CLOZAPINE A 3-IN-1 MEDICAL REFERENCE Medical Dictionary Bibliography & Annotated Research Guide TO I NTERNET
R EFERENCES
CLOZAPINE 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
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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., 1960Clozapine: 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: 0-497-00274-4 1. Clozapine-Popular works. I. Title.
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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.
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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 clozapine. 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.
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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.
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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
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CLOZAPINE ............................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Clozapine....................................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 43 The National Library of Medicine: PubMed ................................................................................ 44 CHAPTER 2. NUTRITION AND CLOZAPINE ..................................................................................... 89 Overview...................................................................................................................................... 89 Finding Nutrition Studies on Clozapine ..................................................................................... 89 Federal Resources on Nutrition ................................................................................................... 92 Additional Web Resources ........................................................................................................... 92 CHAPTER 3. ALTERNATIVE MEDICINE AND CLOZAPINE ............................................................... 95 Overview...................................................................................................................................... 95 National Center for Complementary and Alternative Medicine.................................................. 95 Additional Web Resources ......................................................................................................... 102 General References ..................................................................................................................... 103 CHAPTER 4. PATENTS ON CLOZAPINE .......................................................................................... 105 Overview.................................................................................................................................... 105 Patents on Clozapine.................................................................................................................. 105 Patent Applications on Clozapine.............................................................................................. 109 Keeping Current ........................................................................................................................ 110 CHAPTER 5. BOOKS ON CLOZAPINE ............................................................................................. 111 Overview.................................................................................................................................... 111 The National Library of Medicine Book Index ........................................................................... 111 CHAPTER 6. PERIODICALS AND NEWS ON CLOZAPINE ................................................................ 113 Overview.................................................................................................................................... 113 News Services and Press Releases.............................................................................................. 113 Academic Periodicals covering Clozapine.................................................................................. 115 CHAPTER 7. RESEARCHING MEDICATIONS .................................................................................. 117 Overview.................................................................................................................................... 117 U.S. Pharmacopeia..................................................................................................................... 117 Commercial Databases ............................................................................................................... 118 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 121 Overview.................................................................................................................................... 121 NIH Guidelines.......................................................................................................................... 121 NIH Databases........................................................................................................................... 123 Other Commercial Databases..................................................................................................... 125 APPENDIX B. PATIENT RESOURCES ............................................................................................... 127 Overview.................................................................................................................................... 127 Patient Guideline Sources.......................................................................................................... 127 Finding Associations.................................................................................................................. 129 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 131 Overview.................................................................................................................................... 131 Preparation................................................................................................................................. 131 Finding a Local Medical Library................................................................................................ 131 Medical Libraries in the U.S. and Canada ................................................................................. 131 ONLINE GLOSSARIES................................................................................................................ 137 Online Dictionary Directories ................................................................................................... 137
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CLOZAPINE DICTIONARY ....................................................................................................... 139 INDEX .............................................................................................................................................. 197
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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 clozapine 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 clozapine, 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 clozapine, 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 clozapine. 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 clozapine, 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 clozapine. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON CLOZAPINE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on clozapine.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and clozapine, 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 “clozapine” (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: •
Oral Health Care for the Patient with Schizophrenia Source: SCD. Special Care in Dentistry. 11(5): 179-183. September-October 1991. Summary: This article outlines strategies for the oral health care of patients with schizophrenia. The authors note that conceptualizing the disorder as consisting of positive and negative symptoms has led to improved treatment modalities. Medications used in managing the positive symptoms have numerous adverse systemic and orofacial effects that must be recognized by the dentist. Dental treatment strategies for the identification and management of these side effects are described. Negative symptoms are responsible for chronicity of the disorder and frequently impede rehabilitation. These symptoms are potentially devastating to oral health, as they impair a patient's desire and ability to achieve preventive oral hygiene. The authors outline treatment strategies to improve compliance for oral hygiene. A medication, clozapine,
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Clozapine
that is specifically indicated for patients with treatment-resistant disease, has recently been approved for use in the U.S. The authors conclude by reviewing the adverse systemic and orofacial effects of this medication and its influence on dental management. 62 references. (AA-M). •
Conventional vs. Newer Antipsychotics in Elderly Patients Source: American Journal of Geriatric Psychiatry. 7(1): 70-76. Winter 1999. Summary: This article presents a research report on neuroleptics used in treating Alzheimer's disease and other dementing illnesses. The drugs discussed are classified as conventional/typical neuroleptics (haloperidol and thioridazine) or newer/atypical antipsychotics (clozapine, risperidone, olanzapine, and quetiapine). The authors discuss these classes of medications, switching from a conventional neuroleptic to a newer antipsychotic, the economics of using the more expensive atypical antipsychotics, dosing considerations, and polypharmacy. These researchers studied 439 outpatients with a mean age of 65 years in whom antipsychotic treatment was indicated. The authors conclude that the availability of the newer antipsychotic drugs offers clinicians an additional means of treating the symptoms of schizophrenia, other psychotic disorders, and severe behavioral disturbances in patients with dementia. They also conclude that a comprehensive treatment approach for psychotic and other severe behavioral disorders must combine drug therapy with appropriate psychosocial interventions. 2 figures, 1 table, 33 references.
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Criterion Validity: Do the Symptoms Respond to Treatment - Pharmacologic or Nonpharmacologic? Antipsychotic Treatment in Outpatients With Dementia Source: International Psychogeriatrics. 8(Supplement 3): 355-361. 1996. Summary: This journal article reviews the literature on antipsychotic treatment in patients with behavioral disturbances of dementia. First, it reviews results from the four randomized, double-blind, placebo-controlled trials of neuroleptics in dementia which were published in the past 20 years. Then it summarizes findings concerning the efficacy and safety of clozapine, risperidone, and benzodiazepines. Next, the article discusses the optimal dose of haloperidol, the optimal duration of antipsychotic treatment, and antipsychotic side effects. In 1 study of the course of psychopathology, conducted by the author and colleagues, 235 patients with early, probable Alzheimer's disease (AD) were followed at 6-month intervals for up to 5 years. Agitation was found to be the most persistent symptom, which suggests that prolonged treatment may be needed. Finally, the article suggests an approach to initiating and monitoring antipsychotic treatment in older patients with dementia. In the author's opinion, the available data, while limited, suggest that antipsychotic drugs may be effective in treating psychotic symptoms and behavioral problems in some patients with dementia. However, the relative efficacy of antipsychotics in different subtypes of dementia, such as AD and multiinfarct dementia, has not been adequately studied. 35 references.
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Treatment Strategies for Agitation and Psychosis in Dementia Source: Journal of Clinical Psychiatry. 57(Supplement 14): 21-29. 1996. Summary: This journal article reviews treatment strategies for agitation and psychosis in patients with dementia, specifically Alzheimer's disease. It describes types of behavioral disturbances that are associated with dementia and a systematic approach used in evaluating and managing these behavioral complications. It discusses the treatment of psychosis in dementia using traditional antipsychotic agents (haloperidol and
Studies
5
thioridazine), newer antipsychotic agents (clozapine and risperidone), and other drugs. It also discusses the benefits and side effects of treatment of agitation in dementia using antipsychotic agents; anticonvulsant agents (carbamazepine and valproic acid); anxiolytic agents (benzodiazepines and buspirone); antidepressants (trazodone and selegiline); serotonin selective reuptake inhibitors (alaproclate, citalopram, fluvoxamine, fluoxetine, and sertraline); cholinergic therapy; and other therapies such as electroconvulsive therapy, hormonal therapy, and phototherapy. 4 tables, 97 references. •
Drug-Induced Liver Disease Source: Current Opinion in Gastroenterology. 14(3): 208-214. May 1998. Contact: Available from Lippincott-Raven Publishers. 12017 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: This review article discusses the recent literature on drug-induced liver disease, a common and often underappreciated cause of liver injury. There continues to be very little insight into the pathogenesis of hepatotoxicity for most drugs. Acetaminophen is one of the few drugs for which the mechanisms of liver injury are reasonably well understood. With an understanding of these mechanisms, new reports have identified several factors that can increase the severity or risk of developing acetaminophen associated liver injury. These factors include depletion of glutathione stores (caused by fasting or alcohol use). Other studies have improved the understanding of the mechanisms by which halogenated anesthetics cause liver injury. This information has made it possible to correlate the pathway of metabolism of these agents with their incidence of hepatotoxicity and even to potentially predict the risk of liver injury with new anesthetics. Antibiotics continue to be one of the most commonly used medications and one of the more common causes of drug-induced liver disease. Recent reports stress the importance of these drugs as potential causes of liver injury and highlight the frequency with which some antibiotics cause hepatotoxicity. Finally, the author reviews several case reports of other drugs noted to cause liver disease: ketoconazole, octreotide, clozapine, and omeprazole. 84 references (9 annotated). (AAM).
Federally Funded Research on Clozapine The U.S. Government supports a variety of research studies relating to clozapine. 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 clozapine. 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 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).
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Clozapine
animals or simulated models to explore clozapine. The following is typical of the type of information found when searching the CRISP database for clozapine: •
Project Title: 5-HT MODULATION OF NA+ CURRENTS IN PFC PYRAMIDAL CELLS Principal Investigator & Institution: Carr, David B.; Physiology; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-SEP-2002 Summary: The prefrontal cortex (PFC) plays important roles in cognitive and affective function. Dysfunction within PFC circuitry is strongly implicated in the pathophysiology of schizophrenia, particularly in the expression of negative symptoms. The ability of atypical antipsychotics such as clozapine to ameliorate these negative symptoms has focused attention on the serotonin (5-HT) as well as dopamine (DA) modulatory systems within the PFC, as these drugs are potent antagonists at both 5-HT and DA receptors. Despite the importance of these two neuromodulatory systems in regulating PFC neuronal activity, very little is known as to how they affect the ionic conductances that shape information processing within PFC cells. Moreover, almost nothing is known as to how 5-HT and DA interact at the level of individual PFC neurons. To address these issues, a research and training plan is proposed utilizing a combination of electrophysiological, pharmacological and molecular biological techniques to achieve two specific aims. The first is to examine the effect of 5-HT2a/c receptor stimulation on Na+ currents in acutely isolated PFC neurons and to characterize the mediating signaling cascade. The second aim is to characterize the nature and mechanism of interaction of 5-HT2a/c and DA1/5 signaling pathways on Na+ currents will be examined. The achievement of these aims will provide vital information necessary to construct accurate, integrative models of PFC function as well as dysfunctional states such as schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A PHARMACOGENETICS APPROACH TO DRUG INDUCED WEIGHT GAIN Principal Investigator & Institution: Coe, Natalie R.; Jackson Laboratory 600 Main St Bar Harbor, Me 04609 Timing: Fiscal Year 2002; Project Start 26-MAY-2002 Summary: (Scanned from the applicant?s description) Obesity, often the result of a person?s genetic predisposition, can lead to serious medical conditions, including noninsulin dependent diabetes, heart disease, stroke, high blood pressure, kidney failure, and depression. Clozapine is a highly prescribed anti-psychotic drug, but unfortunately, many patients become obese within several months after initiation of this drug therapy. Identification of the clozapine weight responsive genetic locus and subsequent gene identification will 1) further enhance our understanding of obesity, including genetic suscepibility and onset as well as the its underlying molecular basis, 2) allow psychiatric patients to be screened prior to clozapine treatment to avoid potential health risks brought on by obesity, 3) identify potential cross talk of neuronal and obesity-related metabolic pathways, and 4) help aid in the design of new anti-psychotic drugs that do not interfere with metabolic weight homeostasis. The potential correlation (positive or negative) between formation of the principal active metabolite of clozapine(N-desmethyl-clozapine) and the onset of obesity will be explored as a viable tool to screen psychiatric patients genetically predisposed to clozapine induced weight
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gain. The involvement of histamine (H1) receptors and the neuroleptic induced obesity phenotype has abeen eluded to but not formally addressed in the literature. The potential role of the H1 receptor will be examined directly by the proposed work. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AMPAKINES IN SCHIZOPHRENIA Principal Investigator & Institution: Johnson, Steven A.; Senior Scientist; Cortex Pharmaceuticals, Inc. 15231 Barranca Pkwy Irvine, Ca 926182201 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-AUG-2004 Summary: (Adapted From the Applicant's Abstract) Currently available antipsychotics effectively control positive symptoms (hallucinations, delusions), but persistent negative symptoms (withdrawal, apathy) and cognitive deficits are little affected and can be quite disabling in most patients with schizophrenia. Recently, a new class of orallybioavailable molecule that specifically enhances AMPA-type glutamate receptor activity has been developed. AMPAKINES facilitate acquisition and retention of memory in rodents and humans, and synergistically interact with modern antipsychotics. We recently completed an exploratory safety trial of the AMPAKINE CX516 added to clozapine in 19 treatment-resistant patients. CX516 was well tolerated and produced consistent improvements in negative symptoms, attention, and memory. We now propose to conduct a larger, placebo-controlled trial of CX516 added to olanzapine in patients with schizophrenia. The primary hypothesis is that CX516 will improve negative symptoms, attention, and verbal memory. Secondary aims are: 1) to asses the safety and tolerability of CX516 compared to placebo in olanzapine-treated patients; 2) to assess CX516 effects on positive symptoms, anxiety, depressive symptoms, executive function, and verbal fluency; and 3) to assess effects on extrapyramidal symptoms, including parkinsonism, akathisia and tardive dyskinesia. Positive effects on clinical (negative, positive, extrapyramidal) and neuropsychological (cognition, memory, attention) symptoms in a larger trial will strongly suggest that AMPAKINES may be useful for treatment of schizophrenia. PROPOSED COMMERCIAL APPLICATION: This research may lead to the development of a new, improved class of antipsychotic drug for schizophrenia. These new drugs have the potential to treat the diverse symptoms of this complex disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANTIPSYCHOTIC DRUG INDUCED DYSKINESIAS Principal Investigator & Institution: Casey, Daniel E.; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002 Summary: Antipsychotic (neuroleptic) drug-induced neurological dysfunctions in the motor system are substantial limitations of therapy. These motor disorders include acute dystonic reactions and drug-induced parkinsonism. They occur at the initiation of neuroleptic treatment and may continue in many patients throughout the course of treatment. The underlying pharmacological basis of these disorders is poorly understood. A recently developed drug, Clozapine, appears to have very few of these neurological side effects yet maintains good clinical antipsychotic efficacy. Therefore, it is important to study Clozapine and other potentially new antipsychotic drugs to identify the possible mechanism of action that will lead to reduced neurological side effects. To better understand this issue, we have studied 31 Cebus monkeys in shortterm trials lasting a few days to a few months. Drugs which affect the receptor subtypes
