impression of the optic chiasm. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also

Dictionary 307

communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Vesicles: Membrane-bound compartments which contain transmitter molecules. Synaptic vesicles are concentrated at presynaptic terminals. They actively sequester transmitter molecules from the cytoplasm. In at least some synapses, transmitter release occurs by fusion of these vesicles with the presynaptic membrane, followed by exocytosis of their contents. [NIH] Synchrony: The normal physiologic sequencing of atrial and ventricular activation and contraction. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tachykinins: A family of biologically active peptides sharing a common conserved Cterminal sequence, -Phe-X-Gly-Leu-Met-NH2, where X is either an aromatic or a branched aliphatic amino acid. Members of this family have been found in mammals, amphibians, and mollusks. Tachykinins have diverse pharmacological actions in the central nervous system and the cardiovascular, genitourinary, respiratory, and gastrointestinal systems, as well as in glandular tissues. This diversity of activity is due to the existence of three or more subtypes of tachykinin receptors. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Terminalis: A groove on the lateral surface of the right atrium. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH]

308 Melatonin

Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetani: Causal agent of tetanus. [NIH] Tetanic: Having the characteristics of, or relating to tetanus. [NIH] Tetanus: A disease caused by tetanospasmin, a powerful protein toxin produced by Clostridium tetani. Tetanus usually occurs after an acute injury, such as a puncture wound or laceration. Generalized tetanus, the most common form, is characterized by tetanic muscular contractions and hyperreflexia. Localized tetanus presents itself as a mild condition with manifestations restricted to muscles near the wound. It may progress to the generalized form. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thermoregulation: Heat regulation. [EU] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thoracic: Having to do with the chest. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [NIH] Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and

Dictionary 309

multiply. The thymus is in the chest behind the breastbone. [NIH] Thymus Gland: A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. [NIH] Thymus Hormones: Humoral factors secreted by the thymus gland. They participate in the development of the lymphoid system and the maturation of the cellular immune response. [NIH]

Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tonicity: The normal state of muscular tension. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Topoisomerase inhibitors: A family of anticancer drugs. The topoisomerase enzymes are responsible for the arrangement and rearrangement of DNA in the cell and for cell growth and replication. Inhibiting these enzymes may kill cancer cells or stop their growth. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH]

310 Melatonin

Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Toxoid: The material resulting from the treatment of toxin in such a way that the toxic properties are inactivated whilst the antigenic potency remains intact. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transducin: A heterotrimeric GTP-binding protein that mediates the light activation signal from photolyzed rhodopsin to cyclic GMP phosphodiesterase and is pivotal in the visual excitation process. Activation of rhodopsin on the outer membrane of rod and cone cells causes GTP to bind to transducin followed by dissociation of the alpha subunit-GTP complex from the beta/gamma subunits of transducin. The alpha subunit-GTP complex activates the cyclic GMP phosphodiesterase which catalyzes the hydrolysis of cyclic GMP to 5'-GMP. This leads to closure of the sodium and calcium channels and therefore hyperpolarization of the rod cells. EC 3.6.1.-. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock,

Dictionary 311

producing a disturbance. [NIH] Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [NIH] Triazolam: A short-acting benzodiazepine used in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries. [NIH] Trichotillomania: Compulsion to pull out one's hair. [NIH] Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tryptophan Hydroxylase: An enzyme that catalyzes the hydroxylation of tryptophan to 5hydroxytryptophan in the presence of NADPH and molecular oxygen. It is important in the biosynthesis of serotonin. EC 1.14.16.4 [NIH] Tryptophan Synthase: An enzyme that catalyzes the conversion of L-serine and 1-(indol-3yl)glycerol 3-phosphate to L-tryptophan and glyceraldehyde 3-phosphate. It is a pyridoxal phosphate protein that also catalyzes the conversion of serine and indole into tryptophan and water and of indoleglycerol phosphate into indole and glyceraldehyde phosphate. (From Enzyme Nomenclature, 1992) EC 4.2.1.20. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ubiquinone: A lipid-soluble benzoquinone which is involved in electron transport in mitochondrial preparations. The compound occurs in the majority of aerobic organisms, from bacteria to higher plants and animals. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulceration: 1. The formation or development of an ulcer. 2. An ulcer. [EU] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This

312 Melatonin

condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Univalent: Pertaining to an unpaired chromosome during the zygotene stage of prophase to first metaphase in meiosis. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinate: To release urine from the bladder to the outside. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterine Contraction: Contraction of the uterine muscle. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Valerian: Valeriana officinale, an ancient, sedative herb of the large family Valerianaceae. The roots were formerly used to treat hysterias and other neurotic states and are presently used to treat sleep disorders. [NIH] Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilatation: A state of increased calibre of the blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is

Dictionary 313

used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasogenic: Acute peripheral circulatory failure due to loss of capillary tone associated with a reduced circulating blood volume. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Ventilation: 1. In respiratory physiology, the process of exchange of air between the lungs and the ambient air. Pulmonary ventilation (usually measured in litres per minute) refers to the total exchange, whereas alveolar ventilation refers to the effective ventilation of the alveoli, in which gas exchange with the blood takes place. 2. In psychiatry, verbalization of one's emotional problems. [EU] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Vestibulocochlear Nerve: The 8th cranial nerve. The vestibulocochlear nerve has a cochlear part (cochlear nerve) which is concerned with hearing and a vestibular part (vestibular nerve) which mediates the sense of balance and head position. The fibers of the cochlear nerve originate from neurons of the spiral ganglion and project to the cochlear nuclei (cochlear nucleus). The fibers of the vestibular nerve arise from neurons of Scarpa's ganglion and project to the vestibular nuclei. [NIH] Vestibulocochlear Nerve Diseases: Diseases of the vestibular and/or cochlear (acoustic) nerves, which join to form the vestibulocochlear nerve. Vestibular neuritis, cochlear neuritis, and acoustic neuromas are relatively common conditions that affect these nerves. Clinical manifestations vary with which nerve is primarily affected, and include hearing loss, vertigo, and tinnitus. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral vector: A type of virus used in cancer therapy. The virus is changed in the laboratory and cannot cause disease. Viral vectors produce tumor antigens (proteins found on a tumor cell) and can stimulate an antitumor immune response in the body. Viral vectors may also be used to carry genes that can change cancer cells back to normal cells. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or

314 Melatonin

viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Visual Cortex: Area of the occipital lobe concerned with vision. [NIH] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] Visual Pathways: Set of cell bodies and nerve fibers conducting impulses from the eyes to the cerebral cortex. It includes the retina, optic nerve, optic tract, and geniculocalcarine tract. [NIH]

Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Void: To urinate, empty the bladder. [NIH] Volition: Voluntary activity without external compulsion. [NIH] Vomeronasal Organ: A specialized part of the olfactory system located anteriorly in the nasal cavity within the nasal septum. Chemosensitive cells of the vomeronasal organ project via the vomeronasal nerve to the accessory olfactory bulb. The primary function of this organ appears to be in sensing pheromones which regulate reproductive and other social behaviors. While the structure has been thought absent in higher primate adults, data now suggests it may be present in adult humans. [NIH] Wakefulness: A state in which there is an enhanced potential for sensitivity and an efficient responsiveness to external stimuli. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Weight-Bearing: The physical state of supporting an applied load. This often refers to the weight-bearing bones or joints that support the body's weight, especially those in the spine, hip, knee, and foot. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the

Dictionary 315

cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Wounds, Gunshot: Disruption of structural continuity of the body as a result of the discharge of firearms. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH]

317

INDEX 5 5-Hydroxytryptophan, 143, 168, 227, 311 A Abdomen, 227, 238, 271, 275, 287, 288, 304, 305, 308, 312 Abdominal, 28, 176, 227, 228, 271, 287, 288, 312 Abdominal Pain, 176, 227, 312 Ablation, 27, 35, 227 Acatalasia, 227, 241 Acceptor, 227, 274, 286 Accommodation, 227, 253, 281 Acetylcholine, 28, 227, 243, 283 Acne, 186, 227 Acoustic, 169, 227, 313 Actin, 227, 280, 281 Action Potentials, 11, 227 Activities of Daily Living, 227, 253 Acyl, 161, 227 Adaptability, 227, 242 Adaptation, 61, 64, 98, 106, 136, 163, 173, 176, 227, 250, 291 Adenine, 227, 296 Adenocarcinoma, 227, 284 Adenosine, 36, 54, 124, 227, 239, 289 Adipocytes, 75, 228, 273 Adjunctive Therapy, 110, 228 Adjustment, 178, 227, 228, 250 Adjuvant, 81, 119, 122, 124, 125, 126, 128, 134, 165, 228, 262 Adolescence, 12, 228 Adrenal Cortex, 228, 249, 258, 293 Adrenal Glands, 228, 230 Adrenal Medulla, 228, 241, 257, 284 Adrenalin, 178, 228 Adrenergic, 44, 47, 62, 137, 173, 177, 228, 232, 253, 257, 306 Adrenergic Antagonists, 62, 228 Adverse Effect, 228, 230, 233, 272, 302 Aerobic, 228, 311 Aetiology, 228 Afferent, 19, 180, 228, 273, 290 Affinity, 27, 38, 57, 69, 77, 155, 156, 161, 164, 174, 175, 177, 228, 234, 274, 282, 303 Agonist, 7, 44, 65, 69, 77, 84, 95, 107, 155, 164, 175, 177, 184, 185, 228, 233, 253, 257, 281, 306, 307 Airway, 8, 229

Airway Obstruction, 8, 229 Akathisia, 169, 229, 233 Albumin, 229, 286, 291 Alertness, 4, 8, 18, 21, 25, 40, 178, 229, 239 Algorithms, 229, 237 Alimentary, 187, 229 Alkaline, 229, 230, 240 Alkaloid, 229, 240, 246, 279 Alkylating Agents, 229, 250 Allergen, 229, 252 Aloe, 63, 121, 143, 229 Alopecia, 172, 229, 249 Alpha Particles, 229, 296 Alpha-1, 47, 229 Alternative medicine, 201, 229 Alveolar Process, 229, 298 Amblyopia, 32, 230 Amenorrhea, 230, 292 Amino Acid Sequence, 20, 230, 231, 236, 262, 294 Amino Acids, 81, 157, 178, 194, 230, 234, 236, 262, 283, 288, 292, 294, 300, 301, 306, 310 Ammonia, 230, 263 Amnestic, 230, 278 Amnion, 230 Amniotic Fluid, 85, 230, 262 Amyloid, 25, 62, 87, 97, 137, 166, 230, 301 Amyloidosis, 166, 230 Anaesthesia, 76, 135, 230, 269 Anal, 187, 230, 257 Analgesic, 44, 138, 164, 184, 185, 230, 274, 279, 285 Analog, 25, 155, 230, 260, 284 Analogous, 35, 230, 310 Anaphylatoxins, 230, 246 Anaplasia, 231, 282 Anatomical, 10, 28, 33, 36, 169, 231, 235, 247, 252, 269, 287, 300 Anemia, 211, 231, 260, 288 Anesthesia, 73, 93, 138, 186, 229, 231, 255, 278 Anesthetics, 55, 231, 236, 257 Anestrus, 33, 231 Aneurysm, 231, 312 Anginal, 231, 283 Animal model, 12, 35, 42, 50, 52, 54, 114, 231

318 Melatonin

Annealing, 231, 292 Anorexia, 13, 41, 140, 231, 286 Anovulation, 33, 231, 292 Antagonism, 9, 44, 83, 231, 239, 252 Anterior Cerebral Artery, 231, 243 Anterior chamber, 33, 231, 271 Antiandrogens, 165, 231 Antiarrhythmic, 154, 231 Antibacterial, 231, 304 Antibiotic, 231, 288, 304 Antibodies, 10, 231, 264, 268, 276, 291 Antibody, 20, 31, 35, 228, 231, 232, 246, 264, 266, 268, 269, 272, 273, 276, 279, 296, 297, 304, 315 Antibody-Dependent Cell Cytotoxicity, 232, 273 Anticarcinogenic, 94, 112, 232 Anticonvulsant, 184, 185, 232 Antidepressant, 227, 232, 245, 260 Antidote, 232, 290 Antiemetic, 232, 233, 252 Antiepileptic, 227, 232 Antigen, 228, 231, 232, 246, 266, 267, 268, 269, 276, 296 Antigen-Antibody Complex, 232, 246 Anti-inflammatory, 44, 49, 113, 144, 187, 232, 262, 284 Anti-Inflammatory Agents, 44, 232 Antimetabolite, 232, 260 Antineoplastic, 229, 232, 240, 249, 260, 291 Antiproliferative, 128, 232 Antipsychotic, 232, 282, 300 Antitussive, 233, 252, 285 Antiviral, 233, 270 Anus, 230, 233, 238, 297 Anxiety, 23, 51, 140, 154, 164, 169, 229, 233, 272, 286, 287, 300 Anxiety Disorders, 233, 287 Anxiolytic, 59, 233, 278 Aorta, 122, 233, 248, 313 Apathy, 233, 282 Aperture, 233, 259, 296 Apomorphine, 76, 127, 233 Aponeurosis, 233, 261 Apoptosis, 20, 21, 34, 70, 86, 136, 177, 233, 241 Aqueous, 100, 155, 233, 236, 244, 250, 256, 266, 273 Aqueous humor, 233, 244 Arachidonate 12-Lipoxygenase, 233, 274 Arachidonate 15-Lipoxygenase, 233, 274 Arachidonate Lipoxygenases, 233, 274

Arachidonic Acid, 6, 233, 255, 274, 294 Arcuate Nucleus, 110, 234 Arginine, 157, 185, 230, 234, 283 Aromatic, 30, 234, 289, 307 Arrestin, 16, 234 Arrhythmia, 154, 231, 234 Arterial, 234, 243, 248, 267, 294, 307 Arteries, 56, 57, 187, 233, 234, 235, 238, 243, 248, 272, 275, 278, 280, 296, 308 Arterioles, 234, 238, 240 Arteriolosclerosis, 234 Arteriosclerosis, 186, 234, 267 Articular, 234, 285 Aspartate, 154, 234 Aspartic, 234, 241 Aspartic Acid, 234, 241 Assay, 37, 42, 234, 268, 296 Astigmatism, 234, 298 Astrocytes, 234, 262, 282 Asymptomatic, 45, 227, 235 Ataxia, 210, 211, 235, 308 Atherogenic, 187, 235 Atmospheric Pressure, 235, 267 Atrial, 154, 235, 248, 307, 311 Atrial Fibrillation, 154, 235 Atrioventricular, 235, 248 Atrium, 235, 248, 307, 311, 313 Atrophy, 210, 211, 235, 282 Attenuation, 13, 98, 136, 235 Atypical, 235, 300 Auditory, 235, 276, 312 Auricular, 125, 235 Autoimmune disease, 235, 280 Autoimmunity, 36, 235 Autonomic, 33, 175, 227, 233, 235, 284, 288, 303, 306 Autonomic Nervous System, 175, 235, 288, 303, 306 Autoradiography, 30, 44, 235 Avian, 135, 235 Avulsion, 46, 235 Axonal, 18, 28, 235 Axons, 28, 235, 251, 252, 282, 285, 299 Axotomy, 46, 236 B Bacteria, 227, 231, 232, 236, 237, 255, 266, 275, 278, 280, 291, 297, 301, 302, 304, 310, 311, 312 Bacterial Physiology, 227, 236 Bactericidal, 236, 258 Bacteriophage, 236, 291, 310 Barbiturates, 236, 290

Index 319

Basal Ganglia, 233, 235, 236, 244, 261 Basal Ganglia Diseases, 235, 236, 244 Base, 17, 227, 236, 251, 262, 272, 291, 307 Basophils, 236, 264, 273 Benign, 165, 166, 234, 236, 261, 264, 282, 297 Benign prostatic hyperplasia, 165, 166, 236 Benzene, 236 Benzodiazepines, 143, 199, 236 Beta-Endorphin, 110, 236 Beta-pleated, 230, 236 Bilateral, 237, 292 Bile, 78, 237, 261, 265, 266, 275, 305 Bile Acids, 237, 305 Bile Acids and Salts, 237 Biliary, 237, 265 Bilirubin, 64, 229, 237 Binding Sites, 135, 191, 237 Bioassay, 69, 237 Bioavailability, 62, 172, 237 Biogenesis, 24, 237 Biological Clocks, 32, 237 Biological Factors, 162, 237 Biological response modifier, 130, 237, 270 Biological therapy, 237, 264 Biomarkers, 49, 237 Biosynthesis, 6, 24, 29, 30, 40, 47, 178, 191, 234, 237, 263, 301, 311 Biotechnology, 57, 59, 83, 107, 193, 201, 207, 209, 210, 211, 212, 237 Biotinylation, 26, 238 Biotransformation, 238 Bladder, 190, 236, 238, 269, 280, 294, 312, 314 Blastocyst, 238, 247, 291 Bloating, 238, 261 Blood Coagulation, 238, 240 Blood Glucose, 238, 265, 267, 270 Blood Platelets, 238, 301 Blood pressure, 16, 63, 136, 175, 238, 241, 267, 268, 279, 283, 296, 303 Blood Volume, 238, 313 Blot, 56, 238 Body Composition, 18, 238 Body Fluids, 177, 237, 238, 254, 303, 311 Body Mass Index, 8, 238 Bone Marrow, 122, 236, 238, 258, 264, 265, 268, 275, 279, 303 Bone Marrow Cells, 238, 264 Bowel, 230, 238, 252, 271, 273, 284, 305, 312 Bowel Movement, 238, 252, 305

Brachytherapy, 238, 270, 272, 296, 315 Bradykinin, 239, 283, 291 Brain Injuries, 7, 239 Brain metastases, 149, 239 Brain Stem, 239, 242 Branch, 223, 239, 255, 275, 276, 285, 287, 289, 295, 304, 308 Breakdown, 13, 239, 252, 261 Breeding, 33, 35, 42, 158, 159, 161, 163, 180, 239 Bronchi, 239, 257, 310 Bronchial, 8, 239, 266 Buccal, 159, 239 Bulimia, 169, 239 Butyric Acid, 167, 183, 239 C Caffeine, 98, 239, 296 Calcification, 169, 234, 239 Calcitonin Gene-Related Peptide, 130, 239 Calcium, 27, 28, 47, 52, 82, 121, 239, 240, 246, 252, 278, 280, 283, 286, 302, 310 Calcium Channels, 240, 310 Calmodulin, 83, 240 Camptothecin, 127, 240, 271 Capillary, 122, 239, 240, 313 Capsular, 154, 240 Capsules, 240, 253, 262 Carbohydrate, 13, 29, 157, 160, 240, 263, 292, 300 Carbon Dioxide, 240, 291, 298, 313 Carboplatin, 123, 240 Carcinogen, 34, 136, 240 Carcinogenesis, 112, 129, 187, 240, 243 Carcinogenic, 229, 236, 240, 269, 294, 305 Carcinoma, 65, 106, 162, 240, 284, 304 Cardiac arrest, 54, 240, 306 Cardiopulmonary, 54, 240 Cardiopulmonary Resuscitation, 54, 240 Cardiorespiratory, 241, 278 Cardiovascular, 16, 28, 39, 53, 56, 88, 175, 184, 186, 240, 241, 274, 301, 303, 307 Cardiovascular disease, 28, 53, 56, 175, 241 Cardiovascular System, 16, 186, 241 Carnitine, 126, 194, 241 Carotene, 241, 299 Carrier Proteins, 241, 291, 296 Case report, 241, 245 Case series, 241, 245 Caspases, 20, 241 Catabolism, 13, 241 Catalase, 156, 227, 241

320 Melatonin

Catecholamine, 178, 241, 253 Catheters, 29, 241, 269, 270 Caudal, 241, 252, 268, 292 Causal, 33, 49, 56, 241, 257, 308 Cell Adhesion, 21, 158, 242 Cell Count, 46, 242, 288 Cell Cycle, 242, 245, 258 Cell Death, 20, 21, 46, 48, 86, 95, 233, 242, 258, 281 Cell Differentiation, 242, 302 Cell Division, 210, 236, 242, 249, 258, 264, 277, 279, 291, 294 Cell membrane, 240, 241, 242, 251, 261, 289, 303 Cell Physiology, 29, 137, 242 Cell proliferation, 35, 172, 187, 234, 242, 302 Cell Size, 242, 260 Cell Survival, 21, 242, 264 Cellobiose, 242 Cellulose, 173, 242, 291 Central Nervous System Infections, 242, 264 Centrifugation, 242, 278 Cerebellar, 235, 242, 297 Cerebellum, 239, 242, 261, 297 Cerebral, 46, 56, 101, 130, 135, 137, 167, 181, 187, 231, 235, 236, 239, 242, 243, 248, 251, 257, 258, 261, 273, 278, 295, 307, 308, 314 Cerebral Aqueduct, 242, 261, 308 Cerebral Arteries, 56, 130, 243, 278 Cerebral hemispheres, 236, 239, 243, 273, 307 Cerebral Infarction, 135, 181, 243 Cerebrospinal, 62, 68, 96, 169, 177, 243 Cerebrospinal fluid, 62, 68, 96, 169, 177, 243 Cerebrovascular, 55, 65, 194, 236, 241, 243, 283, 308 Cerebrum, 242, 243, 290, 307, 311 Ceroid, 64, 243, 274 Cervical, 180, 243, 304 Cervix, 243, 298 Character, 243, 250 Chemopreventive, 107, 243 Chemotactic Factors, 243, 246 Chemotherapy, 63, 81, 118, 119, 120, 121, 128, 143, 243 Chlorpyrifos, 112, 243 Cholesterol, 118, 187, 237, 243, 248, 254, 267, 274, 275, 305, 307