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Clozapine
of dopamine D1 and D2 and serotonin 5HT1A and 5HT2 have been studied. All these drugs produce typical signs of dystonia and parkinsonism, with the exception of Clozapine and 5HT1A agonists. These findings suggest that the mechanism of Clozapine is as yet unknown. Combinations of receptor antagonists of dopamine and serotonin subtypes have not yet identified a clear line of drug development to pursue for creating new antipsychotic drugs that free of neurological side effects. FUNDING NIH MH36657 PUBLICATIONS Casey DE. Effects of clozapine (Clozaril) therapy in schizophrenic individuals at risk for tardive dyskinesia. J Clin Psychiatry 59(Suppl 3):3137, 1998. Casey DE, Garver DC, Lasagna L, Marder SR, Masand PS, Miller D, Pickar D, Tandon R. Clinical trial evaluations and outcome measures in psychiatry. J Clin Psychiatry 59(Suppl 12):1-52, 1998. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANTIPSYCHOTIC MEDICATION Principal Investigator & Institution: Newcomer, John W.; Associate Professor; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 20-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant) Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Type 2 diabetes mellitus is characterized by disturbances in insulin action on skeletal muscle, liver and adipose tissue. Diabetes causes increased morbidity and mortality due to acute (e.g., diabetic ketoacidosis) and long-tenn (e.g., cardiovascular disease) complications. The combination of hyperglycemia, dyslipidemia and abdominal adiposity is even more strongly associated with increased cardiovascular morbidity and mortality. The association of type 2 diabetes and hyperglycemia with schizophrenia was first noted prior to the introduction of antipsychotic medications, suggesting that these patients may be at increased risk. Since then, however, additional glucoregulatory abnormalities (e.g., new Onset diabetes), dyslipidemia, and increased weight and adiposity have all been associated with antipsychotic medications. Concern about antipsychotic effects on glucose, lipids and adiposity has increased recently, focusing on the widely-used newer medications, clozapine and olanzapine. Increased abdominal adiposity can secondarily decrease insulin sensitivity and antipsychotics can increase adiposity. However, medication effects on glucose control and insulin action may also occur independent of differences in adiposity. This project aims to a) evaluate the effects of selected antipsychotic medications on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (whole-body lipolysis), b) evaluate the effects of selected antipsychotic medications on abdominal adipose tissue mass, total body fat and total fat-free mass, and c) explore the longitudinal effects of treatment with selected ant:ipsychotics on glucose tolerance, lipid profiles, abdominal adipose tissue mass, total body fat and total fat-free mass. These hypotheses will be evaluated by measuring 1) whole-body glucose and lipid kinetics with the use of gold-standard stable isotopetracer methodology, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, and 3) longitudinal changes in glucose tolerance and lipid profiles. The aims will be addressed in non-diabetic schizophrenia patients chronically treated with risperidone, olanzapine, clozapine, or haloperidol, and untreated healthy controls. Re-evaluations will also be performed in patients treated with olanzapine and risperidone (from groups above), crossed over to treatment with the other agent for 6 months. Relevant data is critically needed to target basic research, identify long-term cardiovascular consequences, and plan therapeutic interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANTIPSYCHOTIC TREATMENT RESPONSE Principal Investigator & Institution: Miller, Del D.; Psychiatry; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-MAY-2000; Project End 30-APR-2005 Summary: (Adapted from the Applicant's Abstract): In this application for a Mentored Patient-Oriented Research Career Development Award, Del D. Miller will obtain expertise in clinical trials methodology with the intent of studying the biological aspects of antipsychotic response with the goal of improving outcome in persons suffering from schizophrenia. Despite the use of newer atypical agents, many patients with schizophrenia continue to suffer from chronic symptoms and never return to baseline functioning. Dr. Miller will examine plasma concentrations and the presence of mutations of genes that code for neurotransmitter receptors to determine their roles in the clinical response of treatment-refractory persons with schizophrenia receiving clozapine. The candidate proposes a training and research program using the resources of a preventive medicine department devoted to training clinical investigators in the intricacies of treatment trials, a psychiatry department with a long history of research, and a Mental Health Clinical Research Center devoted to the neurobiology of schizophrenia. While Dr. Miller has training in schizophrenia research, he requires additional training in the design of large scale clinical investigations to study the role of biological factors on antipsychotic response. This training will be integrated with a research project seeking: 1) To examine the influence of receptor of polymorphism of the genes that code for neurotransmitter receptors and transporters predicts response to treatment with clozapine 2) To determine whether the combination of clozapine plasma concentrations and presence or absence of genetic polymorphism of neurotransmitter receptors and transporters allows for prediction of response to treatment with clozapine and 3) To develop a model for understanding the relationship between these biological factors and known predictors of clinical outcome. These findings will lead to a therapeutic model for guiding clinicians in choosing treatments for persons with schizophrenia. This award would provide the candidate with the necessary background for further studies of factors influencing antipsychotic response and may yield important algorithms for the pharmacological treatment of schizophrenia. This award will also serve as a mechanism by which the candidate can establish professional collaborative relationships with his mentors and provide him with the background for ongoing research leading to an independent research career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MACHINERY
ANTIPSYCHOTICS
AND
RECEPTOR
DESENSITIZATION
Principal Investigator & Institution: Gurevich, Eugenia V.; Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 05-DEC-2000; Project End 30-NOV-2003 Summary: (Adapted from applicant's abstract) Arrestins and G protein-coupled receptor kinases (GRKs) participate in homologous desensitization of hundreds of G proteincoupled receptors (GPCRs). The rate and extent of desensitization of GPCRs is sensitive to the concentration of arrestins and GRKS in the cells. In its turn, the amount of arrestins and/or GRKs can be modulated by activity of GPCRs. Typical antipsychotic drugs are potent antagonists of the D2 dopamine receptor, whereas atypical drugs interact with several GPCRs. Plasticity of several GPCRs is implicated in schizophrenia pathology and actions of antipsychotic drugs. The a[[;ocamts hypothesize that treatment
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Clozapine
with antipsychotics induces alterations in the concentration of specific arrestins and/or GRKs in selected brain regions, thereby modifying signal transduction via GPCRs in these regions. Exploration of this hypothesis is clinically relevant because molecular mechanisms of the beneficial actions of antipsychotic drugs remain elusive. Mechanism of action of atypical antipsychotics with their higher efficacy against negative symptoms and cognitive deficits is of particular interest. The specific aims designed to test this hypothesis include determination of the repertoire of arrestin and GRK proteins in specific subtypes of output neurons in the striatum and nucleus accumbens, the brain regions that are prime targets of antipsychotics. The second specific aim focuses on comparison of the effects of acute and subchronic treatment with typical antipsychotic haloperidol and atypical drug clozapine on the expression of arrestin and GRK mRNAs and proteins in various brain areas implicated in schizophrenia pathology and action of antipsychotics. The third specific aim is to determine whether alterations in the arrestin and GRK expression are associated with development of tardive dyskinesia induced by chronic treatment with haloperidol. Plasticity of neuronal receptor trafficking system produced by antipsychotic treatment may lead to changes in the concentrations of specific GPCRs and, ultimately, to long-term modulations of neuronal responses to endogenous stimuli and exogenous drugs. Specific modifications in the arrestin/GRK expression may thus be essential for the beneficial or side effects of antipsychotic drugs. We expect that the information gained by examining the response of the key components of the receptor trafficking machinery to antipsychotics will be helpful for targeted design of drugs with improved clinical profile. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTION
ANTIPSYCHOTICS:
TEMPORAL
EFFECTS
ON
COGNITIVE
Principal Investigator & Institution: Terry, Alvin V.; Clinical & Administrative Pharmacy; University of Georgia 617 Boyd, Gsrc Athens, Ga 306027411 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2007 Summary: (provided by applicant): Schizophrenia is a debilitating illness that affects up to 1% of the world's population. While the use of antipsychotic (neuroleptic) drugs is the standard of care for treating the psychotic symptoms of the illness, little is known regarding which neuroleptics are best for extended use in those with cognitive impairment. This consistent feature of schizophrenia is now believed to have the most substantial impact on the longterm outcome of the disease. Accordingly, a major longterm goal of this laboratory is to develop mechanistically-based therapeutic strategies for patients suffering from psychotic symptoms and cognitive dysfunction. The objective of this application is to establish potential relationships between the cellular and biochemical effects of chronic neuroleptic exposure and cognitive function in an experimental animal model. We have compelling preliminary evidence from rat studies that chronic exposure to conventional neuroleptics such as haloperidol (in a temporally dependent fashion), but not atypical agents such as clozapine, leads to cognitive impairment and that a reduction in a key marker for cholinergic neurons, choline acetyltransferase, precedes the cognitive symptoms. Due to the pattern of reduced cholinergic enzyme staining and the fact that many of the cholinergic neurons involved in learning and memory are functionally dependent on the neurotrophin, nerve growth factor (NGF), we have developed the hypothesis that chronic exposure to conventional, but not atypical, neuroleptics in rats decreases neurotrophic support to cholinergic neurons, resulting in decreased cholinergic activity in the brain and impairment of cognitive function. The rationale for the proposed animal studies is that a better
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understanding of the differential (chronic) effects of neuroleptics on memory function will facilitate future (clinical) efforts to identify optimal drugs for cognitively impaired psychiatric patients. To test the hypothesis we propose two specific aims: 1): To evaluate differential temporal effects of different classes of neuroleptic drugs on cognitive function in an experimental animal model. 2): To define potential correlative relationships between neuroleptic-induced cognitive changes and temporal changes in biochemical and cellular parameters of cholinergic function in the brain, NGF release, and NGF receptor expression. We will use a water maze task to measure spatial learning, an 8-arm radial arm maze task to assess working memory, and in situ hybridization, western blots, ELISA experiments, immunofluorescence staining, and receptor autoradiography to measure the expression of NGF and key cholinergic markers. We expect that chronic exposure to conventional, but not atypical neuroleptics will negatively affect both spatial learning and working memory and that neurolepticinduced alterations in CNS cholinergic activity will both precede and correlate with detectable manifestations of cognitive dysfunction. These studies, designed to mechanistically define neuroleptics based on their chronic effects on specific biological substrates of memory are significant because they will contribute to the identification of therapeutic agents with optimal effects on cognitive function, and thus potentially benefit many psychiatric patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APOMORPHINE CHALLENGE IN SCHIZOPHRENIA & NORMALS Principal Investigator & Institution: Lee, Myung A.; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ATYPICAL CONCENTRATION
ANTIPSYCHOTICS:
DETERMINANTS
OF
Principal Investigator & Institution: Pollock, Bruce G.; Professor of Psychiatry and Pharmacology; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): The primary goal of this revised application (MH64173), which is ancillary to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), is to reliably capture the concentration exposure of the antipsychotics (risperidone, olanzapine, ziprasidone, fluphenazine, perphenazine, and clozapine) using mixed effect population pharmacokinetic methodologies. The population pharmacokinetic approach is ideally suited for analyzing drug concentration data from large clinical intervention trials because patient-specific as well as overall population pharmacokinetic parameters can be determined using only a few plasma samples per patient. An understanding of pharmacokinetic variability is essential to rational drug prescribing. The population pharmacokinetic approach will permit determination of the extent of variability in drug exposure associated with the use of atypical antipsychotics in large populations under conditions that mirror clinical practice. In addition, the ability of population pharmacokinetic models to capture subjects' drug exposure utilizing single concentration measurements will be assessed in this study. Population pharmacokinetics has also been successfully used to identify
12
Clozapine
sources of variability in drug concentration exposure. Therefore, this ancillary study will provide an innovative way to make optimal use of plasma samples that are being obtained in the CATIE trials. The CATIE trials will recruit up to 2,250 patients providing from 1 to 6 plasma concentration samples per subject for each medication. A separate population pharmacokinetic model will be constructed for each drug incorporating covariate effects. Specific covariates will be then be evaluated as potential contributors to drug exposure variability. Demographic covariates to be examined are age, sex, race/minority status, and body mass index. The potential impact of additional covariates such as prior medication exposure, concomitant medications, smoking status, estimated renal clearance, and treatment adherence will also be assessed. By providing pharmacokinetic data on the atypical antipsychotics under "real world" conditions, this study has broad public health implications, leading to greater awareness of the need to individualize antipsychotics pharmacotherapy for patients suffering from either schizophrenia or Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BEHAVIORAL & PHARMACOLOGICAL ANALYSIS OF DRUGS OF ABUSE Principal Investigator & Institution: Winter, Jerrold C.; Professor; Pharmacology and Toxicology; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2002; Project Start 01-JAN-1985; Project End 30-JUN-2006 Summary: The discovery by Albert Hofmann more than fifty years ago of the hallucinogenic effects of LSD irreversibly altered the course of both biological psychiatry and popular culture. Hallucinogens of all types are subject to widespread and increasing abuse by adolescents and young adults in this country. For example, in 1998 use of hallucinogens exceeded that of cocaine in the age groups 12-17 and 18-25. Indeed, hallucinogens were more commonly ingested than tranquilizers, inhalants, and sedatives combined. Furthermore, LSD was identified in 1999 as a "club drug" in the campaign by the National Institute on Drug Abuse to alert the public to the hazards of these agents. In addition to the well recognized abuse liability of these drugs, hallucinogens are perhaps unique in that an understanding of their mechanisms of action would contribute not only to an amelioration of the burdens of illicit use but might also provide a key to solving the puzzle of psychosis, another major human affliction. The present investigations seek to characterize indoleamine hallucinogens such as LSD and phenethylamine hallucinogens as exemplified by DOM in combined behavioral, biochemical, and analytical [GC-MS] studies. Specifically, studies will also examine the neuroanatomical sites involved in hallucinogen- induced stimulus control. In addition, experiments will further characterize interactions between the serotonergic and glutamatergic systems in the brain. Finally, the mechanisms responsible for the potentiation of LSD and other hallucinogens by fluoxetine and related selective serotonin reuptake inhibitors will be examined. Taken together, the correlational use of powerful methods for the assessment of in vivo and in vitro efficacy and of brain levels of DOM and of neurotransmitters will provide new understanding of the mode of action of hallucinogens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOPHYSICAL STUDY OF ANTIPSYCHOTICS BEHAVIORAL EFFECTS Principal Investigator & Institution: Fowler, Stephen C.; Professor; Human Develmt and Family Life; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAR-2004 Summary: (Adapted from the Investigator's Abstract) The atypical antipsychotic drugs are a major advance over the older drugs that frequently induced extrapyramidal side effects (EPS). These newer drugs, except for clozapine, continue to induce EPS at higher doses. Despite its superior efficacy in the treatment of refractory schizophrenic patients, clozapine produces measurable cognitive side effects as well as distinctive, but not EPSlike, motor effects in both humans and rats. The over arching purpose of this proposal is to quantify, in rats and in inbred strains of mice, the motor and cognitive side effects of clozapine and other atypical antipsychotic drugs as well as to continue efforts to quantitate low-dose EPS in rodents. Three, primary behavioral measurement procedures will be used: 1) the food-anticipation-operant-microcatalepsy (FAOM) task that models low dose EPS (bouts of immobility that interrupt behavior) and bradykinesia (slowing of movements) in both rats and mice; 2) the sustained attention task (SAT) that concurrently measures reaction time and cognitive performance and closely resembles the continuous performance task that reveals deficits characteristic of schizophrenia; 3) the forelimb tremor task (FT) that uses force-transducer technology and Fourier analysis to quantify drug-induced tremor and detects the hypotonia and antitremor effects of clozapine. In the FAOM procedure, the EPS liability of atypical antipsychotics clozapine, risperidone, sertindole, quetiapine, and olanzapine will be evaluated in haloperidol-sensitized rats. When haloperidol-treated inbred strains of mice were compared in the FAOM task, the C57bl/6 mice showed striking EPS-like effects while the Balb/c mice did not-a result suggesting genetic causes. Several inbred strains of mice will be compared to identify strains likely to express EPS-like effects of atypical antipsychotic drugs. The SAT procedure will be used with rats to assess deleterious cognitive effects of chronic clozapine. The FT task will be used with rats to explore clozapine's recently discovered withdrawal effect (tremor rebound), to evaluate other atypical antipsychotics for clozapine-like motor effects, and to assess clozapine's ability to dampen tremor induced by harmaline or physostigmine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BRAIN ERPS AND COGNITIVE DEMAND IN SCHIZOPHRENIA Principal Investigator & Institution: Bruder, Gerard E.; Professor; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 100321098 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 28-FEB-2004 Summary: (Adapted from applicant's abstract): Schizophrenic patients have shown a reduction in amplitude of the P3 brain ERP to tones, which was maximal over left temporal lobe sites. In the initial project period, the investigator replicated this finding in a dichotic complex tone task and found reduced N2 amplitude and asymmetry in schizophrenic patients in a dichotic syllable task. This suggests that left hemisphere dysfunction in schizophrenia for verbal processing occurs as early as 200 ms after stimulus onset. N2 abnormalities in schizophrenic patients were present in both auditory and visual tasks, whereas P3 abnormalities appear to be modality specific. The investigator proposes to conduct four studies to determine the task and patient characteristics necessary for producing these ERP abnormalities and to further resolve their neurophysiologic mechanisms. Study 1 will record ERPs in a large sample of
14
Clozapine