Choline, 137, 194, 243 Cholinergic, 177, 232, 243 Chorea, 169, 232, 243, 244 Choreatic Disorders, 244 Choroid, 244, 273, 299 Chromaffin System, 244, 256 Chromatin, 233, 244, 283 Chromium, 123, 189, 244 Chromosomal, 244, 291, 299 Chronic, 6, 18, 25, 28, 44, 49, 52, 54, 63, 66, 74, 78, 82, 93, 106, 112, 148, 166, 169, 179, 190, 198, 210, 239, 244, 256, 269, 272, 273, 292, 295, 303, 305, 311 Chronic Fatigue Syndrome, 78, 244 Chronic renal, 63, 66, 244, 292 Chronobiology, 8, 50, 60, 61, 64, 65, 66, 79, 80, 85, 88, 98, 99, 121, 122, 124, 126, 137, 190, 244 Ciliary, 16, 19, 233, 244 Ciliary Body, 244 Ciliary processes, 19, 233, 244 Circulatory system, 244, 256, 271 CIS, 31, 34, 72, 244, 299 Cisplatin, 116, 118, 119, 244 Citalopram, 75, 245 Clamp, 28, 245 Clear cell carcinoma, 245, 251 Clinical Medicine, 176, 245, 293 Clinical study, 5, 245 Clinical trial, 4, 45, 149, 150, 151, 207, 245, 247, 295, 297 Clone, 32, 245 Cloning, 57, 164, 237, 245 Coagulation, 238, 245, 265, 291, 308 Cochlear, 245, 309, 313 Cochlear Diseases, 245, 309 Coenzyme, 37, 126, 194, 245 Cofactor, 245, 294 Cognition, 245, 282 Cohort Studies, 245, 257 Colchicine, 132, 246 Colitis, 246 Collagen, 246, 261, 291 Collapse, 239, 246 Colloidal, 229, 246, 255, 302 Color Therapy, 142, 214, 246 Colorectal, 63, 65, 106, 120, 246 Colorectal Cancer, 63, 120, 246 Complement, 157, 172, 230, 232, 246, 247, 262, 291 Complementary and alternative medicine, 117, 118, 145, 246

Index 321

Complementary medicine, 118, 247 Complete remission, 247, 298 Computational Biology, 207, 209, 247 Conception, 165, 247, 259, 305 Concomitant, 18, 247 Cone, 9, 11, 36, 39, 40, 62, 79, 247, 290, 310 Cone cells, 247, 310 Confusion, 247, 253, 267, 282 Conjugated, 237, 247, 250 Connective Tissue, 238, 246, 247, 260, 261, 275, 278 Consciousness, 230, 247, 250, 251, 253, 298, 303 Consolidation, 17, 247 Constrict, 14, 247 Constriction, 56, 172, 247, 272, 312 Constriction, Pathologic, 247, 312 Consumption, 38, 83, 103, 157, 160, 247, 298 Contamination, 92, 247 Contraceptive, 164, 247 Contraindications, ii, 247 Control group, 51, 52, 247 Controlled study, 59, 64, 247 Conventional therapy, 198, 248 Conventional treatment, 248 Convulsions, 232, 248, 267 Coordination, 166, 242, 248, 280 Cor, 8, 248, 294 Cornea, 33, 231, 233, 234, 248, 305, 312 Corneum, 248, 257 Coronary, 60, 68, 85, 93, 241, 248, 278, 280 Coronary Artery Bypass, 93, 248 Coronary heart disease, 60, 241, 248 Coronary Thrombosis, 248, 278, 280 Corpus, 165, 248, 275, 288, 290, 293, 308 Corpus Callosum, 248, 290, 308 Corpus Luteum, 165, 248, 275, 293 Cortex, 230, 235, 243, 248, 249, 257, 258, 278, 297, 314 Cortical, 230, 249, 282, 301, 308 Corticosteroids, 144, 249, 262 Cortisol, 13, 18, 47, 51, 54, 56, 66, 72, 89, 90, 97, 109, 148, 229, 249 Coturnix, 125, 126, 249 Cranial, 183, 242, 249, 258, 264, 267, 271, 285, 288, 312, 313 Craniocerebral Trauma, 236, 249, 264, 308, 309 Creatinine, 7, 249 Cribriform, 249, 284 Cross-Sectional Studies, 249, 257

Cues, 31, 36, 47, 169, 249 Cultured cell line, 5, 249 Cultured cells, 5, 249 Curative, 249, 283, 308 Curettage, 249, 274 Cutaneous, 156, 249, 290 Cyclic, 5, 20, 36, 66, 123, 124, 161, 239, 240, 244, 249, 264, 283, 289, 290, 301, 310 Cyclophosphamide, 81, 128, 143, 249 Cysteine, 241, 249, 306 Cysteine Endopeptidases, 241, 249 Cytochrome, 20, 75, 82, 92, 128, 249 Cytokine, 41, 133, 250 Cytoplasm, 233, 236, 242, 250, 256, 257, 264, 279, 283, 300, 307 Cytotoxic, 24, 96, 176, 183, 250, 297, 302 Cytotoxicity, 96, 245, 250 D Dacarbazine, 59, 250 Dark Adaptation, 48, 250 Databases, Bibliographic, 207, 250 De novo, 26, 250 Decidua, 250, 291 Decubitus, 250, 302 Decubitus Ulcer, 250, 302 Defense Mechanisms, 54, 250 Degenerative, 37, 48, 136, 181, 250, 262 Dehydroepiandrosterone, 72, 109, 118, 133, 135, 194, 215, 250 Deletion, 233, 250 Delirium, 94, 232, 250 Delusions, 251, 295 Dementia, 4, 64, 70, 108, 166, 169, 232, 251, 252 Denaturation, 97, 251, 292 Dendrites, 251, 283, 284 Dendritic, 251, 277, 299 Density, 30, 156, 172, 175, 176, 187, 238, 242, 251, 254, 260, 274, 285 Dentate Gyrus, 251, 266 Depersonalization, 251, 287, 300 Depolarization, 251, 302 Depressive Disorder, 45, 69, 107, 251, 275 Deprivation, 54, 120, 129, 230, 251 Derealization, 251, 287 Dermal, 57, 176, 251 Dermatitis, 251, 254 DES, 109, 113, 114, 230, 251 Desensitization, 26, 252 Detergents, 252, 302 Deuterium, 168, 252, 266 Deuterium Oxide, 168, 252

322 Melatonin

Diabetes Mellitus, 172, 252, 263, 265, 284 Diagnostic procedure, 153, 201, 252 Dialyzer, 252, 265 Diarrhea, 176, 252 Diastolic, 252, 267 Diencephalon, 252, 268, 294, 307, 308 Dietetics, 174, 252 Diffuse Axonal Injury, 239, 252 Digestion, 229, 237, 238, 252, 261, 271, 275, 305 Digestive system, 89, 151, 252 Digestive tract, 172, 252, 303, 304 Dihydrotestosterone, 252, 297 Dilatation, 231, 252, 293, 312 Dilatation, Pathologic, 252, 312 Dilation, 56, 239, 252, 312 Dilator, 56, 252 Diltiazem, 83, 252 Diphenhydramine, 45, 252 Diploid, 253, 291 Direct, iii, 15, 25, 38, 48, 54, 96, 109, 165, 169, 245, 253, 288, 298, 307 Disabled Children, 92, 200, 253 Disinfectant, 253, 258 Disorientation, 247, 251, 253 Dissociation, 24, 228, 253, 271, 310 Dissociative Disorders, 253 Distal, 176, 235, 248, 253, 295 Diuresis, 239, 253 Diurnal, 27, 36, 47, 52, 69, 85, 135, 166, 180, 253 Dizziness, 253, 287 Dominance, 11, 253 Dopa, 162, 253, 274 Dorsum, 253, 261 Dosage Forms, 172, 253 Dose-dependent, 48, 70, 79, 123, 131, 254 Dosimetry, 49, 254 Drive, ii, vi, 9, 44, 105, 179, 254, 274 Drug Interactions, 254 Drug Resistance, 254 Drug Tolerance, 32, 254, 309 Duct, 254, 300 Duodenum, 237, 254, 256, 261, 305 Dyes, 230, 236, 254, 260, 283 Dyskinesia, 87, 169, 171, 198, 233, 245, 254 Dyslipidemia, 28, 254 Dysphoria, 23, 254 Dysphoric, 45, 251, 254 Dysplasia, 62, 211, 254 Dyspnea, 254, 287 Dystonia, 169, 233, 254

Dystrophy, 210, 254 E Eating Disorders, 184, 254 Eczema, 186, 254 Edema, 46, 114, 183, 254, 271, 273, 280 Effector, 24, 161, 227, 232, 246, 254, 255, 273, 283, 289 Effector cell, 232, 255, 273, 283 Efficacy, 5, 10, 21, 26, 32, 44, 45, 54, 59, 84, 117, 150, 158, 179, 255 Eicosanoids, 187, 255 Elasticity, 234, 255, 302 Electric shock, 240, 241, 255 Electroacupuncture, 120, 124, 130, 255 Electrocardiogram, 124, 255 Electrolyte, 251, 255, 292, 303 Electromagnetic Fields, 89, 255 Electron microscope, 107, 255 Electrons, 232, 236, 255, 271, 286, 296, 297 Electrophoresis, 20, 122, 255 Electrophysiological, 11, 36, 125, 255 Embolism, 181, 255 Embolus, 255, 269 Embryo, 230, 238, 242, 255, 269, 304 Emetic, 233, 255 Emodin, 229, 255 Emollient, 255, 263, 284 Empirical, 55, 256 Emulsion, 235, 256 Encapsulated, 21, 256 Endocrine Glands, 256 Endocrine System, 175, 256, 282 Endometrium, 250, 256, 277 Endorphins, 256, 294 Endoscopic, 256, 278 Endothelial cell, 256, 260 Endothelium, 172, 256, 283 Endothelium, Lymphatic, 256 Endothelium, Vascular, 256 Endothelium-derived, 256, 283 Endotoxins, 246, 256 End-stage renal, 66, 244, 256, 292 Energy balance, 257, 273, 290 Enhancer, 194, 257 Enkephalin, 44, 236, 257, 294 Entorhinal Cortex, 7, 257, 266 Environmental Exposure, 257, 285 Environmental Health, 48, 129, 206, 208, 257 Enzymatic, 20, 178, 240, 241, 246, 257, 266, 292, 299 Enzyme Inhibitors, 50, 257, 291

Index 323

Eosinophil, 257, 264 Ependyma, 234, 257, 308 Ephedrine, 215, 257 Epidemiologic Studies, 7, 257 Epidemiological, 22, 117, 257 Epidermal, 66, 257, 272, 277 Epidermal Growth Factor, 66, 257 Epidermis, 161, 248, 257, 266, 272, 293, 296 Epinephrine, 3, 46, 228, 253, 257, 284, 311 Epithelial, 16, 29, 227, 244, 250, 257, 258 Epithelial Cells, 16, 257, 258 Epithelium, 16, 256, 258, 271 Erectile, 190, 258, 288 Erection, 258 Erythrocytes, 96, 231, 238, 258, 297 Erythropoietin, 199, 258 Esophagectomy, 67, 258 Esophagus, 252, 258, 289, 305 Esotropia, 258, 305 Essential Tremor, 169, 210, 258 Estradiol, 33, 38, 72, 83, 109, 258 Estrogen, 33, 35, 55, 215, 258, 293, 301, 307 Estrogen receptor, 33, 56, 258 Ethanol, 155, 170, 245, 258 Ethinyl Estradiol, 67, 258 Ethmoid, 258, 284 Etoposide, 118, 119, 123, 258 Eukaryotic Cells, 258, 269, 285 Evacuation, 258, 261, 273, 296 Evoke, 258, 305 Excipient, 169, 258 Excitability, 259, 281, 282 Excitation, 259, 260, 310 Excitotoxicity, 177, 259 Exhaustion, 231, 259 Exogenous, 14, 37, 51, 99, 107, 109, 119, 127, 171, 238, 254, 259 Exotropia, 259, 305 Extensor, 259, 295 External-beam radiation, 259, 272, 296, 315 Extracellular, 36, 56, 230, 234, 247, 259, 278, 282, 303 Extracellular Space, 259, 278 Extraction, 68, 259 Extraocular, 73, 90, 259 Extrapyramidal, 229, 233, 253, 259 Eye Movements, 32, 259 Eyecup, 36, 259 F Fallopian Tubes, 259, 298 Family Planning, 207, 259

Fat, 42, 157, 228, 233, 237, 238, 239, 241, 248, 250, 255, 259, 273, 274, 280, 292, 303, 309 Fatigue, 23, 176, 244, 259, 265, 277 Fatty acids, 194, 229, 255, 259, 263, 274, 294, 303 Feeding Behavior, 38, 259 Fetus, 24, 258, 259, 291, 304, 312 Fibrinogen, 259, 291, 308 Fibroblast Growth Factor, 66, 260 Fibrosis, 211, 260, 300 Fibula, 260, 292 Fistula, 260, 284 Flatus, 260, 261 Flow Cytometry, 35, 260 Fluorescence, 5, 48, 68, 96, 122, 260 Fluorescent Dyes, 260 Fluorouracil, 63, 81, 120, 128, 143, 260 Fluoxetine, 66, 116, 260 Foam Cells, 172, 260 Folate, 172, 260 Fold, 50, 177, 260 Folic Acid, 160, 189, 215, 260 Follicles, 81, 129, 173, 261 Forearm, 238, 261 Fourth Ventricle, 243, 261, 308 Fraud, 214, 261 Frontal Lobe, 231, 243, 261 Fructose, 189, 261 Fungi, 261, 264, 278, 280, 315 G Gallate, 76, 127, 261 Gallbladder, 227, 237, 252, 261 Gamma Rays, 261, 296, 297 Ganglia, 180, 227, 236, 261, 282, 288, 304, 306 Ganglion, 15, 30, 36, 261, 299, 304, 313 Gap Junctions, 261, 307 Gas, 7, 230, 240, 260, 261, 266, 283, 284, 306, 313 Gastric, 76, 82, 241, 253, 257, 261, 266, 271 Gastric Emptying, 261 Gastrin, 261, 266 Gastrointestinal, 39, 76, 84, 95, 160, 239, 257, 258, 261, 274, 301, 303, 306, 307, 311 Gastrointestinal tract, 95, 258, 261, 274, 301, 303, 311 Gastroparesis, 190, 261 Gelatin, 261, 263, 308 Gene Expression, 6, 16, 18, 29, 30, 36, 43, 48, 73, 108, 137, 211, 262 Genetic Code, 262, 284

324 Melatonin

Genetic Engineering, 237, 245, 262 Genetic Markers, 158, 262 Genetic testing, 262, 292 Genetics, 12, 31, 62, 111, 131, 253, 262 Genitourinary, 262, 307 Genomics, 6, 262 Genotype, 262, 289 Gestation, 15, 262, 291, 304 Gestational, 160, 262 Gestational Age, 160, 262 Ginseng, 118, 189, 194, 262 Gland, 29, 30, 34, 36, 44, 49, 50, 51, 63, 94, 106, 107, 134, 138, 148, 150, 162, 163, 164, 166, 168, 169, 170, 173, 174, 177, 191, 192, 228, 244, 262, 275, 287, 290, 294, 301, 305, 309 Glioma, 88, 262 Gliosis, 18, 262 Glomeruli, 262, 284 Glucocorticoid, 47, 131, 262 Glucose, 28, 189, 210, 238, 242, 244, 252, 262, 263, 265, 267, 270, 300 Glucose Intolerance, 28, 252, 263 Glucose tolerance, 263 Glucose Tolerance Test, 263 Glutamate, 9, 25, 28, 30, 177, 259, 263, 272 Glutamic Acid, 260, 263 Glutamine, 157, 263 Glutathione Peroxidase, 263, 301 Glyceraldehyde 3-Phosphate, 263, 311 Glycerol, 54, 239, 263, 289, 311 Glycerophospholipids, 263, 289 Glycine, 157, 237, 263, 301 Glycols, 155, 263, 267 Glycoprotein, 258, 259, 263, 264, 271 Gonad, 263 Gonadal, 34, 42, 53, 56, 84, 166, 263, 305 Gonadotropin, 33, 148, 263 Gout, 246, 263 Governing Board, 264, 293 Graft, 21, 264, 266, 269, 280 Graft Rejection, 264, 269 Graft Survival, 21, 264 Grafting, 21, 58, 93, 248, 264, 269 Granulocyte-Macrophage ColonyStimulating Factor, 128, 264 Granulocytes, 35, 264, 273, 280, 302, 314 Granulosa Cells, 165, 264, 275 Grasses, 260, 264 Growth factors, 21, 172, 264 Guanylate Cyclase, 264, 283

H Habitual, 9, 40, 243, 264 Haloperidol, 65, 121, 171, 264 Haploid, 264, 291 Haptens, 228, 264, 296 Headache, 101, 110, 138, 140, 176, 198, 200, 239, 264, 265, 267 Headache Disorders, 264, 265 Heart Arrest, 240, 241, 265 Heart attack, 172, 241, 265 Heart failure, 257, 265 Heartbeat, 265, 306 Hematologic malignancies, 118, 265 Heme, 237, 249, 265 Hemiparesis, 239, 265 Hemodialysis, 66, 252, 265, 273 Hemodynamics, 175, 265 Hemoglobin, 97, 231, 258, 265, 273 Hemoglobinuria, 210, 265 Hemorrhage, 249, 264, 265, 280, 296, 305 Hemostasis, 265, 301 Hepatic, 69, 122, 229, 251, 263, 265 Hepatobiliary, 95, 265 Hereditary, 244, 263, 265, 282, 288, 299 Heredity, 262, 265 Heterogeneity, 11, 228, 265 Heterotropia, 265, 305 Heterozygotes, 253, 266 Hippocampus, 7, 251, 266, 305 Histamine, 230, 232, 252, 266 Histiocytosis, 94, 266 Homeostasis, 111, 266, 303 Homologous, 31, 266, 307 Homotypic, 24, 266 Homozygotes, 253, 266 Hormonal, 14, 32, 45, 85, 98, 157, 181, 235, 266, 288 Hormone Replacement Therapy, 56, 65, 266 Hormone therapy, 180, 266 Horny layer, 257, 266 Host, 41, 236, 264, 266, 268, 274, 299, 314 Human growth hormone, 157, 180, 181, 266, 303 Humoral, 126, 264, 266, 309 Humour, 266 Hybrid, 15, 31, 245, 266 Hydrogen, 161, 162, 227, 236, 240, 241, 251, 252, 263, 266, 267, 274, 279, 283, 286, 288, 295 Hydrogen Peroxide, 241, 263, 266, 274

Index 325

Hydrolysis, 234, 238, 242, 244, 267, 289, 292, 295, 310 Hydrophilic, 173, 252, 267 Hydrophobic, 173, 252, 263, 267, 274 Hydroxides, 267 Hydroxyl Radical, 62, 136, 147, 161, 267 Hydroxylation, 267, 311 Hygienic, 267, 302 Hyperbaric, 119, 125, 267 Hyperbaric oxygen, 119, 125, 267 Hypercholesterolemia, 254, 267 Hyperlipidemia, 254, 267 Hyperopia, 33, 267, 298 Hyperphagia, 13, 23, 267 Hypersensitivity, 79, 229, 252, 257, 267, 274 Hypertension, 28, 154, 172, 179, 234, 241, 267, 271, 284 Hypertriglyceridemia, 254, 267 Hypertrophy, 236, 248, 267, 311 Hypnotic, 40, 44, 79, 138, 163, 164, 170, 174, 252, 267, 278 Hypoglossal Nerve, 46, 267 Hypoglycaemia, 251, 267 Hypoglycemia, 47, 267 Hypoglycemic, 46, 267 Hypophyseal, 31, 164, 268 Hypotensive, 16, 268 Hypothalamic, 18, 23, 33, 42, 46, 111, 137, 164, 175, 268 Hypoxemia, 181, 268 Hypoxia, 21, 251, 268, 308 I Id, 115, 139, 215, 222, 224, 268 Idiopathic, 94, 99, 268 Immaturity, 160, 268 Immune function, 35, 41, 53, 86, 268 Immune response, 35, 41, 125, 126, 228, 232, 235, 264, 268, 306, 309, 313, 314 Immunity, 63, 89, 111, 121, 125, 127, 268 Immunization, 268 Immunoassay, 7, 268 Immunodeficiency, 36, 210, 214, 268 Immunogenic, 268, 296 Immunoglobulin, 64, 231, 268, 279 Immunohistochemistry, 18, 268 Immunologic, 243, 262, 268, 297, 309 Immunology, 73, 86, 135, 228, 260, 268 Immunosuppressant, 229, 260, 268 Immunosuppressive, 249, 262, 268 Immunosuppressive therapy, 268 Immunotherapy, 119, 237, 252, 268