schizophrenic patients (n=120) and normal controls (n=40) on verbal and nonverbal binaural oddball tasks, and will assess the influence of response mode (silent counting, right hand or left hand). These large samples will enable the investigator to examine the relation of ERP abnormalities in schizophrenia to symptom features, outcome of treatment with neuroleptics, familial history of schizophrenia, and neuroimaging measures. Study 2 will develop and apply new verbal and nonverbal tasks that incorporate advantages of dichotic listening procedures, but utilize a simple oddball paradigm. Study 3 compares ERPs of schizophrenic patients and controls in auditory and visual continuous word recognition tasks, which are thought to reflect left medial temporal lobe function. Study 4 continues the investigator's study of visuospatial processing in schizophrenia using a revised paradigm designed to disentangle effects of selective attention and later cognitive processing. Patients will be tested while off medication and again after six weeks of treatment with haloperidol or an atypical neuroleptic (clozapine or risperidone). A more long range clinical goal is to contribute toward the development of tests that could predict response to treatment with conventional or atypical neuroleptic medications for schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BUILDING SCHIZOPHRENIA
A
MOUSE
MODEL
WITH
RELEVANCE
TO
Principal Investigator & Institution: Fish, Kenneth N.; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The career development and research program described in this proposal supports the application for a Mentored Research Scientist Development Award for Dr. Kenneth N. Fish, and is intended to provide the candidate with the background knowledge, research experience, and research management skills that will prepare him for an independent research career in schizophrenia. Training will take place at the Harold L. Dorris Neurological Research Center in the Department of Neuropharmacology (Dr. Floyd E. Bloom, Chair) of the Scripps Research Institute, under the direct supervision of Dr. Tamas Bartfai. Dr. Bartfai is highly qualified to serve as Preceptor for the Candidate, because of his experience with the methodologies to be used, his active research program in depression and schizophrenia, and his commitment to the development of junior research scientists. The Department of Neuropharmacology emphasizes a multi-disciplinary approach to problems of mental disorders. Thus, this is an ideal environment for the Candidate to materialize his goal of developing a multidisciplinary research approach to the neurobiology of schizophrenia. The overall objective of the research plan is to perform a thorough analysis of the reeler and scrambler mice to define test parameters that will be used to study new mouse models and to determine their applicability as models to study schizophrenia. Tests will include a morphological analysis of the neocortex, cerebellum, and hippocampus using three-dimensional reconstruction with NeuroZoom, immunocytochemical analysis of DA, GLU, and GABA expression, quantitative behavioral measurements [prepulse inhibition (PPI) of the startle response], and their responsiveness to clinically effective antipsychotics (haloperidol, risperidone, and clozapine). In addition, to further characterize the reeler phenotype we will generate a transgenic mouse in which reelin expression is temporally regulated and generate a mouse model that has a conditional block of reelin function to induce specific changes in brain morphology that are required to alter prepulse inhibition and/or induce ataxia. These studies will advance our understanding of how neurodevelopmental abnormalities relate to behavioral changes
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and will assist in the development of new antipsychotic drugs with relevance to schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CAMP/PKA SCHIZOPHRENIA
SIGNALING
&
ENDOPHENOTYPES
OF
Principal Investigator & Institution: Druhan, Jonathan P.; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002 Summary: (provided by applicant): Recent evidence suggests that disturbances in intracellular signaling may underlie some of the cognitive and neurobehavioral dysfunctions observed in schizophrenia. Studies in humans suggest that the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway is upregulated within the central nervous systems of schizophrenic patients. Our preliminary studies indicate that transgenic mice overexpressing a constitutively active form of the signaling protein Gs(Gs-*) in forebrain neurons exhibit deficits in two neurobehavioral processes known to be disrupted in schizophrenics, inhibitory gating and explicit learning. Studies in this proposal will examine the effects of increased cAMP/PKA signaling on inhibitory gating and learning in mice to determine whether signaling disturbances could contribute to these endophenotypes of schizophrenia. Studies in Aim 1 will test transgenic mice that overexpress constituents of the cAMP/PKA signaling pathway (i.e. Gs-*, the catalytic subunits of PKA, or a nuclear target of PKA, CREB) in animal models of inhibitory gating and learning to determine whether such mice show deficits in these paradigms (prepulse inhibition, P20/N40 gating, and Morris water maze). Offspring of Gs-* mice crossbred with mice having reduced PKA or CREB activity also will be tested in these behavioral paradigms to determine whether reductions in PKA or CREB can normalize the behavioral deficits produced by the overexpression of Gs-*. Studies in Aim 2 will measure inhibitory gating and learning after localized stimulation of cAMP/PKA activity in forebrain regions of wild-type mice, or after localized inhibition of cAMP/PKA in forebrain regions of Gs-* mice, to determine whether localized pharmacological manipulation of cAMP/PKA activity modifies gating and learning processes. Studies in Aim 3 will determine whether drugs effective at treating symptoms of schizophrenia will normalize gating and learning deficits in mice with upregulated cAMP/PKA activity. These studies will provide important new information about the role that intracellular signaling in cAMP/PKA pathways plays in the expression of gating and learning endophenotypes of schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CANNABIS AND SCHIZOPHRENIA: CLOZAPINE VS RISPERIDONE Principal Investigator & Institution: Green, Alan I.; Professor; Psychiatry; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 30-NOV-2002 Summary: (Applicant's Abstract) Cannabis use disorder contributes to the morbidity of schizophrenia, leading to, poorer overall functioning. The typical antipsychotic drugs are of limited value in controlling cannabis use in these "dual diagnosis" patients. This study will assess whether new antipsychotic medications, introduced into clinical practice in the past decade, are of value for this purpose. Preliminary data suggest that the atypical antipsychotic drug clozapine (CLOZ), currently used primarily for treatment resistant patients, may limit cannabis use in "dual diagnosis" patients with
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Clozapine
schizophrenia much more effectively than do either typical antipsychotics or the "novel" (post-CLOZ) antipsychotic risperidone (RISP). In a recently published paper, we have hypothesized (a) that CLOZ will lessen substance use in such "dual diagnosis" patients in part because of its mechanism of action that includes release of dopamine (DA) in the prefrontal cortex (PFC), and (b) that the CLOZ-induced release of DA in the PFC will decrease negative symptoms (an effect shared especially by the novel antipsychotic RISP). Moreover, we have further hypothesized, (c) that through its diverse effects on both dopaminergic and noradrenergic systems, CLOZ (but not RISP or typical antipsychotics) will help to normalize dysfunctional brain reward circuits that may underlie the comorbid substance use in patients with schizophrenia. In the proposed study, patients comorbid for both schizophrenia and a cannabis use disorder will be randomly assigned to double-blind treatment (for 12 weeks) with either CLOZ or RISP. The primary aim of this study is to launch a carefully controlled pharmacological trial of the short-term effects of CLOZ and RISP on cannabis use in this population to test the hypothesis that patients treated with CLOZ will have decreases in cannabis use as compared to patients treated with RISP. A secondary aim is to begin to investigate the process by which CLOZ produces its effects on cannabis use through study of negative symptoms. A subsidiary aim is to begin to address key auxiliary measures of the effects of CLOZ in this "dual diagnosis" population: psychiatric symptoms, quality of life, and measures of neuropsychological functions. If the results of this study confirm the preliminary data, they could suggest a new use for CLOZ, one that could have important public health implications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CLOZAPINE IMPROVEMENT
&
SENSORY
INHIBITION:
MECHANISM
OF
Principal Investigator & Institution: Simosky, Johanna K.; Pharmacology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-APR-2002 Summary: (provided by applicant): Although control subjects will inhibit the evoked electrophysiological response to the second of paired auditory stimuli, schizophrenics are unable to do so. Inhibitory pathways in the hippocampus, which can be modulated through alpha7 nicotinic cholinergic receptors, are insufficiently activated in schizophrenia patients. This results in an inability to appropriately inhibit the response to repetitive sensory stimuli. Clozapine, unlike typical antipsychotics, is able to normalize this deficit in sensory inhibition. The mechanism of this normalization is unknown, but its elucidation would allow better understanding of clozapine?s efficacy. We propose that clozapine-induced increases in cholinergic neurotransmission are responsible for the increased inhibition of response. This hypothesis will be tested in DBA/2 mice, a mouse model of the deficit which shares both phenotypic and genotypic attributes with the deficit observed in schizophrenia. After construction of a dose response curve for the effects of clozapine on sensory inhibition we will carry out mechanistic studies. The first of these will determine how the normalizing effects of clozapine on sensory inhibition are affected by pretreatment of the mice with various nicotinic antagonists, to infer if (and which) nicotinic receptors are involved in mediating the effects of clozapine. In the final aim, the techniques of hippocampal in vivo microdialysis and single unit recording will be used to determine if clozapine increases the release of acetylcholine and/or increases the activity of septohippocampal cholinergic neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CLOZAPINE AND OLANZAPINE IN VIOLENT SCHIZOPHRENICS Principal Investigator & Institution: Krakowski, Menahem I.; Senior Research Scientist; Nathan S. Kline Institute for Psych Res Psychiatric Research Orangeburg, Ny 10962 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: Chronic violence and hostility in schizophrenic patients represent a serious problem which impacts on the perpetrators, other patients and caregivers. In preliminary studies, we have identified a group of schizophrenic patients who evidence persistent violence and hostility linked to specific schizophrenic symptoms. These patients are responsible for a high percentage of all inpatient assaults. The literature suggests that clozapine (CLO) has specific anti- aggressive effects and it improves psychotic symptoms and cognitive impairments similar to those which we identified in these patients. Olanzapine's (OLZ) without the latter's potentially serious side effects suggests that it may have an important place in the treatment of these patients. We will examine the examine the comparative efficacy of CLO, OLZ and standard agent haloperidol (HAL) in the treatment of persistent. We will also how underlying symptoms and deficits are associated with persistent violence and how they improve with each of these three treatments. Violent patients (N=212) will enter a 12-week clinical trial in which they will be randomized to either CLO, OLZ or HAL under double-bind conditions. Outcomes measures include the Modified Overt Aggression Scale, the Buss-HAL under double-blind conditions. Outcomes measured include the Modified Overt Aggression Scale, the Buss-Durkee Hostility inventory, and the NOSIE. Patients' reduction in psychotic symptoms will be assessed by PANSS and CGI. Reduction in cognitive impairment will be assessed by the Wisconsin Card Sorting Test, in impulsivity by the Barrat Impulsiveness scale. It is hypothesized that: 1) the effects of CLO on physical assaults, hostility and social functioning will be superior to those of OLZ, which, in turn, will be superior to HAL's. 2) Improvement in the outcome variables-violence, hostility and social functioning-will be related to improvement in underlying symptoms, i.e. ability to utilize environmental feedback, impulsivity, and psychosis. Similar to the outcome measures, these symptoms will improve more with CLO than OLZ and more with OLZ than HAL. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CLOZAPINE DRUG DISCRIMINATION IN C57BL/6J MICE Principal Investigator & Institution: Philibin, Scott Commonwealth University Richmond, Va 232980568
D.;
Psychology;
Virginia
Timing: Fiscal Year 2003; Project Start 18-AUG-2003; Project End 17-AUG-2006 Summary: (provided by applicant): Clozapine is the prototypical atypical antipsychotic drug and represents a tremendous improvement over conventional antipsychotics in terms of therapeutic efficacy and reduced side effect liability for the treatment of schizophrenia. Understanding the pharmacological properties that are important for clozapine's unique profile can help lead to the discovery of improved and safer antipsychotic drugs for the treatment of schizophrenia. One approach for investigating the molecular bases underlying the relationship of pharmacological agents and behavior has been the use of gene-targeted knockout or transgenic animals. This technique allows for the manipulation of receptors for which selective pharmacological ligands do not exist. One restriction of this approach is that most of the knockout mutations that have been developed are available only in mice - not rats. Therefore, it is necessary to have preclinical assays for mice in order to utilize these new and potentially powerful new techniques. The current proposal represents an important first step in this process. Two-
18
Clozapine
lever drug discrimination is a valuable preclinical behavioral model that has been used to investigate the discriminative stimulus properties of clozapine in rats and has helped identify neurotransmitter receptor targets for putative atypical antipsychotics. Wildtype mice (C57BL/6J) will be trained to discriminate clozapine from vehicle and then a series of atypical and typical antipsychotic drugs will be tested to determine which drugs generalize to clozapine's discriminative cue. Establishing this procedure in wildtype mice will allow for the future use of knockout and transgenic mice and will expand the tools available to molecular geneticists and behavioral pharmacologists. This will help to increase our understanding of the perplexing pharmacology of schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CLOZAPINE EFFECTS ON GLUTAMATE TRANSMISSION AND DOPAMINE Principal Investigator & Institution: Hasenkamp, Wendy; Biology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-OCT-2002; Project End 31-JUL-2005 Summary: (provided by applicant): The broad objective of the proposed research is to elucidate the effects of clozapine treatment on subpopulations of midbrain dopaminergic neurons. Specifically, the molecular and neurochemical changes in NMDA-mediated glutamate transmission induced by acute (1d) versus chronic (21d) treatment of clozapine will be evaluated through two aims. In the first aim, the prefrontal cortex and nucleus accumbens of rats will be injected with retrograde tracer prior to acute or chronic clozapine (or vehicle) treatment. Following drug administration, mRNA from retrogradely-labeled mesolimbic or mesocortical dopaminergic neurons will be amplified and hybridized to a custom cDNA microarray for determination of global changes in gene expression. In the second aim, microdialysis will be used to evaluate changes in extracellular dopamine in the prefrontal cortex and nucleus accumbens, as well as glutamate in the midbrain, after acute and chronic clozapine. In addition, the functional response of midbrain dopaminergic neurons to NMDA and AMPA antagonists will be analyzed based on changes in dopamine release in response to these compounds. These studies will further our understanding of atypical neuroleptic action, and in doing so, may help elucidate the underlying neuropathology of schizophrenia, in addition to identifying ways of improving current pharmacotherapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CLOZAPINE TREATMENT OF SCHIZOPHRENIC PATIENTS Principal Investigator & Institution: Buchanan, Robert W.; Professor; Psychiatry; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-APR-1990; Project End 31-DEC-2006 Summary: This is a submission of a competitive renewal application, MH 45074: "Clozapine Treatment of Schizophrenic Outpatients". Over the last ten years, the new generation antipsychotics clozapine, risperidone, olanzapine, quetiapine, and ziprasidone have been approved and introduced for the treatment of schizophrenia. Of these agents, only clozapine has been shown to have superior efficacy to conventional antipsychotics, and is FDA approved for treatment-resistant patients with schizophrenia. However, up to 50 percent of patients adequately treated with clozapine will fail to respond, and will continue to exhibit clinically significant residual positive and negative symptoms and cognitive impairments. These patients represent a major
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therapeutic challenge and raise the question: What treatment options are available for these patients? The major emerging treatment trend is to use a second antipsychotic medication. This clinical practice has become relatively widespread, but there is little empirical evidence to support the validity of this approach. We will conduct a 16-week randomized, parallel group, double-blind comparison of adjunctive risperidone and placebo in clozapine-treated patients with schizophrenia to address two primary aims: is adjunctive risperidone superior to placebo for the treatment of persistent positive symptoms and cognitive impairments in clozapine-treated patients with schizophrenia, and three secondary aims: is adjunctive risperidone superior to placebo for the treatment of persistent negative symptoms and functional impairments, and is adjunctive risperidone associated with increased incidence of side effects as compared to placebo in clozapine-treated patients with schizophrenia. We will perform biweekly positive and negative symptom and side effect assessments, and baseline and end of study neuropsychological and functional assessments. The study will provide new information on the clinical utility of adjunctive risperidone in treatment-resistant patients who fail to adequately respond to clozapine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONSTITUTIVELY ACTIVE SEROTONIN RECEPTORS Principal Investigator & Institution: Teitler, Milt; Professor; Pharmacology & Neuroscience; Albany Medical College of Union Univ Albany, Ny 12208 Timing: Fiscal Year 2002; Project Start 01-JUL-1997; Project End 31-MAR-2006 Summary: (provided by applicant): We have shown that clozapine and risperidone, atypical antipsychotic drugs, have potent inverse agonist properties at constitutively activated mutant (CAM) forms of the rat 5SHT2A and 5HT2C receptors. Inverse agonist activity may be a significant property of antipsychotic drugs, given the revised ternary complex model of G-protein coupled receptors (GPCR), which predicts a steady-state level of activation of receptors in the absence of ligand stimulation. Further studies of antipsychotic drug actions at CAM forms of clozapine-sensitive human SHT receptors are necessary to determine if inverse agonist activity is a key property of atypical antipsychotic drugs. In order to expand the studies to the human 5HT6 and 5HT7 receptors we have attempted to make CAM forms of these receptors by mutating two well-documented regions of GPCR constitutive activity. Initial experiments involving mutations in these areas have produced forms of the receptor either lacking robust constitutive activity or producing apparently null mutant forms of the receptor (5HT6). While these results have slowed progress on determining the inverse agonist activity of antipsychotic drugs on these receptors they open up interesting avenues of research on the variability in structure within the GPCR family and within 5HT receptors in particular. Therefore we propose to pursue three specific aims: 1) we will continue to test typical and atypical antipsychotic drugs at human CAM forms of the 5HT2A and 5HT2C receptors; 2) we will continue to mutate the human 5HT6 and 5HT7 receptors to produce CAM forms of these receptors and test antipsychotic drugs for inverse agonist activity at these receptors; 3) we will examine effects of constitutive activation on clozapine-sensitive 5HT receptor cellular trafficking, and the effects of inverse agonists on the trafficking of the mutated receptors. The results of these studies should reveal the role inverse agonist activity of antipsychotic drugs plays in the atypical properties of clozapine, and may indicate a major role for one or more of the clozapine-sensitive receptors in the atypical properties of clozapine. This information should be very helpful in designing a new generation of atypical antipsychotic drugs sharing clozapine's unique antipsychotic properties, but lacking its deleterious hematological