Impairment, 40, 129, 169, 194, 235, 251, 254, 269, 277, 295 Implant radiation, 269, 271, 272, 296, 315 Implantation, 21, 247, 269 Impotence, 258, 269 In situ, 18, 30, 33, 41, 44, 269 In Situ Hybridization, 18, 30, 33, 41, 44, 269 Incision, 269, 271 Incontinence, 163, 257, 269 Indicative, 43, 158, 190, 269, 287, 312 Induction, 22, 46, 71, 114, 167, 173, 183, 186, 232, 269, 293 Infarction, 181, 243, 269, 298 Infection, 41, 135, 235, 237, 243, 244, 251, 268, 269, 275, 276, 283, 288, 305, 314 Infertility, 33, 269 Inflammation, 6, 8, 93, 112, 227, 229, 232, 241, 244, 246, 251, 260, 264, 269, 274, 299, 311, 312 Infusion, 46, 269, 280 Ingestion, 28, 157, 263, 267, 269, 291 Initiation, 46, 161, 187, 269, 275, 310 Inlay, 269, 298 Innervation, 180, 267, 270 Inorganic, 244, 267, 270, 280 Inositol, 121, 270, 301 Inositol Phosphates, 121, 270 Inotropic, 253, 270 Insight, 22, 42, 45, 46, 270 Insulator, 270, 280 Insulin, 28, 66, 70, 97, 108, 122, 125, 263, 270 Insulin-dependent diabetes mellitus, 270 Insulin-like, 66, 70, 97, 108, 122, 270 Intensive Care, 67, 270 Interferon, 59, 270 Interferon-alpha, 59, 270 Interleukin-2, 59, 89, 111, 119, 124, 270 Intermittent, 17, 163, 270 Internal Medicine, 74, 256, 270 Internal radiation, 270, 272, 296, 315 Interstitial, 238, 259, 271, 272, 298, 315 Intestinal, 241, 263, 271, 276 Intestine, 237, 238, 246, 271, 273 Intoxication, 251, 271, 315 Intracellular, 10, 19, 27, 37, 161, 239, 241, 269, 271, 283, 292, 297, 300, 301, 302 Intracranial Hypertension, 264, 271, 309 Intracranial Pressure, 183, 271 Intraocular, 16, 19, 179, 271, 284 Intraocular pressure, 16, 19, 179, 271, 284

326 Melatonin

Intraperitoneal, 137, 271 Intravenous, 29, 135, 269, 271 Intrinsic, 9, 17, 20, 228, 271 Intrinsic Factor, 20, 271 Invasive, 5, 7, 134, 268, 271 Invertebrates, 171, 271, 277 Involuntary, 171, 236, 243, 258, 271, 280, 281, 298, 303 Ion Channels, 11, 234, 271, 282, 283 Ionization, 271 Ionizing, 176, 229, 257, 271, 297 Ions, 236, 240, 253, 255, 266, 271, 279, 290, 303 Irinotecan, 63, 120, 271 Iris, 231, 248, 271, 296 Irradiance, 15, 272 Irradiation, 19, 113, 272, 315 Ischemia, 21, 46, 87, 93, 101, 114, 128, 181, 187, 235, 250, 272, 280, 298 Ischemic stroke, 169, 272 Isozymes, 128, 272 J Jet lag, 12, 21, 32, 37, 53, 56, 64, 71, 82, 83, 88, 130, 162, 163, 164, 178, 182, 198, 199, 272 Joint, 159, 234, 255, 272, 295, 306 K Kainate, 7, 272 Kava, 93, 134, 143, 144, 272 Kb, 206, 272 Keratin, 272 Keratinocytes, 161, 272 Kidney Disease, 151, 190, 206, 211, 272 Kidney Failure, 256, 272 Kidney stone, 273, 312 Killer Cells, 123, 273 Kinetic, 44, 50, 271, 273 L Labile, 246, 273 Laceration, 273, 308 Lactation, 273, 286, 293 Lag, 21, 83, 102, 141, 165, 273 Large Intestine, 246, 252, 271, 273, 297, 303 Larva, 273, 278 Larynx, 138, 273, 310, 312 Latency, 25, 45, 198, 273 Lateral Ventricles, 273, 308 Laxative, 154, 255, 273 Lens, 61, 233, 240, 273, 314 Leptin, 13, 28, 60, 107, 273 Lesion, 248, 262, 273, 275, 302, 307, 311 Lethal, 172, 236, 273

Leucine, 236, 273 Leucocyte, 229, 257, 273 Leukemia, 210, 265, 273 Leukocytes, 35, 131, 132, 177, 236, 238, 243, 264, 270, 273, 279, 283, 288 Leukotrienes, 6, 233, 234, 255, 274 Levo, 253, 274 Levodopa, 253, 274 Libido, 157, 274 Library Services, 222, 274 Ligament, 274, 294 Ligands, 27, 68, 100, 170, 171, 274 Ligation, 46, 274 Limbic, 7, 274 Linkage, 242, 262, 274 Lipectomy, 42, 274 Lipid Peroxidation, 24, 118, 125, 126, 129, 138, 274, 286 Lipofuscin, 243, 274 Lipophilic, 171, 274 Lipoprotein, 254, 274, 275 Lipoxygenase, 6, 134, 233, 274 Lithium, 82, 232, 275 Litter, 158, 275 Litter Size, 158, 275 Loading dose, 159, 275 Lobe, 231, 243, 266, 275, 294, 314 Localization, 29, 30, 76, 84, 268, 275 Localized, 114, 156, 175, 230, 239, 256, 269, 274, 275, 291, 308, 311 Locomotion, 275, 291 Locomotor, 27, 42, 66, 88, 168, 275 Low-density lipoprotein, 254, 274, 275 Luciferase, 30, 275 Lumen, 172, 178, 256, 275 Luteal Phase, 38, 45, 275 Lutein Cells, 275, 293 Lymph, 119, 243, 244, 256, 266, 275, 305 Lymph node, 119, 243, 275 Lymphatic, 256, 269, 275, 278, 303, 304, 308 Lymphatic system, 275, 303, 304, 308 Lymphocyte, 83, 129, 232, 273, 276 Lymphoid, 231, 249, 273, 276, 309 Lymphoma, 210, 265, 276 Lysine, 157, 276 M Macrophage, 172, 232, 264, 276 Malabsorption, 210, 276 Malaise, 254, 276 Malignant, 69, 119, 176, 210, 227, 232, 234, 266, 276, 282, 297

Index 327

Malignant tumor, 176, 276 Malnutrition, 229, 235, 276, 280 Malondialdehyde, 96, 276 Mammary, 34, 86, 92, 112, 124, 248, 276, 307 Mammogram, 239, 276, 278 Mandible, 229, 276, 298 Mania, 276 Manic, 168, 232, 275, 276, 295 Manic-depressive psychosis, 276, 295 Manifest, 12, 13, 235, 276, 305 Maximum Tolerated Dose, 254, 276 Meatus, 276, 312 Medial, 234, 258, 259, 276, 285 Mediate, 12, 17, 41, 164, 253, 273, 276 Mediator, 253, 270, 276, 301 Medical Records, 276, 299 MEDLINE, 207, 209, 211, 276 Megaloblastic, 260, 277 Meiosis, 277, 307, 312 Melanin, 38, 161, 271, 277, 289, 311 Melanocytes, 156, 161, 175, 277 Melanoma, 59, 67, 119, 210, 277 Melanophores, 57, 133, 137, 277 Melanosomes, 277 Membrane, 11, 17, 24, 29, 109, 125, 161, 230, 234, 242, 244, 246, 251, 252, 257, 258, 259, 271, 273, 277, 278, 279, 285, 289, 290, 292, 299, 302, 306, 307, 310, 314 Memory, 19, 32, 137, 194, 231, 251, 277 Meningeal, 167, 277 Meninges, 242, 249, 277 Menopause, 60, 141, 277, 292, 293 Menstrual Cycle, 38, 45, 184, 275, 277, 293 Menstruation, 230, 250, 275, 277, 284, 293 Mental Disorders, 152, 168, 169, 246, 277, 295 Mental Fatigue, 47, 277 Mental Health, iv, 4, 32, 150, 152, 206, 208, 277, 295 Mental Processes, 253, 277, 295 Mental Retardation, 63, 212, 277 Mercury, 260, 277 Mesenchymal, 257, 264, 278 Metabolite, 7, 34, 38, 56, 77, 96, 97, 238, 278, 293 Metamorphosis, 58, 278, 284 Metastasis, 278, 282 Metastatic, 59, 63, 89, 111, 120, 278 Methionine, 168, 236, 278, 294, 306 Methyltransferase, 30, 278 MI, 80, 88, 99, 119, 168, 225, 278

Microbe, 278, 310 Microbiology, 83, 227, 235, 278 Microcalcifications, 239, 278 Microdialysis, 31, 278 Micronutrients, 125, 278 Microorganism, 245, 278, 314 Microscopy, 5, 9, 18, 20, 41, 278 Microsomal, 82, 122, 278 Midazolam, 73, 278 Middle Cerebral Artery, 135, 278 Migration, 24, 278, 282 Mineralization, 279, 286 Mitosis, 233, 279 Mitotic, 136, 173, 258, 279 Modification, 90, 133, 178, 262, 279, 296 Molecular, 5, 6, 9, 11, 12, 15, 16, 20, 22, 23, 29, 30, 31, 32, 33, 36, 43, 46, 48, 50, 58, 75, 76, 83, 86, 88, 91, 106, 110, 111, 130, 131, 133, 134, 136, 164, 169, 187, 190, 207, 209, 237, 240, 247, 251, 260, 263, 279, 293, 297, 306, 311 Molecular Structure, 279, 311 Monitor, 47, 48, 69, 70, 97, 249, 279, 284 Monoclonal, 272, 279, 296, 315 Monocytes, 35, 260, 274, 279, 280 Mononuclear, 279 Mood Disorders, 43, 45, 50, 168, 279 Morphine, 44, 233, 279, 281, 285 Morphogenesis, 133, 279 Morphological, 11, 21, 255, 277, 279 Morphology, 18, 28, 279 Motility, 279, 301 Motion Sickness, 279, 281 Motor Neurons, 46, 279 Mucinous, 261, 279 Mucins, 279, 300 Mucosa, 279, 293 Mucosal Ulceration, 76, 279 Mucus, 279, 312 Multiple sclerosis, 169, 180, 280 Muscle Contraction, 135, 280 Muscle Fibers, 280, 281 Muscular Atrophy, 210, 280 Muscular Dystrophies, 254, 280 Mutagenesis, 15, 50, 88, 280 Mutagens, 280 Mycotoxins, 126, 280 Mydriatic, 252, 280 Myelin, 24, 106, 280, 282, 284 Myeloid Cells, 122, 280 Myocardial infarction, 67, 107, 248, 278, 280