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effects. Information concerning alterations in cellular processing of CAM receptors should also be forthcoming, including information on the molecular domains involved in directing cellular compartmentalization, believed to play a key role in cellular receptor sensitivity states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--KNOWLEDGE TRANSFER Principal Investigator & Institution: Mendelowitz, Alan; Long Island Jewish Medical Center New Hyde Park, Ny 11040 Timing: Fiscal Year 2002 Summary: The overall goal of this new Knowledge Transfer Unit (KTU) is to better inform the medical community, patients, and their families about schizophrenia. There are 4 aims of the KTU. First is to improve the recognition of prodromal and early signs of schizophrenia and stress the importance of early intervention. Second is to improve knowledge and utilization of best treatments for schizophrenia. Third is to improve knowledge about the size effects of anti-schizophrenia medications. Finally, the KTU aims to increase the knowledge concerning poor treatment response and the role of clozapine in the method of "academic detailing" seems to be a worthy intellectual centerpiece for this unit. The leaders of the KTU are both junior, and there are examples of issues that seem internalized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENTAL ANTIPSYCHOTICS
PSYCHOPHARMACOLOGY
OF
Principal Investigator & Institution: Wiley, Jenny L.; Associate Professor; Pharmacology and Toxicology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Antipsychotics are administered to children and adolescents for a number of disorders with chronic use often continuing into adulthood. Yet, little is known about short- and long-term effects of these agents on the developing brain and behavior. Research on the effects of atypical antipsychotics (e.g., clozapine) that do not produce extrapyramidal motor effects is particularly lacking. The major hypotheses of this grant proposal are that (1) developing animals are more sensitive to the effects of dopamine antagonists, including antipsychotics, on motor processes than are adult animals and (2) chronic dosing with antipsychotics during development produces long-term changes in response to challenges with dopaminergic agents in later life such that animals are more sensitive to the effects of dopamine agonists and less sensitive to those of dopamine antagonists. In order to test the first hypothesis, rats of different ages (postnatal day 22 to adult) will be administered acute doses of selected antipsychotics; subsequently, they will be evaluated in behavioral procedures designed to measure motor activity (locomotion and catalepsy). In order to test the second hypothesis, rats will be chronically injected with selected antipsychotics during development. After reaching adulthood, these rats will be evaluated in behavioral procedures to evaluate motor activity (locomotion and catalepsy), cognition (sensorimotor gating, acquisition of a response, short-term memory), and the reinforcing efficacy of food. In addition to baseline activity in these procedures, the effects of challenges with antipsychotics and dopamine agonists will also be assessed in these rats. In order to determine possible underlying changes in dopamine receptor binding and distribution, autoradiography of the brains of rats that received identical chronic
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injection regimens will be performed using radioligands selective for dopamine D1 and D2 receptors. The proposed studies will provide empirical information on acute and long-term effects of traditional and atypical antipsychotics on the developing brain and behavior. This information will help to provide a more rational basis for making treatment decisions concerning children and adolescents who may benefit from treatment with an antipsychotic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOPAMINE DEFICIT AND SCHIZOPHRENIA Principal Investigator & Institution: Roth, Robert H.; Professor; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 25-SEP-1997; Project End 31-DEC-2005 Summary: (Adapted from applicant's abstract) The cognitive deficits that occur in schizophrenia are arguably the most debilitating of the symptoms, and the most resistant to pharmacological treatment. While the atypical antipsychotic drug, clozapine, is the one of the few drugs with any success in treating the negative and cognitive symptoms of schizophrenia, its mechanism of action is not fully understood and this has hindered development of other agents that are more effective than clozapine and lack its dangerous side effects. In man, repeated use of phencyclidine (PCP) can often induce an enduring schizophrenic-like syndrome. In the monkey, we have found that subchronic exposure to PCP induces a decrease in doparnine function in the prefrontal cortex (PFC), which persists for more than a month. Demonstrates, neurochemical and anatomical specificity. This PCP-induced PFC dopamine deficiency correlates with cognitive impairments in the monkey, which resemble those occurring in schizophrenia Furthermore, these cognitive deficits are partially ameliorated by administration of clozapine Using in vivo and ex vivo techniques in rats and monkeys, this project will examine the mechanisms responsible for the neurobiological changes induced by repeated PCP administration on the anatomical integrity, neurotransmitter regulation and behavioral functions associated with the PFC. In addition, the mechanisms involved in the pharmacological reversal of the cognitive deficits produced by subchronic exposure to PCP will be evaluated. The research plan will address the following four specific aims: (1) What neurobiological changes; responsible for the reduction in dopamine function in the PFC following repeated PCP administration, (2) clozapine's ability to reverse the PCP-induced cognitive impairment mediated by a preferential increase dopamine turnover in the PFC, and what receptors are essential for this action? (3) Determine if atypical antipsychotic drugs (or receptor specific agents) that reverse the PFC dopamine deficit in PCP-treated monkey attenuate the cognitive impairments, and (4) Determine whether there are regionally specific adaptive changes the parvalbumin GABAergic interneurons of the PFC in the monkey repeatedly treated with PCP. The generation of critical neurochemical and behavioral data in this monkey model of PFC dopamine deficiency and impaired cognition will provide important new insights concerning the neural systems relevant the frontal cortical cognitive dysfunction in schizophrenia. These data will aid in the development of novel strategies for ameliorating the neurochemical and behavioral deficits in this potential animal model, and in the cognitive dysfunctions associated with schizophrenia and other psychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Clozapine
Project Title: DOPAMINE SYSTEM INTERACTIONS AND SCHIZOPHRENIA Principal Investigator & Institution: Deutch, Ariel Y.; Professor; Psychiatry; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-MAY-1989; Project End 30-NOV-2004 Summary: The thalamic paraventricular nucleus (PVT) has generally been considered as one of the non-specific thalamic nuclei. More recent data indicate there is a high degree of specificity in the efferent projections of the PVT and argue against a non-specific role for the PVT. The PVT projects to several key sites linked to the pathophysiology of schizophrenia and drug abuse, including the prefrontal cortex (PFC), the shell of the nucleus accumbens (NAS), and the central and basolateral nuclei of the amygdala. The PVT also receives a dopamine (DA) innervation and PVT neurons express the D3 (but not other) DA receptor transcripts. We hypothesize that the PVT is both regulated by DA afferents and coordinately regulates DA function in mesocorticolimbic regions, including the NAS and PFC. Three related specific aims will explore the anatomical and functional organization of the PVT and test our hypotheses. 1)Tract-tracing-immunohistochemistry studies will determine the origins of the DA innervation of the PVT, examine the relationship of efferent projections to the extended amygdala and NAS, and characterize the phenotype of PVT neurons that innervate the NAS and other corticolimbic areas. 2)A series of studies will examine the regulation of the dopamine system of the PVT. These studies will determine the efferent targets of PVT neurons that are activated by clozapine and psychostimulants, determine if the Fos response of PVT neurons occurs in D3 receptor-expressing cells, and assess the regulation of D3 gene expression by chronic clozapine and psychostimulants. 3)The ability of the PVT to functionally regulate the DA innervations of mesocorticolimbic terminal fields, including the NAS and PFC, will be examined using in vivo microdialysis. These studies will assess the responsiveness of the NAS and PFC DA innervations to agents that evoke DA release (KC1 and amphetamine) and to excitatory amino acid agonists (NMDA and AMPA). These studies should reveal new aspects of thalamic regulation of mesocorticolimbic DA function that may be deranged in schizophrenia and drug abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ECT IN CLOZAPINE REFRACTORY SCHIZOPHRENIA Principal Investigator & Institution: Petrides, Georgios; Associate Professor; Long Island Jewish Medical Center 270-05 76Th Ave New Hyde Park, Ny 11040 Timing: Fiscal Year 2002; Project Start 01-DEC-2000; Project End 30-NOV-2003 Summary: (Applicant's abstract): As many as 30% of schizophrenic patients are resistant to standard antipsychotic medications. Clozapine represents a unique treatment in our armamentarium for schizophrenia as it is helpful in treating 30-50% of the treatmentrefractory patients. However, 50-70% of these unfortunate patients do not respond adequately to clozapine, and are left without any viable treatment options. They continue to suffer unrelentingly, and represent a considerable burden to their families and society. This study will investigate electroconvulsive therapy (ECT) as an augmentation strategy for patients who have failed to adequately respond to clozapine. The choice of ECT is based on three converging lines of evidence: in the preantipsychotic medication era, ECT was often an effective treatment for schizophrenia; the combination of ECT and antipsychotic medications provides enhanced clinical response; and several case series suggest a benefit when ECT is added to clozapine. Continued clozapine monotherapy and clozapine augmentation with ECT in clozapine refractory schizophrenic patients will be compared in a prospective, random assignment
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study. We will treat patients who have had at least 12 weeks of an adequate clozapine trial. Sixty-four subjects (32 randomized to clozapine and 32 randomized to clozapine plus ECT) will be treated for up to eight weeks; subjects in the ECT plus clozapine arm will receive up to 16 to 20 bilateral treatments. A naturalistic follow-up will compare subjects who receive continuation ECT with those who do not for an additional 6 months. The results of the study will guide clinicians faced with the problem of how to treat patients who have not been helped by standard antipsychotic medications and do not show an adequate response to clozapine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ATYPICALS
EFFECTIVENESS
OF
SWITCHING:
CONVENTIONALS
TO
Principal Investigator & Institution: Essock, Susan M.; Professor; Psychiatry; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: Effectiveness of Switching: Conventionals to Atypicals Over the past several years, new, so-called "atypical," antipsychotic medications have become available to treat schizophrenia. Olanzapine and risperidone are the two most widely prescribed antipsychotics; together they account for over 40 percent of all antipsychotic prescriptions. Given their wide usage, we know surprisingly little about the effectiveness of these newer medications in routine practice settings. Despite a decade of availability of atypical antipsychotics, about 40 percent of the antipsychotic prescriptions filled in the United States today are still for conventional agents. Given that the atypical antipsychotics may be more effective than the conventional ones and have less burdensome side effects, should people who are relatively stable on the older medications but who are still symptomatic or troubled by medication side effects be switched to an atypical medication? What are the benefits and risks associated with such medication switches? A total of 300 consenting patients with schizophrenia from a large, diverse public mental health system, who are living in the community and taking conventional antipsychotic medications but who are still troubled by symptoms or medication side effects, will be randomly assigned to stay on their current conventional antipsychotic medication (N =100) or to switch to olanzapine (N =100) or risperidone (N=100). This design specifically controls for process of changing medications because one group continues on current treatment. The proposed study, therefore, will assess what incremental risks and benefits can be expected from switching from a conventional to a first-line atypical antipsychotic agent. All medications will be open label, and treatment will be by the study participants' routine providers. Study participants will be asked to stay in their assigned treatment condition for 6 months, after which time medication decisions will be up to the patient and the prescribing psychiatrist. Study participants will be interviewed with quantitative instruments at baseline and at followup intervals for 1 year to determine clinical course and the types of services used. The study will determine the incremental risks and benefits of switching from a conventional to the most commonly prescribed atypical antipsychotics, and the relative risks and benefits of switching to olanzapine versus switching to risperidone. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECTS OF ANTIPSYCHOTIC DRUGS ON BRAIN AND BEHAVIOR Principal Investigator & Institution: Tarazi, Frank I.; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478
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Clozapine
Timing: Fiscal Year 2004; Project Start 01-MAR-2004; Project End 28-FEB-2006 Summary: (provided by applicant): This revised R03 proposal, submitted in response to a RFA (PA-00-114) encouraging research on developmental psychopharmacology, will study behavioral and molecular effects of antipsychotic drugs on cerebral dopamine (DA) and serotonin (5-HT) systems in developing vs. adult rats. DA and 5-HT receptors are critical sites of action of most antipsychotics, probably mediating, at least in part, clinically useful psychiatric benefits as well as adverse neurological effects. DA and 5HT receptors are also implicated in the neurobiology of several neuropsychiatric disorders including schizophrenia, which affects children and adolescents as well as adults. Childhood-onset schizophrenia, an uncommon form of the disease, produces severe developmental and life-long morbidity and disability. Nevertheless, the neuropathology and pathophysiology of juvenile schizophrenia are far less well studied than in the adult disorder largely owing to the lack of access to postmortem brain tissue from young patients. There is also a striking paucity of systematic investigation of the pharmacology of antipsychotic agents in pediatric psychotic patients or of parallel studies in maturing laboratory animals. This project will examine effects of antipsychotic drug administration on brain and behavior in young and mature animals, and will compare rats at three selected ages: juveniles, adolescents, and adults. Behavioral effects of representative typical (fluphenazine), atypical (clozapine) and newer (olanzapine) antipsychotic agents will be assessed in behavioral paradigms that are predictive of antipsychotic activity or neurological side effects at the three ages to compare responses developmentally, and to establish age-specific half-maximal effective doses (ED50) for each tested agent. The calculated ED50 doses will be used to examine long-term effects of the same agents on expression of representative DA (D2 and D4) and 5-HT (5-HT1A and 5-HT2A) receptors, that we have found to be altered by repeated administration of antipsychotic drugs in adult rats. Expression of genes (mRNA) for these receptors will then be quantified to further clarify age related molecular mechanisms underlying hypothesized changes in receptor levels. Expected findings should clarify potency and mechanisms of action of antipsychotic drugs in juvenile and adolescent vs. adult rats, and should evolve new principles for improved treatments for childhood-onset schizophrenia and other major pediatric psychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC SCREEN FOR ANTIPSYCHOTIC DRUG RESPONSE Principal Investigator & Institution: Pickar, David; Chief Science Officer; Gabriel Pharma, Llc 6500 Seven Locks Rd, Ste 220 Cabin John, Md 20818 Timing: Fiscal Year 2002; Project Start 25-SEP-2002; Project End 24-MAR-2003 Summary: (provided by applicant): Screening for antipsychotic drug response is a research priority to identify new drugs with long-term efficacy and minimal side effects for drug resistant individuals. Schizophrenia, a major public health problem afflicting approximately 1% of Americans, costs over $40 billion annually. The discipline of pharmacogogenomics utilizes genetic information to predict therapeutic drug response. New atypical antipsychotic drugs enhance therapeutics and outcomes of schizophrenia, but differences in individual patient response exist. Other treatment barriers include undesirable side effects impeding medication compliance, an important public health priority. Pharmacogenetics' promises to identify a priori response predictors guiding informed pharmacotherapeutics, enabling patient screening for tolerance and medication compliance. Key NIMH clinical studies of schizophrenic patients yielded unique longitudinal clinical information. We propose to combine this clinical information with contemporaneous patient DNA samples (Cl-DNA database) to test
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feasibility of a new genetic screen for pharmacogenetics of antipsychotic drug response. This Cl-DNA database has longitudinal behavioral ratings of antipsychotic treatment, placebo washout and treatment with the current gold standard stypical antipsychotic, clozapine (limited due to small but real risk of death). This study will provide preliminary validation for pharmacogenomic investigation by screening drug response to clozapine in relation to variants for the gene coding for catechol-O-methyl transferase, a known marker for dopamine. Phase II will modify, refine and expand the Cl-DNA database for full-scale validation with additional data from other antipsychotic treatments. This proposal will create a unique screen with broad and immediate research application including drug development and clinical practice and important preliminary information regarding gene variants in relation to clozapine treatment. The goal is a commercial individualized treatment screen to identify genetic of antipsychotic drug response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HIGH THROUGHPUT IN VIVO DRUG DISCOVERY-PHASE 1 Principal Investigator & Institution: Leahy, Emer; Psychogenics, Inc. 4 Skyline Dr Hawthorne, Ny 10532 Timing: Fiscal Year 2004; Project Start 06-FEB-2004; Project End 31-JAN-2006 Summary: (provided by applicant): The current trend in drug discovery is to develop drugs with a high level of selectivity for a single receptor. Although this is a real improvement for certain therapeutic areas, this may present a real issue for the development of novel treatments for neurological and psychiatric disorders. Indeed, neuropsychiatric disorders are complex, multigenic disorders that involve multiple neuronal circuits. Therefore, it is not surprising that many of the most efficacious drugs in psychiatry, such as clozapine, are considered "dirty drugs" (i.e. have multiple targets), that were discovered by screening in vivo, i.e. looking at their behavioral impact using various animal models, rather than making predictions of their function based on their receptor profile. Although attractive, this approach was neither efficient nor scalable until now. PsychoGenics is developing a proprietary, high throughput, in vivo platform known as Smart Cube TM, which is being used to screen and select drug candidates with potential to treat major psychiatric disorders including depression, psychosis, and anxiety disorders. This approach examines the behavioral response of a mouse to various challenges under normal and perturbed (e.g. drug treated) conditions. Using computer vision algorithms, behavior is captured and bioinformatic tools are applied to reveal the temporal behavioral profile or "signature" in response to treatment. PsychoGenics is building a database of signatures for known and approved compounds, which it can use to compare to the profiles of NCEs. PsychoGenics aims to demonstrate that this behavior-driven approach to drug discovery can yield clinical candidates selected from high quality libraries designed with compounds that have drug-like chemical and structural properties. The goal is to screen 120 compounds in Abstract compounds in Smart CubeTM in Phase I to find "hits" which, with the aid of novel computational chemistry algorithms, undergo behavior-driven (i.e. Smart Cube TM) lead optimization in Phase II. Using this behavior-driven approach, PsychoGenics has already identified two compounds for the treatment of ADD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Clozapine