328 Melatonin

Myocardial Reperfusion, 280, 298 Myocardial Reperfusion Injury, 280, 298 Myocardium, 278, 280, 299 Myoclonus, 169, 281 Myometrium, 101, 281 Myopia, 129, 281, 298 Myosin, 280, 281 Myotonic Dystrophy, 210, 281 N Naloxone, 236, 281 Naltrexone, 89, 111, 281 Narcolepsy, 169, 257, 281 Narcosis, 281 Narcotic, 44, 279, 281 Natural selection, 237, 281 Nausea, 176, 232, 253, 261, 281, 287 NCI, 1, 117, 149, 151, 205, 244, 281 Nearsightedness, 281 Necrosis, 233, 243, 269, 278, 280, 281, 298 Need, 3, 18, 154, 159, 166, 168, 180, 186, 189, 193, 194, 216, 228, 244, 281, 309 Neoplasia, 210, 282 Neoplasms, 63, 121, 232, 282, 297, 308 Neoplastic, 191, 231, 276, 282 Nephropathy, 272, 282 Nerve Fibers, 282, 314 Nervous System, 19, 23, 28, 30, 54, 75, 93, 121, 156, 164, 169, 175, 177, 186, 210, 227, 228, 235, 236, 239, 240, 242, 257, 261, 263, 274, 276, 279, 280, 281, 282, 283, 285, 288, 301, 306, 307 Nervousness, 51, 282 Networks, 27, 130, 282 Neurobehavioral Manifestations, 239, 252, 282 Neuroblastoma, 62, 282 Neurodegenerative Diseases, 6, 24, 37, 44, 95, 164, 236, 282 Neuroendocrine, 13, 16, 18, 34, 35, 42, 53, 55, 113, 126, 169, 183, 184, 282 Neuroglia, 262, 282 Neuroleptic, 171, 229, 232, 282 Neurologic, 86, 181, 239, 282 Neurology, 39, 42, 44, 51, 64, 85, 102, 110, 184, 281, 282 Neuromuscular, 227, 282, 283 Neuromuscular Junction, 227, 283 Neuronal, 7, 10, 11, 26, 27, 28, 30, 36, 46, 64, 166, 236, 240, 245, 281, 282, 283, 301 Neurons, 7, 9, 11, 24, 26, 27, 29, 31, 40, 46, 54, 111, 177, 251, 259, 261, 274, 279, 282, 283, 306, 307, 313

Neuropathy, 169, 283 Neuropeptide, 16, 239, 283 Neurosecretory Systems, 256, 283 Neurotic, 283, 312 Neurotoxic, 7, 283 Neurotransmitters, 3, 9, 11, 283, 303 Neutrons, 229, 272, 283, 296 Neutrophils, 187, 233, 264, 266, 274, 283 Niacin, 283, 311 Nifedipine, 83, 283 Nimodipine, 52, 89, 283 Nitric Oxide, 89, 103, 109, 147, 283 Nitrogen, 63, 97, 177, 229, 249, 263, 283, 311 Non-small cell lung cancer, 119, 284 Norepinephrine, 3, 47, 77, 106, 134, 168, 228, 253, 257, 284 NSAIDs, 144, 284 Nuclear, 7, 17, 86, 91, 112, 171, 236, 240, 252, 255, 258, 261, 281, 284, 299 Nuclei, 18, 23, 156, 164, 175, 180, 229, 231, 255, 262, 279, 283, 284, 285, 295, 313 Nucleic acid, 161, 262, 269, 280, 284, 296 Nymph, 278, 284 O Octreotide, 114, 284 Ocular, 15, 16, 19, 23, 91, 179, 184, 258, 259, 284 Ocular Hypertension, 179, 284 Odour, 234, 284 Ointments, 186, 253, 284, 302, 303 Olfactory Bulb, 120, 284, 314 Oligodendroglial, 24, 284 Oligomenorrhea, 284, 292 Oncogene, 124, 210, 284 Oncology, 72, 94, 96, 110, 111, 113, 149, 285 On-line, 31, 78, 225, 285 Opacity, 251, 285 Ophthalmic, 33, 61, 285 Ophthalmologic, 15, 285 Ophthalmology, 9, 14, 16, 19, 67, 114, 285 Opium, 279, 285 Opsin, 6, 10, 16, 39, 285, 299 Optic Chiasm, 268, 285, 306 Optic disc, 179, 285 Optic Nerve, 33, 179, 230, 285, 299, 314 Orbital, 259, 285 Orderly, 28, 285 Organ Culture, 285, 309 Organelles, 242, 250, 277, 279, 285 Orthostatic, 233, 284, 285

Index 329

Osmosis, 285 Osmotic, 46, 229, 285, 302 Osteoarthritis, 49, 285 Osteomalacia, 100, 286 Outpatient, 13, 23, 286 Ovalbumin, 171, 286 Ovarian Follicle, 248, 264, 286 Ovaries, 259, 286, 292, 298, 302 Ovary, 248, 258, 263, 286 Ovulation, 38, 162, 231, 264, 275, 286 Ovum, 248, 250, 262, 286, 293, 315 Oxazepam, 166, 286 Oxidants, 25, 286 Oxidation, 147, 155, 227, 232, 233, 238, 249, 263, 274, 286 Oxidation-Reduction, 238, 286 Oxidative Stress, 20, 24, 103, 112, 155, 156, 187, 199, 286 Oxygenation, 268, 286 Oxytocin, 185, 286 P Pacemaker, 15, 19, 40, 49, 52, 54, 178, 286 Palliative, 287, 308 Palpitation, 176, 287 Palsy, 169, 287 Pancreas, 227, 237, 252, 270, 287, 303, 311 Pancreatic, 210, 241, 287 Pancreatic cancer, 210, 287 Panic, 140, 169, 287 Panic Disorder, 169, 287 Paralysis, 181, 258, 265, 287 Parenchyma, 183, 287 Paresthesias, 287 Parkinsonism, 169, 233, 274, 287 Paroxysmal, 210, 265, 287 Partial remission, 287, 298 Particle, 287, 310 Parturition, 287, 293 Patch, 5, 28, 156, 287, 310 Pathogenesis, 31, 114, 287 Pathologic, 25, 233, 248, 267, 287, 295, 298 Pathologic Processes, 233, 287 Pathologies, 14, 15, 28, 41, 172, 187, 288 Pathophysiology, 15, 45, 106, 108, 288 Patient Education, 214, 220, 222, 225, 288 Pelvic, 288, 294 Penicillin, 231, 288 Penis, 288, 298 Peptide, 16, 25, 38, 167, 236, 239, 260, 272, 273, 288, 292, 294, 295, 309 Perception, 247, 251, 288, 300 Perfusion, 165, 268, 288

Periodicity, 288, 300 Peripheral blood, 113, 270, 288 Peripheral Nervous System, 282, 287, 288, 304, 306 Peripheral vision, 288, 314 Peritoneal, 271, 288 Peritoneal Cavity, 271, 288 Perivascular, 239, 288 Pernicious, 271, 277, 288 Pernicious anemia, 271, 288 Peroral, 162, 163, 288 Peroxidase, 28, 233, 274, 288 Peroxide, 288 PH, 18, 29, 39, 165, 288 Phagocyte, 286, 289 Phagocytosis, 35, 289 Pharmaceutical Preparations, 242, 258, 262, 289, 294 Pharmaceutical Solutions, 253, 289 Pharmacodynamics, 25, 289 Pharmacokinetic, 289 Pharmacologic, 31, 58, 96, 110, 231, 289, 310 Pharynx, 289, 312 Phenotype, 9, 33, 34, 55, 289 Phenyl, 54, 68, 289 Phenylalanine, 154, 289, 311 Phosphodiesterase, 289, 310 Phospholipases, 289, 302 Phospholipids, 123, 174, 259, 270, 274, 289 Phosphorus, 240, 289 Phosphorylated, 234, 245, 289 Phosphorylates, 30, 289 Phosphorylation, 12, 26, 29, 30, 133, 289, 294 Photobiology, 178, 289 Photodynamic therapy, 290 Photoperiod, 29, 35, 41, 55, 148, 166, 290 Photoreceptor, 5, 10, 11, 17, 20, 23, 29, 36, 39, 48, 60, 62, 183, 290 Photosensitivity, 6, 290 Photosensitization, 176, 290 Photosensitizer, 176, 290 Phototherapy, 168, 183, 246, 290, 300 Phototransduction, 6, 15, 16, 22, 94, 234, 290, 301 Physical Examination, 262, 290 Physiologic, 8, 15, 34, 50, 54, 228, 237, 253, 277, 278, 281, 290, 297, 298, 307 Phytic Acid, 270, 290 Picrotoxin, 9, 290

330 Melatonin

Pigment, 29, 237, 243, 274, 277, 285, 290, 299 Pigmentation, 156, 161, 290 Pilot Projects, 22, 290 Pilot study, 45, 92, 110, 290 Pineal Body, 180, 290 Pituitary Gland, 34, 57, 260, 290, 294 Placenta, 87, 258, 291, 293 Plaque, 235, 291 Plasma cells, 231, 291 Plasma protein, 124, 229, 256, 291, 302 Plasmid, 177, 291, 313 Plasticity, 21, 28, 33, 52, 58, 291 Platelet Activation, 291, 302 Platelet Aggregation, 187, 230, 283, 291, 308 Platelets, 177, 187, 233, 283, 291, 308 Platinum, 59, 244, 291 Podophyllotoxin, 258, 291 Point Mutation, 31, 291 Poisoning, 233, 251, 271, 277, 281, 290, 291 Polychromatic, 10, 292 Polycystic, 79, 81, 211, 292 Polycystic Ovary Syndrome, 81, 292 Polymerase, 7, 292 Polymerase Chain Reaction, 7, 292 Polymers, 173, 292, 294 Polypeptide, 230, 246, 257, 259, 292, 293, 294, 303 Polyposis, 246, 292 Polysaccharide, 232, 242, 292 Polyunsaturated fat, 94, 123, 129, 138, 174, 292, 308 Popliteal, 90, 292 Posterior, 230, 235, 242, 244, 253, 271, 286, 287, 290, 292 Postmenopausal, 60, 65, 68, 292 Postnatal, 10, 32, 292, 304 Postsynaptic, 9, 28, 292, 302, 306 Post-traumatic, 239, 265, 292 Postural, 94, 292 Potassium, 82, 292, 303 Potentiate, 35, 44, 292 Potentiating, 23, 293 Potentiation, 58, 293, 302 Practice Guidelines, 208, 293 Precancerous, 243, 293 Preclinical, 95, 117, 124, 293 Precursor, 21, 227, 234, 243, 249, 253, 254, 256, 257, 274, 284, 289, 293, 294, 311 Pregnancy Tests, 262, 293 Pregnenolone, 106, 293