Project Title: HIPPOCAMPAL RECURRENT INHIBITION AND N-ACETYL ASPARTYL GLUTAMATE Principal Investigator & Institution: Greene, Robert W.; Research Health Scientist; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: The behavioral abnormalities associated with schizophrenia are likely to involve pathological function of the limbic system. Functional and structural neuroimaging studies in the limbic region of schizophrenic brains have provided compelling evidence in support of this assertion. Ingestion of phencyclidine (PCP) or systemic injection of ketamine produces a syndrome that mimics the symptoms of acute schizophrenic psychosis. These pharmacological observations raise the possibility that a decrease of normal NMDA receptor (NMDAR) function can elicit psychotic symptoms similar to those suffered by schizophrenic patients. Recently, Mohn, et al (1999) describe a transgenic mouse model of schizophrenia, a partial knock out of the NR1 subunit of the NMDAR (5% expression), with behavioral deficits such as increased motor activity, stereotype and deficits in social and sexual interactions. This partial "knock down" of NR1 expression is rescued by haloperidol and clozapine. However, the mechanism(s) of action of decreased NMDA- receptor function that result in the observed deficits in information processing integral to the syndrome of psychosis have been little investigated. Our findings have lead to the following hypotheses: the psychotogenic action of NMDA antagonists may be attributed to selective blockade of the NMDAdependent drive of inhibitory circuits (Grunze). The decreased excitatory drive of interneurons disrupts network function so that abnormal information processing consistent with cognitive deficits associated with psychosis, ensues. In particular, [Specific Aim I] it is hypothesized that the EPSP of CAL interneurons has a significant NMDA-dependent component that is larger than the NMDA component of the feedforward Schaffer collateral input to CA1 pyramidal neurons, and/or EPSC is more sensitive to NMDA antagonists. Accordingly, NMDAR antagonists have a selectively greater effect on the EPSP's of interneurons (in the CA1 region of the hippocampus the EPSP's and EPSC's that we will test, original from either feed-forward-CA3-or feedbackward-CA1-input or from both) compared EPSC's of projection cells. Pathological NMDAR hypofunction could result from multiple mechanisms, including but not limited to 1) factors affecting NMDAR- binding to glutamate; 2) factors affecting NMDAR-associated channel activity; 3) factors affecting downstream mechanisms associated with NMDAR activation (for example those linked to the NMDA-associated PSD-complex). We plan to examine the first of these mechanisms. We [Specific Aim 4a] hypothesize that an endogenous compound, N-acetyl- aspartylglutamate (NAAG), has NMDAR antagonist activity and can selectively block the NMDAR-component of EPSC's on interneurons in the CA1 region of the hippocampus. We further [Specific Aim 4b] hypothesize that the turnover of NAAG is sufficiently high that inhibition of NAAG's catabolic enzyme will block the NMDAR-component of EPSC's and exposure to a soluble form of these catabolic enzyme [Specific Aim 4c] will enhance the NMDARcomponent by decreasing endogenous NAAG. Our preliminary data demonstrates that inhibition of GCP II increases endogenous NAAG sufficient to significantly reduces NMDAR synaptic activation in CA1 pyramidal cells and interneurons in the hippocampal slice, probably as a result of the high rate of turnover of NAAG in vitro. The effects on NMDAR activity of a knockout of the GCP III gene are hard to predict in part because: 1) the mechanisms responsible for the rate of production of the NAAG mediating this response are unknown; 2) NMDAR activity in response to a chronic increase in NAAG is unknown. Nevertheless, a state of chronic NMDAR hypofunction is a distinct possibility that, in consideration of its association with psychosis ought to be
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examined as a first step towards the phenotypic characterization of these animals. We [Specific Aim 5] hypothesize that NMDAR function will be reduced in the CA1 region of the hippocampi of GCP II knockout mice compared to wild type mice. If true, thee ko mice may serve in behavioral studies of NMDAR hypofunction in the development and maintenance of place (or other specific associations) hippocampal cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INSULIN SCHIZOPHRENIA
SENSITIVITY/SECRETION/
GLUCOSE
IN
Principal Investigator & Institution: Henderson, David C.; Executive Secretary (Dfo); Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LABEL D4 DOPAMINE RECEPTOR IN PREFRONTAL CORTEX & HIPPOCAMPUS OF MONKEY BRAIN Principal Investigator & Institution: La Garza, Richard De.; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: At least five subtypes of DA receptors, D1-D5, have been identified While the receptor distribution and some functional sequelae of D1, D2, and D3 receptors are known, information regarding the physiological or pathological role of D4 receptors is scant Mounting evidence indicates potential involvement of these receptors in "noveltyseeking" behaviors, psychostimulant effects, attention deficit hyperactivity disorder, Parkinson's disease and depression To clarify the role of this receptor subtype in primates, we developed a map of D4 receptor distribution in rhesus monkey brain and compared it with reported D4 mRNA sites Because of its reported selectivity for the D4 receptor, the D4 receptor probe [3H]U-101,958 (1-benzyl-4-[N-(3-isopropoxy-2pyridinyl)-N-methyl]-aminopiperidine) was custom-synthesized for the current study Autoradiography was conducted in triplicate in three separate animals (N=3) with adjacent coronal sections (20 um) to measure total ([3 H]U-101, 958, 1 nM) and nonspecific binding Specific binding was measured in the presence of clozapine or L745,870 Data was generated from eight anterior-to-posterior coronal planes and 75 distinct subnuclei and cortical areas A region-specific distribution of [3H]U-101,958 binding was detected The highest densities (>20 pmol/g tissue equivalents) of [3H]U101,958 binding sites (clozapine baseline) were found in areas 12, 14 and 9 of the prefrontal cortex High levels of [3H]U-101,958 binding sites (>17 pmol/g) were also observed in other prefrontal cortex regions, inferior temporal gyrus, subiculum, fusiform gyrus, uncus, paraventricular nucleus of thalamus, median eminence of the hypothalamus, medial longitudinal fasciculus, and hippocampus [3H]U-101,958 binding sites in caudate/putamen were clearly below levels observed in the prefrontal cortex and other cortical areas Lower levels (<12 pmol/g) of [3H]U-101,958 binding sites were found in specific nuclei of the thalamus, and the midbrain, pons, cerebellum and medulla The heterogeneity of [3H]U-101,958 binding within subnuclei of the thalamus, hippocampus, and cortex appear to reflect discreet localization of D4 dopamine receptors The following conclusions can be drawn from this study 1 The brain distribution of the D4 receptor, measured with [3H]U101,958, corresponds to the distribution reported for species; 2 The distribution is similar to, but not identical with
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Clozapine
D4 mRNA distribution; 3 [3H]U-101,958 binding in non-human primate brain appears to reflect D4 receptors, and therefore emerges as a suitable probe for investigation of D4 receptors in the brain; 4 D4 dopamine receptor density gradients do not correspond to dopamine levels or dopamine transporter gradients in brain, suggesting that dopamine level regulation at the D4 receptor may differ than for the D1 and D2 receptor The significance of a dense localization of D4 receptors in prefrontal cortex and hippocampus, and broad distributio n in other brain areas, allows for speculation on how these receptors may relate to specific neuropsychiatric disorders or effects produced by psychostimulants The autoradiographic map of D4 receptor distribution reported herein provides a detailed substrate for further investigation of the D4 receptor in nonhuman primates Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF ABNORMAL EXCRETION IN SCHIZOPHRENIA Principal Investigator & Institution: Goldman, Morris B.; Director; Psychiatry; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-DEC-1998; Project End 30-NOV-2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MODELING ANTIPSYCHOTIC-INDUCED WEIGHT GAIN IN RATS Principal Investigator & Institution: Fernstrom, John D.; Associate Prof of Neuroendocrinology; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 24-DEC-2003; Project End 30-NOV-2005 Summary: (provided by applicant): This revised Exploratory/Developmental grant application seeks funding through an NIMH R21mechanism (PA- 00-073) to conduct exploratory experiments to determine if the chronic delivery to rat, of antipsychotic drugs by constant infusion, to achieve sustained, therapeutic plasma concentrations (for humans) will (a) cause body weight gain (primary aim), and/or (b) modify neuropeptide neurons in hypothalamic appetite control circuitry suggestive of appetite stimulation (secondary aim). Antipsychotic drugs cause significant weight gain in schizophrenic humans, but in almost all cases examined to date, not in rats. This surprising species dichotomy may be due to the manner used to deliver antipsychotics to rats, chronically (single, daily injections) and the more rapid metabolic rate in rats than in humans, such that rats are exposed only a few hours each day to therapeutic plasma drug levels. In this project, adult male and female rats will be implanted with Osmette minipumps to deliver a constant infusion of each of several antipsychotic drugs (haloperidol, clozapine, olanzapine, risperidone, sulpiride, ziprasidone) for 28 days. Food intake, body weight, and blood and brain drug levels will be monitored. Drug dose will be adjusted to set plasma concentrations in the clinically effective range to optimize the chance of observing weight gain. This paradigm will then be used to explore for changes, using in situ mRNA analysis, in the activity of neuropeptide neurons embedded in hypothalamic appetite control circuitry (arcuate neuropeptide-Y and proopiomelanocortin/alphaMSH, paraventricular corticotropin releasing hormone, and lateral hypothalamic orexin). The successful identification of an experimental paradigm in rats that cause, antipsychotics to induce weight gain would allow its application to the study of the underlying mechanisms causing this unwanted side-
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effect, and could then be applied to the development of adjunct or new treatments that would minimize weight gain, while maintaining antipsychotic efficacy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MONOAMINERGIC MODULATION OF PREFRONTAL CORTEX Principal Investigator & Institution: Surmeier, D James.; Professor and Chairman; Physiology; Northwestern University Office of Sponsored Research Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from the Investigator's Abstract) Disordered dopamine signaling has long been known to be a critical factor in the etiology of schizophrenia. This view is based upon several key observations. Foremost among them is the ability of neuroleptics that antagonize DA receptors to alleviate the positive symptoms of schizophrenia. However, in recent years, the exclusive involvement of DA in schizophrenia has been questioned. In part, the clinical effectiveness of atypical neuroleptics like clozapine has motivated this new line of thought. The ability of atypical neuroleptics to antagonize both DA receptors and serotonin receptors is generally thought to be critical to their efficacy. Although there is evidence for altercations in neuronal function at several levels of the neuroaxis in schizophrenia, most experimental evidence points to the prefrontal cortex. It is the central hypothesis of this proposal that the cognitive deficits observed in schizophrenics and their close relatives are a direct consequence of altered DA and 5-HT signaling within the prefrontal cortex. This disruption may have a common cellular locus-that is, interactions between these two monoamines at the single cell level may be responsible for the pathophysiology in schizophrenia. However, at present there are fundamental gaps in our understanding of how DA and 5-HT regulate neural activity in the PFC. To begin to fill these gaps, we propose to apply a combination of electrophysiological, anatomical, pharmacological and molecular techniques to achieve four specific aims. Our initial aim is to use single cell RT-PCR techniques and retrograde labeling to identify the DA and 5HT receptors expressed by PFC pyramidal neurons participating in circuits thought to be affected in schizophrenia. Next, the impact of D1/D5 DA receptors on voltagedependent Na and Ca channels will be determined in retrogradely identified PFC pyramidal neurons using a combination of RT-PCT, voltage-clamp and fluorometry. In parallel, the modulatory effects of 5-HT-2 receptors on these same channel populations will be determined using a similar combination of techniques. Lastly, the nature of the interaction between these two schizophrenia linked signaling pathways in the modulation of Na and Ca channels will be determined. It is our thesis that these two pathways synergistically interact in ways critical to the disease process. Achieving these specific aims will provide the molecular and cellular framework necessary to begin building an accurate, integrative model of PFC function and dysfunction in schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOTOR EFFECTS OF ATYPICAL ANTIPSYCHOTICS Principal Investigator & Institution: Salamone, John D.; Professor; Psychology; University of Connecticut Storrs Unit 1133 Storrs-Mansfield, Ct 06269 Timing: Fiscal Year 2002; Project Start 15-FEB-2001; Project End 31-JAN-2004 Summary: (Verbatim from the Applicant's Abstract) Clozapine is an antipsychotic drug with a unique clinical, biochemical and behavioral profile. However, clozapine also produces agranulocytosis, which has led to a vigorous search for other "atypical"
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antipsychotics with properties that resemble clozapine. Previous research has indicated that research on tremulous jaw movements in rats may be useful for identifying drugs with motor properties similar to clozapine. Unlike typical antipsychotics, clozapine generally fails to induce tremulous jaw movements in repeated administration procedures. In addition, clozapine acts to suppress the jaw movements induce by the anticholinesterase tacrine. The suppression of tacrine-induced jaw movements by clozapine occurs at a relatively low dose; clozapine suppressed tacrine-induced jaw movements with an ED50 lower than that observed for suppression of lever pressing. Using acute injection procedures, olanzapine and risperidone also were relatively potent at suppressing jaw movements, while haloperidol was ineffective. In studies involving repeated 14 day injection procedures, the rank order of the ratios of the ED50s for suppression of tacrine-induced jaw movements and lever injection procedures, the rank order of the ratios of the ED50s for suppression of tacrine-induced jaw movements and lever pressing was (from lowest to highest) as follows: clozapine < olanzapine < thioridazine < haloperidol. This pattern is consistent with human clinical data on the production of extrapyramidal side effects. Thus, it is reasonable to suggest that behavioral studies involving tremulous jaw movements could be useful for characterizing the pharmacological characteristics that underlie the suppression of jaw movement activity by atypical antipsychotics are uncertain. Although there is considerable evidence indicating that the anticholinergic properties of clozapine may contribute to the motor effects of this drug, less is known about the possible contribution of serotonergic antagonist properties. In view of the studies indicating that 5-HT systems may be involved in mediating some of the motor effects of atypical antipsychotics, the proposed studies will investigate the involvement of 5-HT mechanisms in the suppression of jaw movement activity. The first group of studies will assess the effects of additional antipsychotic drugs that have 5-HT antagonist properties. Tests will be conducted after both acute and repeated dosing procedures. The second group of proposed experiments is designed to investigate the effects of 5-HT2a/2c antagonism on tacrine- and haloperidol-induced jaw movements. The third group of proposed studies will employ intracranial drug injections to determine that brain loci at which 5-HT2a/2c antagonists and atypical antipsychotics suppress jaw movements activity. Taken together, the results of these experiments will help to identify the pharmacological characteristics and brain circuits that underlie the motor effects of clozapine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUROPATHOLOGY SCHIZOPHRENIA
OF
DOPAMINE
SYSTEMS
IN
Principal Investigator & Institution: Roberts, Rosalinda C.; Professor; Psychiatry; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Schizophrenia is a devastating illness, with unknown pathophysiology, that affects 1% of the world's population. The experiments in the following revised proposal will focus on the basal ganglia and dopamine (DA) pathology in schizophrenia (SA1) and relate these changes to those occurring in rats treated with antipsychotic drugs (APDs) (SA2). Our preliminary data shows abnormalities in morphology of DAergic neurons in the substantia nigra (SN) and in the number of TH+ striatal synapses in electron microscopic (EM) studies of postmortem tissue from subjects with schizophrenia (SZ), similar structural changes and a decrease in number of TH+ cells in rats treated with APD. SA1 tests the hypothesis that the DA
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system is perturbed in the basal ganglia of SZ, using tissue from normal controls, SZ treated with typical or atypical APDs or off-drug. SA2 tests the hypothesis that anatomical changes observed in SN and ventral tegmental area (VTA) of SZ are the results, in part, of APDs, and will determine the contributing physiological mechanisms. In both aims, we will determine if the morphological alterations seen will show regional variations that are consistent with the differential effects of typical and atypical APDs on the activity of midbrain DA neurons. In this revision, we have modified the EM analysis of the SN and added 3 parallel experiments in both the human tissue and rats (treated with haloperidol or clozapine or controls). In SA1a the synaptic organization of DA labeled profiles will be analyzed in the human striatum at the EM level. In SA1b & SA2a, the number and size of Nissl stained, and TH+ cells double labeled with the DA transporter (DAT), or a selective marker of DA cells, SK3, will be determined using stereological methods in the SN/VTA. In SA1c & SA2b at the EM level, the integrity of subcellular organelles and the synaptic organization to the TH+ neurons (also labeled with DAT or SK3) will be studied. Using in situ hybridization SA1d & SA2e will determine if TH synthesis is affected at the level of transcription. SA1c & SA2d will determine if cytoskeletal proteins are upregulated. SA1f & SA2e will determine if the loss of TH in neurons is due to changes at the translational level by using Western blot analysis. SA2f will study the time course of the anatomical changes observed during APD treatment and relate these changes to the development of depolarization (DP) block. SA2g tests the hypothesis that morphological alterations in SN/VTA neurons will not occur in rats treated with APD if DP block is prevented (with a unilateral striatal lesion). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUROSTEROIDS AND SCHIZOPHRENIA Principal Investigator & Institution: Marx, Christine E.; Psychiatry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2006 Summary: (Adapted from applicant's abstract) My career goal is to become an academic psychiatrist and independent investigator in the areas of schizophrenia focusing on its neurobiology and therapeutics, applying molecular mechanism-based research to prospective clinical studies. Specifically, I propose to investigate the importance of neurosteroids in schizophrenia. Neurosteroids are differentially expressed in males and females, modulate GABAA and NMDA receptors, regulate neuronal cytoarchitecture, demonstrate neuroprotective effects, play a role in neurodevelopment, and possess memory-enhancing effects. Neurosteroids are therefore logical candidates of investigation to elucidate schizophrenia pathophysiology, since they are potential modulators of schizophrenia gender differences, GABAergic and glutamatergic dysregulation, neurodevelopmental insults associated with increased schizophrenia risk, cytoarchitectural abnormalities in postmortem specimens from patients with schizophrenia, and cognitive disturbances in the disorder. The laboratory has demonstrated that neurosteroids protect embryonic cerebral cortical neurons against anoxia, a neurodevelopmental insult associated with increased schizophrenia risk. We have also demonstrated that acute olanzapine and clozapine administration alters cerebral cortical neurosteroids in rodents. The investigators hypothesize that neurosteroids are important modulators of schizophrenia pathophysiology (including the pronounced gender differences of the disorder) and antipsychotic drug action. We also propose that compounds affecting neurosteroid expression or neurosteroids themselves may be developed as novel therapeutic agents in the treatment of