Premenopausal, 81, 128, 293 Premenstrual, 45, 169, 293 Presynaptic, 28, 88, 293, 306, 307 Prevalence, 8, 17, 38, 166, 293 Prickle, 272, 293 Probe, 20, 23, 92, 278, 293 Prodrug, 161, 293 Progesterone, 46, 81, 165, 185, 293, 305 Progression, 16, 18, 34, 84, 121, 187, 194, 231, 293 Progressive, 18, 28, 169, 172, 179, 234, 242, 244, 251, 254, 264, 280, 281, 282, 291, 293, 298, 311 Projection, 250, 284, 285, 293, 297 Prolactin, 3, 34, 83, 122, 125, 176, 293 Promoter, 31, 161, 171, 294 Prone, 45, 294 Pro-Opiomelanocortin, 137, 256, 294 Prophase, 294, 307, 312 Prophylaxis, 28, 110, 180, 294 Propofol, 135, 294 Proportional, 31, 294 Propylene Glycol, 170, 294 Prosencephalon, 252, 294, 307 Prostaglandins, 123, 234, 255, 294 Prostate, 63, 78, 86, 108, 128, 129, 141, 142, 210, 236, 237, 294, 298, 311 Prostate gland, 294 Prostatic Hyperplasia, 294 Protein C, 229, 230, 236, 272, 274, 294 Protein Conformation, 230, 272, 294 Protein Kinases, 19, 294 Protein S, 31, 44, 193, 211, 237, 262, 266, 294, 300 Protein-Tyrosine Kinase, 187, 294 Proteolytic, 229, 246, 260, 295 Protocol, 5, 9, 23, 49, 51, 149, 150, 295 Protons, 229, 266, 271, 295, 296 Proximal, 46, 122, 253, 293, 295 Pruritic, 254, 295 Pruritus, 252, 295 Pseudarthrosis, 114, 295 Psoriasis, 156, 186, 295 Psychiatric, 15, 21, 23, 31, 32, 50, 51, 53, 108, 164, 168, 191, 193, 277, 295, 303 Psychic, 274, 295, 301 Psychology, 18, 41, 53, 106, 119, 253, 295 Psychomotor, 22, 251, 282, 295 Psychosis, 67, 232, 262, 295 Puberty, 33, 158, 161, 176, 295, 309 Public Health, 55, 167, 208, 295 Public Policy, 54, 207, 295

Index 331

Publishing, 57, 190, 295 Pulmonary, 238, 247, 248, 273, 274, 296, 313 Pulmonary Artery, 238, 296, 313 Pulmonary hypertension, 248, 296 Pulse, 5, 33, 45, 279, 296 Pupa, 278, 296 Pupil, 248, 252, 280, 296 Purgative, 255, 273, 296 Purines, 296, 301 Purpura, 99, 296 Pyridoxal, 296, 311 Pyridoxal Phosphate, 296, 311 Q Quality of Life, 34, 49, 70, 181, 296, 306 R Race, 253, 279, 296 Radiation therapy, 149, 259, 267, 271, 272, 296, 315 Radioactive, 235, 266, 269, 270, 271, 272, 284, 296, 297, 315 Radiography, 262, 296 Radioimmunoassay, 6, 96, 127, 296 Radiolabeled, 272, 296, 297, 315 Radiological, 169, 297 Radiology, 297 Radiotherapy, 238, 272, 296, 297, 315 Randomized, 10, 23, 45, 49, 51, 63, 83, 118, 119, 120, 123, 149, 255, 297 Reaction Time, 124, 297 Reactive Oxygen Species, 24, 46, 82, 131, 132, 297 Reagent, 275, 297 Reality Testing, 295, 297 Receptors, Serotonin, 297, 301 Recombinant, 6, 30, 31, 84, 161, 177, 297, 313 Recombination, 262, 297 Rectal, 40, 71, 108, 297 Rectum, 233, 238, 246, 252, 260, 261, 269, 273, 294, 297 Recur, 288, 297, 300 Recurrence, 244, 276, 288, 297, 300 Red blood cells, 97, 103, 258, 297, 300 Red Nucleus, 235, 297 Reductase, 166, 297 Refer, 1, 239, 246, 253, 256, 261, 275, 282, 283, 295, 298 Reflex, 126, 259, 298 Refraction, 32, 281, 298, 304 Refractive Errors, 137, 230, 298 Refractive Power, 281, 298

Refractory, 99, 298 Regeneration, 260, 298 Regimen, 34, 180, 255, 298, 299 Relapse, 23, 119, 298 Reliability, 37, 101, 298 Remission, 69, 276, 297, 298 Renal failure, 251, 298 Reperfusion, 54, 87, 93, 101, 114, 128, 131, 280, 298 Reperfusion Injury, 54, 93, 298 Reproductive system, 42, 166, 294, 298 Resection, 51, 298 Resorption, 99, 110, 298 Respiration, 240, 279, 298, 299 Restoration, 21, 157, 280, 298, 315 Resuscitation, 54, 240, 241, 298 Retinal, 5, 9, 11, 13, 14, 17, 20, 23, 29, 30, 33, 36, 40, 48, 67, 81, 114, 136, 137, 147, 164, 179, 234, 247, 285, 290, 299 Retinal Ganglion Cells, 14, 30, 179, 285, 299 Retinal pigment epithelium, 48, 299 Retinaldehyde, 285, 299 Retinoblastoma, 127, 136, 210, 299 Retinoid, 35, 299 Retinol, 158, 299 Retreatment, 95, 299 Retrospective, 4, 299 Retrospective study, 4, 299 Retrovirus, 135, 299 Rheumatic Heart Disease, 154, 299 Rheumatoid, 286, 299 Rhinitis, 257, 299 Rhythmicity, 6, 11, 13, 15, 17, 27, 28, 36, 40, 42, 148, 160, 300 Ribose, 227, 300 Ribosome, 300, 310 Rigidity, 271, 287, 291, 300 Risk factor, 7, 49, 257, 300 Risperidone, 65, 121, 300 Rod, 6, 11, 36, 40, 48, 62, 90, 245, 290, 300, 310 Rod cells, 300, 310 S Saliva, 66, 73, 101, 106, 300 Salivary, 9, 22, 40, 54, 56, 60, 61, 64, 252, 287, 300, 305 Salivary glands, 252, 300 Saphenous, 248, 300 Saphenous Vein, 248, 300 Saponins, 300, 305 Schizoid, 300, 314

332 Melatonin

Schizophrenia, 74, 142, 164, 169, 300, 314 Schizotypal Personality Disorder, 251, 300, 314 Sclerosis, 141, 181, 210, 234, 280, 300 Scoliosis, 94, 114, 300 Screening, 158, 170, 171, 173, 177, 245, 300 Seasonal Affective Disorder, 10, 23, 35, 52, 142, 149, 150, 169, 182, 184, 185, 214, 300 Second Messenger Systems, 283, 300 Secretion, 7, 10, 19, 23, 28, 34, 43, 45, 47, 49, 51, 67, 69, 70, 72, 74, 77, 80, 84, 87, 90, 91, 93, 95, 99, 109, 113, 114, 123, 149, 150, 169, 171, 174, 175, 180, 200, 244, 257, 266, 270, 273, 279, 284, 301 Secretory, 301, 306 Sedative, 163, 174, 253, 272, 278, 301, 312 Seizures, 86, 130, 199, 200, 251, 287, 301 Selective estrogen receptor modulator, 301, 307 Selenium, 107, 172, 301 Sella, 253, 290, 301 Semen, 294, 301 Semisynthetic, 240, 258, 301 Senescence, 129, 301 Senile, 167, 301 Senile Plaques, 167, 301 Sensibility, 230, 301 Sepsis, 80, 301 Sequencing, 292, 301, 307 Serine, 194, 301, 311 Serologic, 268, 301 Serous, 256, 302 Serum Albumin, 296, 302 Sex Characteristics, 228, 295, 302, 308 Sex Determination, 211, 302 Shedding, 14, 48, 302 Shock, 93, 281, 302, 310 Signal Transduction, 11, 15, 19, 29, 31, 43, 110, 118, 270, 302 Signs and Symptoms, 298, 302 Skeletal, 245, 280, 302 Skeleton, 227, 272, 302, 303 Skin Aging, 156, 302 Skin Care, 156, 302 Skull, 249, 271, 303, 307 Sleep Deprivation, 54, 303 Sleep Paralysis, 169, 303 Small cell lung cancer, 303 Small intestine, 254, 266, 271, 303 Smooth muscle, 172, 230, 239, 260, 266, 279, 281, 303, 306 Sneezing, 302, 303

Soaps, 302, 303 Social Environment, 296, 303 Sodium, 73, 82, 154, 263, 290, 303, 310 Sodium Channels, 290, 303 Soft tissue, 238, 302, 303 Solid tumor, 89, 111, 149, 303 Solitary Nucleus, 235, 303 Solvent, 236, 258, 263, 285, 289, 294, 303 Somatic, 228, 266, 277, 279, 288, 303, 312 Somatostatin, 284, 303 Soporific, 25, 150, 304 Soybean Oil, 292, 304 Specialist, 216, 252, 304 Specificity, 27, 38, 50, 228, 233, 240, 304 Spectrum, 10, 15, 28, 39, 49, 60, 62, 65, 106, 173, 246, 304 Spinal cord, 169, 234, 239, 242, 243, 257, 261, 277, 282, 283, 288, 298, 304, 306 Spinal Cord Injuries, 169, 304 Spinous, 257, 272, 304 Spleen, 122, 230, 275, 304 Spontaneous Abortion, 138, 304 Sporadic, 282, 299, 304 Squamous, 284, 304 Squamous cell carcinoma, 284, 304 Steel, 245, 304 Stellate, 91, 304 Stellate Ganglion, 91, 304 Stem Cells, 21, 258, 304 Sterility, 60, 81, 249, 269, 305 Steroid, 8, 34, 46, 56, 91, 171, 237, 249, 293, 300, 305 Stimulant, 239, 266, 290, 305 Stimulus, 47, 163, 184, 230, 254, 255, 259, 270, 271, 273, 287, 297, 298, 305, 308 Stomach, 112, 227, 252, 258, 261, 263, 266, 281, 288, 289, 303, 304, 305 Stool, 269, 273, 305 Strabismus, 32, 230, 305 Strand, 292, 305 Stress, 21, 25, 41, 56, 60, 85, 93, 127, 134, 154, 164, 169, 186, 235, 241, 249, 281, 286, 305 Striatum, 21, 305 Stroke, 86, 135, 152, 172, 194, 198, 206, 241, 272, 305 Stroma, 271, 287, 305 Stupor, 281, 305 Subacute, 269, 305 Subarachnoid, 261, 264, 305 Subclinical, 269, 301, 305