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schizophrenia. To test this hypothesis, three investigational strategies are proposed: 1.) A preclinical study examining the effects of antipsychotics on cerebral cortical and serum neurosteroid levels in rodents, 2.) A postmortem study determining neurosteroid levels in parietal cortex and posterior cingulate specimens provided by the Stanley Foundation from patients with schizophrenia compared to control subjects, and 3.) A clinical study examining neurosteroid levels in subjects with schizophrenia from two UNC clinical trials (Dr. Lieberman, PI) to determine if serum or CSF neurosteroid alterations are correlated with antipsychotic efficacy, neurocognitive changes, and/or structural changes on MRI. Results from these preliminary investigations will inform the design of future prospective clinical studies to confirm initial findings and target neurosteroids as therapeutic agents in schizophrenia. To achieve these goals, the candidate will receive training through formal coursework in neuropharmacology, clinical trials design, drug development, and biostatistics. She will also learn highly sensitive and specific gas chromatography mass spectrometry (GC/MS) and other stateof-the-art neurosteroid detection methods. The mentorship of Drs. Jeffrey Lieberman and Leslie Morrow will be critical to the overarching goal of this proposal, the successful translation of exciting preclinical neurosteroid findings to prospective clinical studies examining neurosteroids in schizophrenia pathophysiology and therapeutics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUROTOXICITY OF NMDA RECEPTOR ANTAGONISTS Principal Investigator & Institution: Sharp, Frank R.; Professor; Neurology; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2002; Project Start 12-SEP-2002; Project End 31-JUL-2006 Summary: (Adapted from applicant?s abstract): The non-competitive NMDA receptor antagonists, including phencyclidine (PCP, angel dust), ketamine (Special K), and dizocilpine (MK-801), have been used as anesthetics, protect against experimental stroke, are increasing as drugs of abuse, and continue to be developed for treatment of various neurological diseases. However, these drugs produce psychosis in normal people and exacerbate psychosis in patients with schizophrenia. The drugs also injure rodent limbic cortex, killing some neurons and injuring others that have cytoplasmic vacuoles and express HSP7O and HO-i heat shock proteins. Since anti-psychotic drugs prevent the injury, the circuits mediating the injury in rodents may be similar to the circuits that mediate psychosis in humans. Our preliminary data demonstrate that NMDA antagonists injure limbic, retrosplenial cortex of rats by blocking NMDA receptors on GABA neurons in anterior thalamus, leading to thalamic excitotoxic injury of retrosplenial cortical pyramidal neurons via AMPA and other non-NMDA receptors. This proposal will continue to define the mechanisms of this neurotoxic injury. The first aim will determine whether injections of Dl, D2 and D4 dopamine receptor antagonists into retrosplenial cortex and anterior thalamus prevent the induction of HSP7O and other markers of injury produced by systemic PCP and MK-801. The second aim will determine whether blockade of NMDA receptors in substantia nigra (SN) and the adjacent ventral tegmental area (VTA) by PCP and ketamine produce and/or aggravate injury to retrosplenial cortex. The third aim will determine whether specific AMPA receptor antagonists, specific kainate receptor antagonists, and specific metabotropic glutamate receptor agents prevent injury to limbic cortex produced by systemic PCP and ketamine. The fourth aim will determine whether activation of substantia nigral ventral tegmental area and limbic cortex GABA receptors with GABA agonists prevent the injury produced by systemic PCP and MK-801. The fifth aim will determine whether visual sensory input contributes to the non-NMDA glutamate-mediated limbic cortical
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injury produced by NMDA antagonists. The last aim will determine whether NMDA receptor antagonists produce limbic cortical injury in cats and whether typical and atypical antipsychotic drugs, like haloperidol and clozapine, block injury. These studies will define the circuits and receptors that mediate the cortical injury produced by NMDA receptor antagonists in experimental animals. These studies will also contribute to understanding the circuits and transmitters that mediate psychosis due to psychomimetic drugs like PCP and Special K in people, and they will also contribute to understanding the circuits and receptors that mediate acute psychosis in patients with schizophrenia and other psychotic disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW TREATMENT AND MECHANISMS IN SCHIZOPHRENIA Principal Investigator & Institution: Goff, Donald C.; Director; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 30-JUN-2006 Summary: Candidate: Dr. Goff completed postgraduate training in 1985 and started the Schizophrenia Program of the Massachusetts General Hospital (MGH) with an NIMH "Faculty Scholar Award in Schizophrenia" in 1988. He has focused on augmentation trials for negative symptoms, and over the past five years has conducted a series of studies examining glutamatergic agents and glutamatergic activity of atypical antipsychotics. Dr. Goff has also established a group of ten young investigators working collaboratively to translate recent advances in the neurosciences to the study and treatment of schizophrenia. Environment: Dr. Goo's group has ample space and access to schizophrenia subjects at the Freedom Trail Clinic of the Lindemann Mental Health Center and to a collaborative network of mental health clinics that he has established for recruitment of research subjects in the greater Boston area. He works closely with the MGH Neuroimaging group, the MGH Biostatistics Center, the MGH Amino Acid Laboratory and collaborates with the Transcranial Magnetic Stimulation Research Group at the Beth Israel Hospital and the Brain Imaging Center at McLean Hospital. Dr. Goff is principal investigator for the clinical trials section of the NIMH-funded Neurosciences Center for the Study of Glutamate in Schizophrenia under the leadership of Dr. Joseph Coyle. Dr. Goff has full institutional commitment from Dr. Jerrold Rosenbaum (interim Chief of Psychiatry, MGH) ensuring protected time and resources to accomplish research and mentoring goals. Research: Dr. Goo's research plan involves continuation of his study of glutamatergic agents in schizophrenia and of the role of glutamatergic activity in the therapeutic action of atypical antipsychotics. He will devote the period of the career development award to completing on-going RO1-funded controlled trials of NMDA receptor agonists, initiating trials of new glutamatergic agents (D-serine and an Ampakine) and developing expertise with new research tools and developing collaborations to apply to his research, including neuroimaging, spectroscopy, transcranial magnetic stimulation and genetics. He will also continue his mentoring activities as he guides the career development of ten junior faculty researchers in his group as well as residents and research fellows working on research projects under his direction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NICOTINIC AGONIST IN SCHIZOPHRENIA Principal Investigator & Institution: Freedman, Robert; Medical Director; Psychiatry; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508
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Timing: Fiscal Year 2002; Project Start 05-FEB-2001; Project End 31-JAN-2005 Summary: (Adapted from applicant's abstract): Schizophrenia likely involves multiple pathophysiological elements, most of which are not affected by current neuroleptic treatments. The goal of this study is to investigate effects of a new drug therapy directed to one of these elements, a recently identified, genetically transmitted deficit in the a7 nicotinic acetylcholine receptor locus. The cx7 nicotinic receptor is a good candidate for the development of new therapeutic strategies for several reasons: (1) this receptor is the only currently identified neurotransmitter receptor for which there is independent biological and genetic evidence of involvement in the pathophysiology of schizophrenia; and (2) the pathophysiological dysfunction is closely associated with disordered attentional function, which has been found to be related to poor psychosocial outcome. The proposed experiments will identify the neurophysiological, neuropsychological, and clinical effects of a7 receptor activation in both schizophrenics and their relatives. Scientific questions about the role of the receptor in the pathophysiology of schizophrenia, as well as the issue of its utility as a therapeutic target, cannot be adequately addressed without the development of strategies for selective activation of the a7 receptor in human subjects. Therefore, included in the experimental plan are Phase 1, proof of principle, tests for a new a7 nicotinic agonist, 3-(2,4 dimethoxybenzylidene) anabaseine (DMXB-A). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COGNITION
NICOTINIC-ANTIPSYCHOTIC
DRUG
INTERACTIONS
AND
Principal Investigator & Institution: Levin, Edward D.; Associate Professor; Psychiatry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 12-DEC-2001; Project End 30-NOV-2006 Summary: Nicotine is self-administered via cigarette smoking by the great majority of patients with schizophrenia. Nicotine has direct effects on cognitive function and interacts with antipsychotic drugs to substantially influence their actions on cognitive function. The cognitive effects of nicotine may present a novel opportunity for improving the treatment of cognitive dysfunction associated with schizophrenia and cognitive dysfunction induced by antipsychotic drugs. Classical neuroleptics such as haloperidol and "atypical" antipsychotics such a clozapine and risperidone have substantially different mechanisms of action and likely interact with nicotine in quite different ways. The proposed project will determine the functional mechanisms by which nicotinic systems interact with antipsychotic drugs to affect cognitive function. Both classical and atypical antipsychotic drugs have been found to impair memory function. Haloperidol-induced working memory deficits have been found in our earlier studies of schizophrenic patients and laboratory rats to be reversed by acute doses of nicotine. Recently, we have found that the working memory impairment caused in rats by clozapine administration can be reversed by nicotine. These effects will be used as a forum in which to determine the critical neural mechanisms by which nicotine interacts with antipsychotic drugs in the control of memory function. We hypothesize that nicotinic receptor systems in the hippocampus are a key mechanism by which nicotine alleviates schizophrenia associated attentional impairment and antipsychotic druginduced memory impairment. Nicotinic innervation of the hippocampus has been found in our previous studies to be critical for nicotine effects on memory. Importantly, we have also shown that hippocampal DA innervation is also important for memory function. The proposed project will specify the mechanisms underlying nicotinic interactions with antipsychotic effects on memory function, including involvement of
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nicotinic receptor subtypes and their anatomic loci in hippocampus important for memory function. Dose response local infusion studies with selective nicotinic antagonist subtypes will be used to determine the relationship of nicotinic systems for memory performance in the benchmark radial-arm maze task as well as an operant attention task. These basic studies will help elucidate important therapeutic issues concerning the impact of nicotinic co- treatment with classic and atypical antipsychotic drugs to improve memory and attentional function. These studies will provide information concerning neural systems likely to underlie nicotinic actions we have seen on a systemic level and facilitate the development of new drug therapies for cognitive dysfunction in schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NMDA RECEPTOR/DOPAMINE RECEPTOR INTERACTION IN HIPPOCAMPUS Principal Investigator & Institution: Lisman, John E.; Professor; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: It is thought that schizophrenia involves dopamine hyperfunction and/or NMDAR hypofunction and that the hippocampus is a key site of aberrant information processing. Our recent work on the Schaffer collateral (sc) and perforant path (pp) inputs to CA1 hippocampal pyramidal cells shows that NMDAR-mediated synaptic transmission is decreased by dopamine. This is the first indication of a site in the hippocampus for dopamine/NMDAR interaction. The goal of this proposal is to investigate presynaptic and postsynaptic sites where the NMDAR is modulated by dopamine. Similar methods will be used to study how the NMDAR is affected by an endogenous antagonist that may be involved in schizophrenia. 1. Specific Aim 1 investigates the dopaminergic modulation of the sc input. Preliminary data suggest that this a clear-cut case of a postsynaptic action of dopamine: paired-pulse facilitation is not changed and only the NMDAR component of the fEPSP is inhibited. This makes the sc input a good system in which to study the postsynaptic dopaminergic modulation at the subcellular level. Ca2+ entry via NMDAR channels into individual synaptic events. If the control is postsynaptic, dopamine should decrease the magnitude of Ca2+ entry when successful transmission occurs, but not affect the probability of transmission. Pharmacological studies will be done to determine which types of dopamine receptors are involved. The literature suggests that dopamine receptors might be present on subsets of spines. Thus, an interesting question in our studies will be whether only a subset of spines is effected by dopamine or whether they are uniformly affected. 2. Specific Aim 2 investigates the action of dopamine on the pp synapses located in distal dendrites. D1 and D2 receptors are especially concentrated in the vicinity of the pp input. Dopamine strongly inhibits the pp fEPSP and increased paired-pulse facilitation, suggesting that the modulation is at least partially presynaptic. However, the NMDAR decrease was much stronger than the AMPA, so a postsynaptic modulation may also occur. Either D1 or D2 antagonists inhibited dopamine action, but only clozapine could block it completely. Moreover, the pp input has much larger NMDAR component of normal transmission than the sc. All this makes dopaminergic modulation of the pp of special relevance to understanding the information processing deficits in schizophrenia. The very distal position of the pp input, however, makes it virtually inaccessible for traditional biophysical studies. By separately studying the probability and size of individual NMDAR-mediated spine Ca2+ signals, we will be able to separately study the presynaptic and postsynaptic components of dopaminergic modulation. We can
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then study which dopamine receptors are responsible for each action. 3. Specific Aim 3 analyzes N-acetylaspartyl-glutamate (NAAG) modulation of the PP and the sc inputs. Initial studies w2ill use extracellular field recording methods. NAAG is known to act via the inhibition of NMDAR and/or activation of mGluR3 receptors. There are reasons to believe that NAAG might differently affect the sc and pp inputs. First, the NMDAR component is larger in the pp that in the sc. Second, the literature suggests that mGlur3 receptors are presynaptic on the pp but not the sc fibers. We will compare the magnitude of the effect of NAAG at sc and pp synapses and use electrophysiological and optical methods to determine whether the effects are presynaptic, postsynaptic or both. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NORMAL PSYCHOTIC COCAINE BEHAVIOR--NATURAL BASIS FOR CLOZAPINE Principal Investigator & Institution: Broderick, Patricia A.; City College of New York 138Th St and Convent Ave New York, Ny 10031 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NOVEL ASSAY FOR RECEPTOR PROFILING OF ANTIPSYCHOTICS Principal Investigator & Institution: Lu, Jianming; Atto Bioscience 15010 Broschart Rd Rockville, Md 208506365 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2004 Summary: (provided by applicant): Schizophrenia affects almost 1% of the world population. While therapeutic benefit has been established with current antipsychotics to treat positive syndromes of schizophrenia, efficacy has not been established in treatment of negative syndromes and cognitive dysfunction of the illness. All current antipsychotic drugs act promiscuously on a family of biogenic amine G protein-coupled receptors (GPCRs). The relationships remain obscure between the psychotic syndromes and specific therapeutic targets, which forms a major obstacle in developing novel antipsychotics. In order to better evaluate the actions of current antipsychotics at receptor level, we propose to establish a multiplexed high throughput functional assay platform applying a novel realtime cAMP assay in combination with a well-establsihed calcium assay. In contrast to the traditional competitive immunoassay of cAMP, the novel assay uses a cyclic nucleotide-gated channel to monitor free [cAMP] in living cells, providing kinetic measurement of activity of both Gs- and Gi-coupled receptors with excellent signal-to-noise ratio and sensitivity. The assay can be scaled up applying FLIPR or potentially the cell-array platform. In this feasibility study, we will apply the novel cAMP assay to measure intrinsic efficacy of several partial agonists against the dopamine D2 receptor, and to determine relative potency and efficacy of the most common antipsychotic drugs, olanzapine, quetiapine, clozapine, and aripiprazole against several potential GPCR targets. The long-term goal of the project is to characterize currently important antipsychotics against all biogenic amine receptors and other potential receptor targets to provide a solid receptor profile of antipsychotics. The link between receptor activity profile and clinical pharmacology of antipsychotics established through this project should facilitate future drug development programs by enabling early prediction of safe and effective new antipsychotics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OCCUPANCY OF EXTRASTRIATAL D2 RECEPTORS BY CLOZAPINE Principal Investigator & Institution: Kessler, Robert M.; Professor of Radiology; Radiology & Radiological Scis; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-JAN-2000; Project End 31-DEC-2003 Summary: (Verbatim from the Applicant's Abstract) The antipsychotic effects of typical neuroleptics are mediated by blockade of dopamine D2 type receptors. It has been proposed that the antipsychotic effects of these drugs are mediated by blockade of cortical and limbic dopamine D2 receptors while extrapyramidal site effects are mediated by dorsolateral striatal D2 receptor blockade. To date, most PET and SPECT studies of antipsychotic drug blockade of D2 receptors have examined the striatum. There are a number of studies which suggest that the atypical profile of clozapine is mediated at least in part by selective effects on cortical and limbic dopaminergic neurotransmission. Our group has developed [18F] N-allyl-5-fluoropropylepidepride as a PET radioligand for visualization of extrastriatal D2 receptors in man. Our Phase I and early Phase II IND studies demonstrate that this ligand allows excellent visualization and quantitation of extrastriatal D2 receptors in man. Wed propose to use [18F] N-allyl5-fluoropropylepidepride PET studies to evaluate 15 schizophrenic subjects off medication and following 6 weeks of haloperidol monotherapy, as well as 15 schizophrenic subjects off medication and following 8 weeks of clozapine monotherapy. The data from these studies will allow evaluation as to whether clozapine, s compared to haloperidol (a typical neuroleptic), selectively occupies extrastriatal dopamine D2 receptors, and whether regional occupancy of D2 receptors can be related to antipsychotic effects. Secondary goals include examining if psychopathological symptom complexes, i.e., positive, negative, and disorganization, as well as cognitive abnormalities in schizophrenia are related to regional levels of D2 receptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OPTIMIZING TREATMENT FOR SCHIZOPHRENIC SMOKERS Principal Investigator & Institution: George, Tony P.; Associate Professor of Psychiatry; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-MAY-2005 Summary: (provided by applicant) Schizophrenic patients have high co-morbid rates of cigarette smoking (up to 90 percent), and are typically nicotine dependent smokers who have great difficulty quitting smoking. This may relate to improvement of extrapyramidal side effects, cognitive dysfunction and information processing deficits by cigarette smoking, as well as shared genetic factors between the two disorders. Over the past three years, our research program has studied the effects of cigarette smoking on clinical and cognitive function in schizophrenic smokers, and the development of pharmacological and behavioral treatment approaches. These studies have suggested that: 1) the atypical antipsychotic clozapine may reduce smoking consumption in schizophrenic outpatients; 2) atypical antipsychotic drugs are superior to typical antipsychotic drugs in combination with the nicotine patch for smoking cessation in treatment-motivated schizophrenic smokers; 3) cigarette smoking may enhance some aspects of cognitive function in schizophrenic patients, and; 4) the anti-smoking agent bupropion (Zyban) appears to be safe and effective for treatment of nicotine dependence in schizophrenia. These findings could have important health benefits for schizophrenic patients, as many often die prematurely from smoking-related medical illness. Furthermore, our findings also suggest that nicotinic receptor mechanisms may be
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important in the biology of schizophrenia. In this randomized, double-blind trial, we propose to study optimal strategies for smoking cessation in n=100 nicotine dependent outpatient schizophrenic smokers. We will compare bupropion (n=50) to placebo (n=50), in combination with nicotine patch and a specialized group therapy program, for smoking cessation in these patients. The effects of antipsychotic medication class (atypical versus typical antipsychotic) on treatment responses will also be evaluated. Our predictions are that: 1) Bupropion will be superior to placebo for smoking cessation in schizophrenia; 2) atypical versus typical antipsychotic treatment status will enhance smoking cessation outcomes in these patients. The results of this study could provide valuable information on effective medication treatments for cigarette smoking in schizophrenic patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PALLIDAL GABA AND ATYPICALITY OF ANTIPSYCHOTIC DRUGS Principal Investigator & Institution: See, Ronald E.; Professor; Physiology and Neuroscience; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-DEC-1999; Project End 30-NOV-2003 Summary: Atypical anti-psychotic drugs (APDs) are primarily differentiated from typical APDs in that they possess a lower motor side effects profile. Experimental approaches to study "atypicality" have generally focused on cortical, striatal, and limbic dopamine terminal regions of the brain. However, research findings on motor syndromes and psychosis also support the critical role of striatopallidal gammaaminobutyric acid (GABA) pathways. Our specific global hypothesis is that decreases in pallidal GABA function mediate the atypical profile of certain APDs and may be a critical mechanism for the low incidence of motor side effects. Recent data from our laboratory has shown that typical APDs (e.g. haloperidol) produce motor side effects and increase GABA release in the globus pallidus, while atypical APDs (e.g. clozapine) produce minimal motor side effects and decrease GABA release in the globus pallidus. Furthermore, only clozapine has an effect on decreasing GABA in the ventral pallidum, a pallidal subregion believed to preferentially mediate "limbic" striatal output. The effect of atypical APDs may result form an inhibition of presynaptic release of GABA, since the density of nerve terminal GABA immunolabeling is increased after clozapine injection. This paradigm of altered GABA release in pallidal pathways could provide clues regarding the low incidence of motor side effects with atypical APDs and further our understanding of pallidal GABA in mediating atypical APD action. The series of studies proposed here will utilize a rodent model of acute and chronic APD administration to answer several questions. The first set of experiments will examine changes in extracellular and presynaptic pallidal GABA after systematic and sitespecific administration of drugs with a high or low motor side effect profile. In order to test the possibility that 5-HT2 receptor subtypes play a role in mediating pallidal GABA function, a second series of experiments will assess 5-HT2A and 5-HT2C receptor agonism and antagonism on pallidal GABA function. In a final set of studies, pallidal GABA function and motor activity will be studied after prolonged periods of APD administration which are similar to the treatment durations utilized in psychotic patients. These studies will provide new insights on the mechanisms of action of APDs and provide a novel means of identifying putative atypical APDs. The information obtained will facilitate the development of optimal pharmacotherapy for mental disorders, particularly schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PARTIAL SCHIZOPHRENIA
DOPAMINEAGONIST
TREATMENT
39
OF
Principal Investigator & Institution: Tamminga, Carol A.; Professor; Psychiatry; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-SEP-1992; Project End 31-MAR-2003 Summary: The strategy of using partial dopamine (DA) agonists as antidopaminergic antipsychotic agents is based on two sets of observations: first, that DA neurons have autoreceptors which function to decrease DA synthesis, release and neuronal firing, and hence mediate antidopaminergic signals; and, second, that partial agonists have full affinity but reduced intrinsic activity at DA receptors, consequently they exert relatively lower receptor stimulation in competition with the natural neurotransmitter, dopamine. The investigators have suggested that antipsychotic treatment with partial DA agonists, compared to treatment with DA receptor antagonists may have significant clinical advantages. Efficacy and side effects of partial DA agonists will depend on the level intrinsic activity of the partial agonist, a range which can extend from less than 10 percent to over 90 percent. The investigators work to date (see Progress Report) suggests that a partial agonist activity somewhat below 40 percent may be optimal for schizophrenia. The investigators most useful partial DA agonist is (-)-3PPP. The strategy of combining a small proporb'on of a full antagonist (e.g. haloperidol or clozopine) with the partial agonist (-)-3PPP, to produce a functionally lower intrinsic activity of (-)-3PPP, adds flexibility to the clinical testing of the partial agonist strategy. The investigators first clinical study will focus on testing the antipsychotic action of a very low dose of haloperidol (0.5 haloperidol + (-)-3PPP (flexible dose range) or (-)3PPP placebo, compared to a third active control arm (5 mg bid haloperidol + (-)-3PPP placebo). Treatment in each of these three aims will be evaluated in the three primary symptom cluster of schizophrenia: 1) hallucinations/delusions; 2) disorganization, and 3) negative symptoms, and on cognitive function. Our second study will be designed exactly like the first study, except that a very low dose of clazopine will be utilized. Clazapine is low affinity tigand and may, in combination with (-)-3PPP, produce a better antipsychotic action based on its greater displacability. Because the investigators have already demonstrated significant efflcacy, but efflcacy to which tolerance occurs, the investigators current goal is to demonstrate that the efficacy of (-)-3PPP treatment, by modifying intrinsic activity and dosing schedules can be extended. If the investigators are able to overcome the efficacy tolerance, then one of these treatments would be ready for broader multicenter testing. Application of this strategy to other syndromes where neuroleptics improve psychosis is also indicated. In the biochemistry laboratory, we propose to use the D2', D4 2. D4 4 and D4 7 cloned receptors in cultured CHO cells to examine the intrinsic activity and the desensitization potential of different DA agonists at the human D2-family receptors, in vitro. Cloned receptor desensitization, change in GTPyS activation, and arachidonic acid release will be used to study the mechanisms of tolerance and desensitization operating here. These data will predict and later help us to select optimal agonist intrinsic activity ior clinical testing for antipsychotic actvity, duration of therapeutic action, and side effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHARMACOGENETICS IN TOURETTE SYNDROM Principal Investigator & Institution: Singer, Harvey S.; Professor; Neurology and Neurosurgery; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2005
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Summary: (provided by applicant): When individuals with Tourette syndrome (TS) are treated with medications to suppress tics, some improve, others have little or no response, and several may develop significant side effects. In order to explain this variability, pharmacogenetic research has focused on two major areas, drug metabolism and drug site of action. In this study, genetic variations of metabolizing enzymes (CYP2D6), dopamine & serotonin transporters (DAT, 5-HTT) dopamine receptors (D2, D3, D4) and serotonin receptors (5HT2a and 5HT2c) will be determined with the goal of predicting a TS patients response to treatment and a diagnostic category (TS or control). Fifteen established polymorphisms will be investigated in individuals with the diagnosis of TS using DNA obtained by buccal swabs. The first major objectives is to determine whether the presence of specific patterns of neurotransmitter polymorphisms predict the tic-suppressing pharmacologic effect of the atypical neuroleptic, risperidone. Patient response to pharmacotherapy will be based on a prospective evaluation of tic reduction, as measured by the Total Tic score of the Yale Global Tic Severity Scale, in 200 individuals with TS. This approach is similar to one that has been successfully used in schizophrenia to predict, with nearly 80% success, the response to the atypical neuroleptic, clozapine. Our second goal is to determine whether there are associations between genetic variations in dopamine or serotonin receptors and the etiology of TS. This question will be addressed in a cohort of 500 individuals with TS & compared with an equal number of age and sex-matched controls. This application, defines a study (to my knowledge, the first of its kind in TS), which will use DNA obtained from buccal mucosa, to establish a predictive therapeutic index in TS patients. The identification of genetic polymorphisms that are associated with clinical disease or treatment success, has obvious benefits. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHARMACOKINETICS OF GENERIC CLOZAPINE VS CLOZARIL Principal Investigator & Institution: Ereshefsky, Larry; Professor; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002 Summary: The purpose of this study is to determine whether the generic form of clozapine (Zenith) differs in bioavailability and pharmacodynamics from the Clozaril brand of the same drug. The study drug is used to treat psychosis and study subjects will have been stabilized on Clozaril. Differences in response to the two drugs will be measured in terms of cognitive tests, PANSS and CGI ratings, and ratings of dyskinesia and akathesia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHOTOPHYSICS AND SKIN PHOTOTOXICITY OF NEUROLEPTIC DRUGS Principal Investigator & Institution: Garcia, Carmelo; University of Puerto Rico at Humacao Box 428, Barrio Tejas Humacao, Pr 00791 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PILOT--RACIAL DIFFERENCES TREATMENT, RESPONSE TO CLOZAPINE
CLINICAL,
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VARIABLES
Principal Investigator & Institution: Kelly, Deanna L.; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2007 Summary: Specific Aims: Aim 1: The primary aim is to assess Clozapine treatment by race in clinical trials as compared to real-world treatment settings for those with schizophrenia. The primary hypothesis is that African-Americans will be under represented in clinical trials as compared to the population typically treated with Clozapine. I also hypothesize that Clozapine use in both real-world settings and clinical trials will be underutilized in minority populations. Aim 2: Baseline symptoms and clinical variables will be examined by race between clinical trial participants and patients treated in routine settings. I hypothesize that people with schizophrenia who are treated in the real-world will have more severe symptomatology such as positive, negative and anxious behavior that are often excluded from clinical trials. Aim 3: Treatment response will be compared by race between the treatment settings with Clozapine. It remains unknown how Clozapine response compares between the realworld settings and clinical trials, particularly with regard to race since clinical trials typically have enrolled low numbers of African-Americans. I hypothesize that response to Clozapine by race will be similar across settings after controlling for baseline differences. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PREFRONTAL CELL PATHOLOGY DISTINGUISHES MENTAL DISORDERS Principal Investigator & Institution: Rajkowska, Grazyna; Professor of Psychiatry; Psychiatry and Human Behavior; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216 Timing: Fiscal Year 2002; Project Start 23-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant) There are established differences and similarities in phenomenology and treatment between schizophrenia (SCHZ) and major depressive disorder (MDD). It is well known that depressed symptoms occur in SCHZ and psychotic symptoms are no uncommon for MDD. It is therefore justified to postulate that different brain regions and/or different cell types using specith neurotransmitters are crucial to distinguish the neuropathology of both disorders. Neuroimaging evidence implicates the dorsolateral prefrontal (dIPFC) and orbitofrontal (ORB) cortical areas in the neuropathology of SCHZ and MDD. Our recent quantitative histopathological studies in postmortem tissue reveal the differential involvement of the dIPFC and ORB region in the neurobiology of MDD and SCHZ. However, the specific types of neurons and glia, which underlie the prefrontal pathology of these mental disorders have not been identified yet. The overall objective of this proposal is to distinguish MDD and SCFIZ by using quantitative immunohistochemistry to identify the region-and layerspecific biochemical types o vulnerableneurons and glia constituting dysfunctional prefrontal Circuits. The specific hypotheses are: 1) Subjects with MDD will be characterized by lower numbers of immunoreactive neurons and glia and lower levels of trophic factors, BDNF an GDNF in both dIPFC and ORB. In contrast, subjects with SCHZ will exhibit reductions similar to MDD only in the ORI region, whereas in the dIPFC, SCHZ will be distinguished from MDD by higher neuronal and possibly, glial cell number. 2 Cellular changes observed in prefrontal regions from MDD and SCHZ
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patients are due to the disease process and therefore they will not be found in analogous regions from rat brains treated chronically with antidepressant or antipsychotic medications If these hypotheses are proven, a provocative interpretation would be that anatomic-functional changes in the dIPFC may b related to cognitive dysfunction. Where as changes in the ORB may be related to depressive symptoms. To test these hypotheses vulnerable cell types will be identified and quantified by the combination of immunohistochemistry and 3-D non-biase stereology. We will identify prefrontal cells with specific antibodies (Nonpyramidal neurons with antibodies to Ca2 binding proteins; Pyramidal neurons with antibodies against neurofilament protein NF-200; Astroglia with an antibody to GFAP; ani-Microglia with antibodies against the bchemokine receptor in subjects with MDD, subjects with SCHZ and in match psychiatrically-normal controls. The proposed study will illuminate disrupted cortical circuits involved in psychotic and depressed symptomatology and possibly cortical Sites of action for antidepressant and antipsychotic medications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TREATING REFRACTORY CHILDHOOD SCHIZOPHRENIA Principal Investigator & Institution: Kane, John M.; Chairman; Long Island Jewish Medical Center 270-05 76Th Ave New Hyde Park, Ny 11040 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-JUL-2003 Summary: (provided by applicant): Schizophrenia is a devastating illness regardless of the age at which it presents. When this disorder occurs in childhood or adolescence (onset of psychotic symptoms by age 17) the consequences in terms of functional impairment, loss of developmental opportunities, family suffering and societal burden are particularly dramatic. If young patients are refractory to treatment, the long-term outcome is likely to be considerably worse. In recent years, there has been considerable concern that very few data are available on the use of psychotropic drugs in young persons. This is no more apparent than in the antipsychotic treatment arena. Because of the evidence supporting the improved efficacy and/or side effect profile of the secondgeneration, or atypical antipsychotic medications in adults, and in the case of clozapine, in treatment refractory adults, it is essential to examine whether the potential benefits of these agents can be extended to children and particularly to treatment refractory children. This trial has been specifically targeted for children and adolescents with schizophrenia who have failed separate trials of olanzapine and risperidone at standard doses. Based on existing pilot and other data clozapine and olanzapine are the drugs of choice for this comparison. Specifically, we propose a 12-week, random-assignment, double-blind comparison of clozapine and high-dose olanzapine in 80 children and adolescents (ages 12 to 17) with treatment refractory schizophrenia (onset of psychotic symptoms by age 17). These treatment options represent viable and novel clinical treatments for patients and their families so that all trial participants, regardless of which treatment they are assigned to, will be receiving a new treatment option. Primary outcome measures will include: 1) overall drug response; 2) positive and negative symptoms; 3) adverse effects profiles. This trial will provide a basis to inform clinical treatment decisions and address the critical question as to whether clozapine or highdose olazapine is more effective in seriously ill children and adolescents who do not respond to other agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ZEISS MICROSCOPE
LSM
510-NLO
MULTIPHOTON
LASER
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SCANNING
Principal Investigator & Institution: Mazurkiewicz, Joseph E.; Micro/Immunol/Molec Genetics; Albany Medical College of Union Univ Albany, Ny 12208 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2004 Summary: (provided by applicant): A group of investigators at the Albany Medical College (AMC) is requesting funds to purchase a Zeiss LSM510-NLO multiphoton laser scanning microscope (MPLSM), an instrument that is not available for their use at AMC. Dr. Rice is analyzing cutaneous innervation in normal and pathologic skin to study pain and neural dysfunction resulting from Herpes Zoster using mutiply-fluorescent-labeled thick samples of human skin. Dr. O'Donnell's work addresses the role of gap junctions in neural synchronizations by performing simultaneous dual whole-cell recordings from a cluster of neurons in the nucleus accumbens and then visualizing the lucifer yellow filled cells coupled with immunofluorescence in thick brain slices, a unique approach that combines cell visualization and electrophysiology to get a better idea of the modulation of gap junction function. Dr. Kimelberg's subcellular localization studies involve double or triple immunolabelling of recorded and dye-filled astrocytes in thick hippocampal sections using MPLSM to study mechanisms of excitatory amino-acid release in ischemia. Dr. Temple's research studies focus on understanding the generation of diverse cell types during development of the central nervous system (CNS). She will use time-lapse MPLSM imaging to follow the division of stem cells in live tissue slices of the cortical ventricular plate coupled with immunofluorescence to identify the progeny of asymetric division of these stem cells. Dr. Teitler proposes that the inverse agonist activity of antipsychotic drugs can be revealed by studying constitutively activated mutant (CAM) Human clozapine-sensitive 5-HT2A, 5-HT2d, 5HT6, and 5-HT7 receptors. He will use CAM human 5HT receptor/GFP fusion proteins coupled with time-lapse MPLSM imaging to examine the effect antipsychotic drugs have on the trafficking of these receptors to the membrane and during receptor downregulation. Dr. Herrick-Davis' goal is to identify molecular mechanisms that regulate 5HT2C receptor activation to understand how 5-HT2C receptors function in normal and disease states. In particular she uses FRET in live cells to determine if mutant receptors physically associate or dimerize with native receptors, and thus form non-functional receptor complexes. Dr. Banas will use MPLSM to study the physiology that results from changes in gene expression in mature, live biofilms made by oral Steprococci. This group will fully utilize the capabilities of the Zeiss LSM510-NLO. 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
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.
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unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “clozapine” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for clozapine in the PubMed Central database: •
Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity. by Wooltorton E.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=102361
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Central effects of clozapine in regulating micturition in anesthetized rats. by Vera PL, Miranda-Sousa AJ, Ordorica RC, Nadelhaft I.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=100786
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Long-term treatment with clozapine in an adult with autistic disorder accompanied by aggressive behaviour. by Gobbi G, Pulvirenti L.; 2001 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=167190
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 clozapine, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “clozapine” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for clozapine (hyperlinks lead to article summaries): •
A case of interstitial nephritis on clozapine. Author(s): Southall KE. Source: The Australian and New Zealand Journal of Psychiatry. 2000 August; 34(4): 6978. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10954407
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A comparison of the covalent binding of clozapine and olanzapine to human neutrophils in vitro and in vivo. Author(s): Gardner I, Leeder JS, Chin T, Zahid N, Uetrecht JP. Source: Molecular Pharmacology. 1998 June; 53(6): 999-1008. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9614201
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. 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.