Index 333

Subcutaneous, 59, 89, 111, 118, 119, 228, 254, 274, 305 Subiculum, 266, 305 Sublingual, 159, 305 Submaxillary, 257, 305 Subspecies, 304, 305 Substance P, 278, 301, 306 Substrate, 10, 12, 14, 50, 257, 306 Suction, 274, 306 Sudden death, 94, 154, 306 Sulfur, 278, 306 Sumatriptan, 14, 306 Superoxide, 177, 306 Supplementation, 28, 120, 122, 125, 126, 127, 129, 131, 132, 133, 135, 137, 157, 306 Supportive care, 82, 306 Suppression, 33, 39, 41, 52, 56, 61, 62, 77, 79, 80, 84, 88, 89, 90, 94, 95, 137, 178, 306 Suppressive, 178, 306 Suprachiasmatic Nucleus, 11, 18, 26, 31, 42, 47, 49, 108, 111, 156, 175, 306 Survival Rate, 55, 306 Sympathetic Nervous System, 42, 235, 306 Sympathomimetic, 253, 257, 284, 306 Symphysis, 294, 306 Symptomatic, 45, 306 Synapses, 9, 283, 284, 306, 307 Synapsis, 307 Synaptic, 10, 11, 33, 52, 302, 306, 307 Synaptic Vesicles, 306, 307 Synchrony, 53, 182, 307 Synergistic, 293, 307 Systemic, 142, 173, 176, 186, 230, 233, 238, 251, 257, 265, 269, 271, 272, 296, 307, 311, 315 Systolic, 267, 307 T Tachykinins, 107, 307 Tamoxifen, 126, 138, 144, 301, 307 Tardive, 87, 169, 171, 198, 233, 245, 307 Telangiectasia, 211, 307 Telencephalon, 58, 236, 294, 307 Temporal, 9, 43, 45, 114, 166, 265, 266, 276, 307 Teratogenic, 229, 252, 307 Terminalis, 307, 308 Testicular, 42, 307 Testis, 258, 307 Testosterone, 18, 42, 122, 137, 164, 166, 185, 215, 297, 308 Tetani, 308 Tetanic, 308

Tetanus, 47, 308 Thalamic, 235, 308 Thalamic Diseases, 235, 308 Therapeutics, 44, 77, 81, 92, 99, 120, 124, 128, 131, 134, 161, 308 Thermal, 253, 283, 292, 308 Thermoregulation, 57, 85, 166, 290, 308 Third Ventricle, 169, 234, 268, 273, 290, 308 Thoracic, 67, 304, 308, 314 Thorax, 227, 308, 312 Threonine, 301, 308 Threshold, 49, 259, 267, 308 Thrombin, 259, 291, 294, 308 Thrombocytes, 291, 308 Thrombosis, 181, 187, 294, 305, 308 Thromboxanes, 234, 255, 308 Thrombus, 248, 269, 272, 280, 291, 308 Thymus, 131, 136, 180, 181, 268, 275, 308, 309 Thymus Gland, 309 Thymus Hormones, 181, 309 Thyroid, 34, 98, 137, 171, 180, 181, 309, 311 Thyroid Gland, 98, 309 Thyroid Hormones, 137, 309, 311 Thyrotropin, 90, 309 Thyroxine, 229, 289, 309 Tin, 291, 309 Tinnitus, 142, 176, 309, 313 Tissue, 9, 21, 31, 40, 46, 69, 107, 110, 112, 113, 132, 165, 176, 183, 228, 232, 233, 235, 236, 237, 238, 239, 240, 243, 244, 245, 247, 249, 254, 255, 256, 258, 259, 263, 264, 268, 271, 273, 274, 275, 276, 277, 278, 280, 282, 283, 288, 290, 291, 292, 298, 299, 302, 303, 304, 305, 307, 309, 310, 311, 315 Tissue Culture, 9, 309 Tolerance, 5, 40, 44, 85, 167, 182, 227, 263, 309 Tonicity, 254, 309 Tooth Preparation, 227, 309 Topical, 156, 173, 185, 186, 258, 266, 303, 309 Topoisomerase inhibitors, 271, 309 Torsion, 269, 309 Toxic, iv, 21, 229, 230, 236, 250, 257, 264, 268, 283, 291, 301, 309, 310 Toxicity, 76, 112, 149, 173, 176, 186, 254, 255, 276, 277, 310 Toxicokinetics, 310 Toxicology, 44, 112, 129, 208, 310

334 Melatonin

Toxins, 230, 232, 240, 256, 269, 280, 310 Toxoid, 47, 310 Trace element, 244, 309, 310 Trachea, 239, 273, 289, 309, 310 Traction, 245, 310 Transcriptase, 299, 310 Transcription Factors, 171, 310 Transdermal, 5, 108, 156, 310 Transducin, 6, 310 Transduction, 11, 302, 310 Transfection, 237, 310 Translation, 5, 310 Translocation, 24, 310 Transmitter, 9, 24, 28, 227, 234, 253, 271, 276, 282, 284, 306, 307, 310 Transplantation, 20, 244, 268, 310 Trauma, 239, 251, 281, 310 Treatment Failure, 26, 311 Triazolam, 79, 145, 311 Trichotillomania, 169, 311 Tricuspid Atresia, 248, 311 Tricyclic, 100, 245, 311 Tryptophan, 14, 29, 30, 67, 168, 178, 192, 215, 246, 263, 301, 311 Tryptophan Hydroxylase, 29, 30, 311 Tryptophan Synthase, 14, 311 Tuberculosis, 58, 247, 311 Tuberous Sclerosis, 102, 211, 311 Tumor marker, 237, 311 Tumour, 112, 261, 311 Tyrosine, 62, 133, 135, 154, 162, 253, 294, 311 U Ubiquinone, 156, 311 Ulcer, 250, 311 Ulceration, 82, 250, 279, 311 Ulcerative colitis, 96, 311 Ultrasonography, 262, 312 Unconscious, 231, 250, 268, 312 Univalent, 267, 286, 312 Urethra, 236, 288, 294, 312 Uric, 123, 264, 296, 312 Urinary, 34, 38, 56, 60, 61, 64, 66, 67, 71, 72, 85, 98, 102, 121, 123, 257, 262, 269, 312 Urinate, 312, 314 Urine, 7, 38, 85, 131, 236, 238, 249, 253, 257, 265, 269, 273, 312 Uterine Contraction, 286, 312 Uterus, 243, 248, 250, 256, 259, 277, 281, 286, 293, 298, 312 Uveitis, 234, 312

V Vaccine, 47, 228, 295, 312 Vagina, 243, 251, 277, 298, 312 Vagus Nerve, 46, 303, 312 Valerian, 45, 93, 134, 145, 312 Valves, 299, 312 Vascular, 21, 29, 56, 158, 172, 244, 256, 265, 269, 283, 286, 291, 308, 309, 312 Vascular endothelial growth factor, 21, 312 Vasoactive, 16, 312 Vasoconstriction, 172, 257, 312 Vasodilatation, 172, 312 Vasodilation, 56, 130, 312 Vasodilator, 56, 177, 239, 240, 253, 266, 280, 283, 313 Vasogenic, 183, 313 Vector, 310, 313 Vein, 231, 271, 284, 300, 313 Venous, 243, 294, 311, 313 Venous blood, 243, 313 Ventilation, 240, 241, 313 Ventral, 234, 268, 313 Ventricle, 235, 248, 266, 273, 296, 307, 311, 313 Ventricular, 99, 248, 280, 307, 311, 313 Venules, 238, 240, 256, 313 Vertebrae, 304, 313 Vesicular, 264, 278, 313 Vestibulocochlear Nerve, 309, 313 Vestibulocochlear Nerve Diseases, 309, 313 Veterinary Medicine, 207, 313 Viral, 31, 299, 310, 313 Viral vector, 31, 313 Virulence, 310, 313 Virus, 214, 236, 242, 257, 262, 270, 291, 310, 313, 314 Visceral, 235, 312, 314 Visceral Afferents, 235, 312, 314 Viscosity, 173, 314 Visual Cortex, 230, 314 Visual field, 80, 179, 285, 314 Visual Pathways, 30, 314 Vitamin A, 157, 270, 299, 314 Vitreous Body, 299, 314 Vitro, 6, 9, 12, 13, 24, 26, 37, 40, 48, 50, 56, 70, 82, 96, 108, 109, 118, 122, 126, 134, 165, 186, 269, 292, 309, 314 Vivo, 9, 18, 19, 20, 27, 30, 34, 37, 38, 40, 47, 50, 59, 92, 109, 121, 127, 128, 165, 175, 186, 269, 278, 286, 308, 314

Index 335

Void, 7, 314 Volition, 271, 314 Vomeronasal Organ, 284, 314 W Wakefulness, 15, 17, 175, 182, 251, 314 Weight Gain, 300, 314 Weight-Bearing, 285, 314 White blood cell, 231, 273, 275, 276, 279, 291, 314 Windpipe, 289, 309, 314 Withdrawal, 23, 30, 52, 100, 167, 199, 251, 286, 314

Womb, 298, 312, 315 Wound Healing, 260, 315 Wounds, Gunshot, 304, 315 X Xenograft, 231, 315 X-ray, 50, 149, 260, 261, 272, 276, 284, 296, 297, 315 X-ray therapy, 272, 315 Y Yeasts, 261, 289, 315 Z Zygote, 247, 315

336 Melatonin

Melatonin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Influenza A - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Facial Paralysis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Wine - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Breast Augmentation - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Cauda Equina Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Magnesium Citrate: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lipomas - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Barbiturates - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cephalexin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Body Dysmorphic Disorder: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lymphedema - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Dermabrasion: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Septra: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Vaginitis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Feet - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Glioblastoma Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Female Infertility - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Living Will - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hip Pain: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Benzene - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Marburg Virus: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Erythema Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Alopecia Areata - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Endometritis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Melatonin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Influenza A - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hepatitis A Vaccine: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Foot and Mouth Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Butternut Squash: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Facial Paralysis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Wine - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Breast Augmentation - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Premenstrual Dysphoric Disorder - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Anagrelide: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Peanut Allergy: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Cauda Equina Syndrome - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Magnesium Citrate: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lipomas - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Barbiturates - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Cephalexin - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Body Dysmorphic Disorder: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Lymphedema - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Dermabrasion: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Septra: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Vaginitis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Feet - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Glioblastoma Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Female Infertility - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Living Will - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Hip Pain: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Benzene - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Marburg Virus: A Medical Dictionary, Bibliography, And Annotated Research Guide To Internet References

Erythema Multiforme - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Alopecia Areata - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Endometritis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

Recommend Documents