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A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes. Author(s): Gardner I, Zahid N, MacCrimmon D, Uetrecht JP. Source: Molecular Pharmacology. 1998 June; 53(6): 991-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9614200
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A pilot trial of clozapine in the treatment of cervical dystonia. Author(s): Burbaud P, Guehl D, Lagueny A, Petiteau F, Bioulac B. Source: Journal of Neurology. 1998 June-July; 245(6-7): 329-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9669485
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A program to convert patients from trade-name to generic clozapine. Author(s): Stoner SC, Lea JW, Dubisar B, Marken PA, Ramlatchman LV, Reynolds J. Source: Pharmacotherapy. 2003 June; 23(6): 806-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820822
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A prospective study of impairment in glucose control caused by clozapine without changes in insulin resistance. Author(s): Howes OD, Bhatnagar A, Gaughran FP, Amiel SA, Murray RM, Pilowsky LS. Source: The American Journal of Psychiatry. 2004 February; 161(2): 361-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14754788
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Accidental clozapine intoxication in a ten-year-old child. Author(s): Borzutzky A, Avello E, Rumie H, Paris E. Source: Vet Hum Toxicol. 2003 December; 45(6): 309-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14640481
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Adjunctive fluvoxamine with clozapine. Author(s): Lu ML, Lane HY. Source: The British Journal of Psychiatry; the Journal of Mental Science. 2003 January; 182: 81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12509328
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alpha2C-Adrenoceptor blockade by clozapine and other antipsychotic drugs. Author(s): Kalkman HO, Loetscher E. Source: European Journal of Pharmacology. 2003 February 21; 462(1-3): 33-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591093
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An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Author(s): Hong CJ, Yu YW, Lin CH, Tsai SJ. Source: Neuroscience Letters. 2003 October 9; 349(3): 206-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12951204
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An association study of the neurotensin receptor gene with schizophrenia and clozapine response. Author(s): Huezo-Diaz P, Arranz MJ, Munro J, Osborne S, Makoff A, Kerwin RW, Austin J, O'Donovan M. Source: Schizophrenia Research. 2004 February 1; 66(2-3): 193-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15061255
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An integrated analysis of acute treatment-emergent extrapyramidal syndrome in patients with schizophrenia during olanzapine clinical trials: comparisons with placebo, haloperidol, risperidone, or clozapine. Author(s): Carlson CD, Cavazzoni PA, Berg PH, Wei H, Beasley CM, Kane JM. Source: The Journal of Clinical Psychiatry. 2003 August; 64(8): 898-906. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12927004
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Anatomical and functional brain variables associated with clozapine response in treatment-resistant schizophrenia. Author(s): Molina V, Reig S, Sarramea F, Sanz J, Francisco Artaloytia J, Luque R, Aragues M, Pascau J, Benito C, Palomo T, Desco M. Source: Psychiatry Research. 2003 November 30; 124(3): 153-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623067
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Approaches to dissecting mechanisms of adverse drug reactions in psychiatry: clozapine-binding sites in the bone marrow. Author(s): Licinio J, Wong ML. Source: The Pharmacogenomics Journal. 2003; 3(4): 189. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12931130
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Association between regional brain volumes and clozapine response in schizophrenia. Author(s): Lauriello J, Mathalon DH, Rosenbloom M, Sullivan EV, Faustman WO, Ringo DL, Lim KO, Pfefferbaum A. Source: Biological Psychiatry. 1998 June 15; 43(12): 879-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9627742
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Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Author(s): Tsai SJ, Hong CJ, Yu YW, Lin CH, Song HL, Lai HC, Yang KH. Source: Schizophrenia Research. 2000 September 1; 44(3): 177-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10962219
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Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Author(s): Lieberman JA, Phillips M, Gu H, Stroup S, Zhang P, Kong L, Ji Z, Koch G, Hamer RM. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2003 May; 28(5): 995-1003. Epub 2003 March 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700715
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Atypical neuroleptic malignant syndrome with clozapine and subsequent haloperidol treatment. Author(s): Spivak M, Adams B, Crockford D. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2003 February; 48(1): 66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12635570
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Augmentation of clozapine partial responders with conventional antipsychotics. Author(s): Rajarethinam R, Gilani S, Tancer M, DeQuardo J. Source: Schizophrenia Research. 2003 March 1; 60(1): 97-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12505145
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Autonomic signs and dosing during the initial stages of clozapine therapy. Author(s): Oyewumi LK, Cernovsky ZZ, Freeman DJ. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2004 February; 10(2): Pi19-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14737054
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Bacterial pneumonia can increase serum concentration of clozapine. Author(s): Raaska K, Raitasuo V, Arstila M, Neuvonen PJ. Source: European Journal of Clinical Pharmacology. 2002 August; 58(5): 321-2. Epub 2002 June 25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12185555
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Behavior therapy attenuates clozapine-induced obsessions and compulsions. Author(s): MacCabe JH, Marks IM, Murray RM. Source: The Journal of Clinical Psychiatry. 2002 December; 63(12): 1179-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12530414
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Behavioral effects of clozapine and dopamine receptor subtypes. Author(s): Josselyn SA, Miller R, Beninger RJ. Source: Neuroscience and Biobehavioral Reviews. 1997 September; 21(5): 531-58. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9353791
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Benztropine versus clozapine for the treatment of tremor in Parkinson's disease. Author(s): Friedman JH, Koller WC, Lannon MC, Busenbark K, Swanson-Hyland E, Smith D. Source: Neurology. 1997 April; 48(4): 1077-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9109903
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Bilateral pulmonary embolism in a patient on clozapine therapy. Author(s): Maynes D. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2000 April; 45(3): 296-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10779890
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Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients. Author(s): Trichard C, Paillere-Martinot ML, Attar-Levy D, Recassens C, Monnet F, Martinot JL. Source: The American Journal of Psychiatry. 1998 April; 155(4): 505-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9545996
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Biogenic amines as predictors of response to clozapine treatment in early-onset schizophrenia. Author(s): Fleischhaker C, Schulz E, Remschmidt H. Source: Journal of Psychiatric Research. 1998 September-October; 32(5): 325-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9789212
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Biotransformation of clozapine in humans. Author(s): Dain JG, Nicoletti J, Ballard F. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 1997 May; 25(5): 603-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9152600
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Biotransformation of post-clozapine antipsychotics: pharmacological implications. Author(s): Caccia S. Source: Clinical Pharmacokinetics. 2000 May; 38(5): 393-414. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10843459
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Biperiden for excessive sweating from clozapine. Author(s): Richardson C, Kelly DL, Conley RR. Source: The American Journal of Psychiatry. 2001 August; 158(8): 1329-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11481174
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Bladder dysfunction associated with clozapine therapy. Author(s): Frankenburg FR, Kando JC, Centorrino F, Gilbert JM. Source: The Journal of Clinical Psychiatry. 1996 January; 57(1): 39-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8543547
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Blood biogenic amines during clozapine treatment of early-onset schizophrenia. Author(s): Schulz E, Fleischhaker C, Clement HW, Remschmidt H. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 1997; 104(10): 1077-89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9503259
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Blood clozapine levels elevated by fluvoxamine: potential for side effects and lower clozapine dosage. Author(s): Armstrong SC, Stephans JR. Source: The Journal of Clinical Psychiatry. 1997 November; 58(11): 499. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9413421
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Blood dyscrasias in clozapine-treated patients in Italy. Author(s): Lambertenghi Deliliers G. Source: Haematologica. 2000 March; 85(3): 233-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10702809
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Branded versus generic clozapine for treatment of schizophrenia. Author(s): Makela EH, Cutlip WD, Stevenson JM, Weimer JM, Abdallah ES, Akhtar RS, Aboraya AS, Gunel E. Source: The Annals of Pharmacotherapy. 2003 March; 37(3): 350-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12639161
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Branded versus generic clozapine: bioavailability comparison and interchangeability issues. Author(s): Lam YW, Ereshefsky L, Toney GB, Gonzales C. Source: The Journal of Clinical Psychiatry. 2001; 62 Suppl 5: 18-22; Discussion 23-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11305844
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Brief report: effects of clozapine on self-injurious behavior of two risperidone nonresponders with mental retardation. Author(s): Hammock R, Levine WR, Schroeder SR. Source: Journal of Autism and Developmental Disorders. 2001 February; 31(1): 109-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11439749
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Bromocriptine as adjunctive therapy to clozapine in treatment-resistant schizophrenia. Author(s): al-Semaan Y. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 1996 September; 41(7): 484-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8884041
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Clinical outcome and plasma levels of clozapine and norclozapine in drug-resistant schizophrenic patients. Author(s): Mauri M, Volonteri LS, Fiorentini A, Invernizzi G, Nerini T, Baldi M, Bareggi SR. Source: Schizophrenia Research. 2004 February 1; 66(2-3): 197-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15061256
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Clozapine and hypertension: a chart review of 82 patients. Author(s): Henderson DC, Daley TB, Kunkel L, Rodrigues-Scott M, Koul P, Hayden D. Source: The Journal of Clinical Psychiatry. 2004 May; 65(5): 686-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15163256
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Clozapine and pregnancy. Author(s): Mendhekar DN, Sharma JB, Srivastava PK, War L. Source: The Journal of Clinical Psychiatry. 2003 July; 64(7): 850. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12934992
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Clozapine as a first treatment for schizophrenia. Author(s): Woerner MG, Robinson DG, Alvir JM, Sheitman BB, Lieberman JA, Kane JM. Source: The American Journal of Psychiatry. 2003 August; 160(8): 1514-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12900316
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Clozapine associated dilated cardiomyopathy. Author(s): Tanner MA, Culling W. Source: Postgraduate Medical Journal. 2003 July; 79(933): 412-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12897222
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Clozapine for the treatment of levodopa-induced dyskinesias. Author(s): Del Dotto P, Bonuccelli U. Source: Lancet. Neurology. 2004 May; 3(5): 268. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15099538
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Clozapine in drug induced psychosis in Parkinson's disease: a randomised, placebo controlled study with open follow up. Author(s): Pollak P, Tison F, Rascol O, Destee A, Pere JJ, Senard JM, Durif F, Bourdeix I. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2004 May; 75(5): 689-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15090561
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Clozapine maintenance therapy in schizophrenia. Author(s): Gaszner P, Makkos Z. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2004 May; 28(3): 465-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15093952
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Clozapine therapy during cancer treatment. Author(s): Rosenstock J. Source: The American Journal of Psychiatry. 2004 January; 161(1): 175. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14702271
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Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: a re-examination. Author(s): Moncrieff J. Source: The British Journal of Psychiatry; the Journal of Mental Science. 2003 August; 183: 161-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893670
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Clozapine with amisulpride for refractory schizophrenia. Author(s): Agelink MW, Kavuk I, Ak I. Source: The American Journal of Psychiatry. 2004 May; 161(5): 924-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15121665
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Clozapine-associated polyserositis. Author(s): Lim A, Sivakumaran P, Israel M. Source: N Z Med J. 2003 October 24; 116(1184): U651. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14583809
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Clozapine-induced aplastic anemia in a patient with Parkinson's disease. Author(s): Ziegenbein M, Steinbrecher A, Garlipp P. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2003 June; 48(5): 352. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12866349
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Clozapine-induced neuroleptic malignant syndrome and subdural hematoma. Author(s): Duggal HS. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2004 Winter; 16(1): 118-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14990770
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Clozapine-induced neutropenia in children: management with lithium carbonate. Author(s): Sporn A, Gogtay N, Ortiz-Aguayo R, Alfaro C, Tossell J, Lenane M, Gochman P, Rapoport JL. Source: Journal of Child and Adolescent Psychopharmacology. 2003 Fall; 13(3): 401-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642024
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Clozapine-induced sialorrhea treated with sublingual ipratropium spray: a case series. Author(s): Freudenreich O, Beebe M, Goff DC. Source: Journal of Clinical Psychopharmacology. 2004 February; 24(1): 98-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709958
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Comorbidity of parkinsonism and schizophrenia in a patient treated with clozapine. Author(s): Urban A, Libiger J, Hosak L, Kupka K. Source: European Psychiatry : the Journal of the Association of European Psychiatrists. 2003 August; 18(5): 258-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12927328
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Comparability of whole-blood and plasma clozapine and norclozapine concentrations. Author(s): Flanagan RJ, Yusufi B, Barnes TR. Source: British Journal of Clinical Pharmacology. 2003 July; 56(1): 135-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12848787
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D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine. Author(s): Potkin SG, Basile VS, Jin Y, Masellis M, Badri F, Keator D, Wu JC, Alva G, Carreon DT, Bunney WE Jr, Fallon JH, Kennedy JL. Source: Molecular Psychiatry. 2003 January; 8(1): 109-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12556915
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D1-, D2-, and 5-HT2-receptor occupancy in clozapine-treated patients. Author(s): Farde L, Nordstrom AL, Nyberg S, Halldin C, Sedvall G. Source: The Journal of Clinical Psychiatry. 1994 September; 55 Suppl B: 67-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7961577
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Death from clozapine-induced constipation: case report and literature review. Author(s): Levin TT, Barrett J, Mendelowitz A. Source: Psychosomatics. 2002 January-February; 43(1): 71-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11927763
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Deaths from diabetic ketoacidosis after long-term clozapine treatment. Author(s): Wehring HJ, Kelly DL, Love RC, Conley RR. Source: The American Journal of Psychiatry. 2003 December; 160(12): 2241-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638600
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Decreased production of reactive oxygen species by blood monocytes caused by clozapine correlates with EEG slowing in schizophrenic patients. Author(s): Gross A, Joffe G, Joutsiniemi SL, Nyberg P, Rimon R, Appelberg B. Source: Neuropsychobiology. 2003; 47(2): 73-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12707488
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Decreased psychopathology & family burden. Associated with clozapine treatment of patients with refractory schizophrenia. Author(s): Snyder N, Goldstein G. Source: Journal of Psychosocial Nursing and Mental Health Services. 2002 May; 40(5): 34-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12016691
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Delayed recovery associated with persistent serum concentrations after clozapine overdose. Author(s): Thomas L, Pollak PT. Source: The Journal of Emergency Medicine. 2003 July; 25(1): 61-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865111
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Delirium during clozapine treatment: incidence and associated risk factors. Author(s): Centorrino F, Albert MJ, Drago-Ferrante G, Koukopoulos AE, Berry JM, Baldessarini RJ. Source: Pharmacopsychiatry. 2003 July; 36(4): 156-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12905102
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Determination of clozapine and its N-desmethyl metabolite by high-performance liquid chromatography with ultraviolet detection. Author(s): Llerena A, Berecz R, Norberto MJ, de la Rubia A. Source: J Chromatogr B Biomed Sci Appl. 2001 May 5; 755(1-2): 349-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11393724
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Different corticostriatal patterns of L-DOPA utilization in patients with untreated schizophrenia and patients treated with classical antipsychotics or clozapine. Author(s): Gefvert O, Lindstrom LH, Waters N, Waters S, Carlsson A, Tedroff J. Source: Scandinavian Journal of Psychology. 2003 July; 44(3): 289-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12914593
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Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. Author(s): Gianfrancesco FD, Grogg AL, Mahmoud RA, Wang RH, Nasrallah HA. Source: The Journal of Clinical Psychiatry. 2002 October; 63(10): 920-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12416602
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Differential effects of the antipsychotics haloperidol and clozapine on G protein measures in mononuclear leukocytes of patients with schizophrenia. Author(s): Avissar S, Roitman G, Schreiber G. Source: Cellular and Molecular Neurobiology. 2001 December; 21(6): 799-811. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12043849
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Diminished suicidal and aggressive behavior, high plasma norepinephrine levels, and serum triglyceride levels in chronic neuroleptic-resistant schizophrenic patients maintained on clozapine. Author(s): Spivak B, Roitman S, Vered Y, Mester R, Graff E, Talmon Y, Guy N, Gonen N, Weizman A. Source: Clinical Neuropharmacology. 1998 July-August; 21(4): 245-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9704166
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Direct-injection high performance liquid chromatography ion trap mass spectrometry for the quantitative determination of olanzapine, clozapine and Ndesmethylclozapine in human plasma. Author(s): Kollroser M, Schober C. Source: Rapid Communications in Mass Spectrometry : Rcm. 2002; 16(13): 1266-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12112253
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Do clozapine and risperidone affect social competence and problem solving? Author(s): Bellack AS, Schooler NR, Marder SR, Kane JM, Brown CH, Yang Y. Source: The American Journal of Psychiatry. 2004 February; 161(2): 364-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14754789
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Do triglycerides modulate the effectiveness of clozapine? Author(s): Pande S, Procyshyn RM, Nazerali M, Attwood D, Chow K. Source: International Clinical Psychopharmacology. 2002 July; 17(4): 197-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131604
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Does participation in psychosocial treatment augment the benefit of clozapine? Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. Author(s): Rosenheck R, Tekell J, Peters J, Cramer J, Fontana A, Xu W, Thomas J, Henderson W, Charney D. Source: Archives of General Psychiatry. 1998 July; 55(7): 618-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9672052
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Does patient education enhance compliance with clozapine? A preliminary investigation. Author(s): Gray R. Source: Journal of Psychiatric and Mental Health Nursing. 2000 June; 7(3): 285-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11249323
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Dosing strategies of clozapine-fluvoxamine cotreatment. Author(s): Lu ML, Lane HY, Jann MW, Chang WH. Source: Journal of Clinical Psychopharmacology. 2002 December; 22(6): 626-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12454566
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Drug Points: Pseudophaeochromocytoma syndrome associated with clozapine. Author(s): Krentz AJ, Mikhail S, Cantrell P, Hill GM. Source: Bmj (Clinical Research Ed.). 2001 May 19; 322(7296): 1213. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11358774
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Early developmental differences between DSM-III-R schizophrenics treated with clozapine and typical neuroleptics. Author(s): Makikyro T, Leinonen E, Koponen H, Jarvelin MR, Hakko H, Saarnisaari O, Isohanni M. Source: Journal of Psychiatric Research. 1998 March-April; 32(2): 105-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9694006
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EEG coherence following acute and chronic clozapine in treatment-resistant schizophrenics. Author(s): Knott VJ, LaBelle A, Jones B, Mahoney C. Source: Experimental and Clinical Psychopharmacology. 2002 November; 10(4): 435-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12498341
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Effect of caffeine-containing versus decaffeinated coffee on serum clozapine concentrations in hospitalised patients. Author(s): Raaska K, Raitasuo V, Laitila J, Neuvonen PJ. Source: Basic Clin Pharmacol Toxicol. 2004 January; 94(1): 13-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14725610
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Effect of clozapine on mortality. Author(s): Howes O, Ohlsen R, Pilowsky LS. Source: The British Journal of Psychiatry; the Journal of Mental Science. 2003 November; 183: 460. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14594927
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Effect of clozapine on serum leptin, insulin levels, and body weight and composition in patients with schizophrenia. Author(s): Kivircik BB, Alptekin K, Caliskan S, Comlekci A, Oruk G, Tumuklu M, Kurklu K, Arkar H, Turk A, Caliskan M, Yesil S. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2003 August; 27(5): 795-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12921912
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Effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia. Author(s): Spina E, Avenoso A, Facciola G, Fabrazzo M, Monteleone P, Maj M, Perucca E, Caputi AP. Source: International Clinical Psychopharmacology. 1998 May; 13(3): 141-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9690983
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Effect of post-mortem changes on peripheral and central whole blood and tissue clozapine and norclozapine concentrations in the domestic pig (Sus scrofa). Author(s): Flanagan RJ, Amin A, Seinen W. Source: Forensic Science International. 2003 March 12; 132(1): 9-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12689746
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Effect size of symptom status in withdrawal of typical antipsychotics and subsequent clozapine treatment in patients with treatment-resistant schizophrenia. Author(s): Pickar D, Bartko JJ. Source: The American Journal of Psychiatry. 2003 June; 160(6): 1133-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777272
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Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients. Author(s): Carrillo JA, Herraiz AG, Ramos SI, Benitez J. Source: Journal of Clinical Psychopharmacology. 1998 August; 18(4): 311-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9690697
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Effects of clozapine and its metabolites on the 5-HT2 receptor system in cortical and hippocampal cells in vitro. Author(s): Heiser P, Schulte E, Hausmann C, Becker R, Remschmidt H, Krieg JC, Vedder H. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2004 March; 28(2): 297-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751426
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Effects of clozapine and typical antipsychotic drugs on plasma 5-HT turnover and impulsivity in patients with schizophrenia: a cross-sectional study. Author(s): Dursun SM, Szemis A, Andrews H, Whitaker P, Reveley MA. Source: Journal of Psychiatry & Neuroscience : Jpn. 2000 September; 25(4): 347-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11022399
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Effects of clozapine on cognitive function in schizophrenia. Author(s): Lee MA, Thompson PA, Meltzer HY. Source: The Journal of Clinical Psychiatry. 1994 September; 55 Suppl B: 82-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7961582
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Effects of clozapine on in vitro immune parameters: a longitudinal study in clozapine-treated schizophrenic patients. Author(s): Hinze-Selch D, Becker EW, Stein GM, Berg PA, Mullington J, Holsboer F, Pollmacher T. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 1998 August; 19(2): 114-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9629565
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Effects of clozapine, fluphenazine, and placebo on reaction time measures of attention and sensory dominance in schizophrenia. Author(s): Zahn TP, Pickar D, Haier RJ. Source: Schizophrenia Research. 1994 September; 13(2): 133-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7986770
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Effects of olanzapine and clozapine upon pulse rate variability. Author(s): Mueck-Weymann M, Rechlin T, Ehrengut F, Rauh R, Acker J, Dittmann RW, Czekalla J, Joraschky P, Musselman D. Source: Depression and Anxiety. 2002; 16(3): 93-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12415532
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Efficacy of clozapine in a non-schizophrenic patient with psychogenic polydipsia and central pontine myelinolysis. Author(s): Mauri MC, Volonteri LS, Fiorentini A, Dieci M, Righini A, Vita A. Source: Human Psychopharmacology. 2002 July; 17(5): 253-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12404683
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Efficacy of clozapine in the treatment of atypical antipsychotic refractory schizophrenia: a pilot study. Author(s): Narendran R, Young CM, Pristach CA, Pato MT, Valenti AM, Fass AR. Source: Journal of Clinical Psychopharmacology. 2003 February; 23(1): 103-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544385
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Epilepsy, psychosis and clozapine. Author(s): Langosch JM, Trimble MR. Source: Human Psychopharmacology. 2002 March; 17(2): 115-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12404701
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Experience of maintaining clozapine medication in patients with 'red-alert zone' neutropenia: long-term follow-up results. Author(s): Ahn YM, Jeong SH, Jang HS, Koo YJ, Kang UG, Lee KY, Kim YS. Source: International Clinical Psychopharmacology. 2004 March; 19(2): 97-101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15076018
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Experiences with clozapine and olanzapine. Author(s): Chatterton R. Source: The Australian and New Zealand Journal of Psychiatry. 1998 June; 32(3): 463. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9672741
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Failure of tolterodine to treat clozapine-induced nocturnal enuresis. Author(s): English BA, Still DJ, Harper J, Saklad SR. Source: The Annals of Pharmacotherapy. 2001 July-August; 35(7-8): 867-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11485135
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Fatal acute fulminant liver failure due to clozapine: a case report and review of clozapine-induced hepatotoxicity. Author(s): Macfarlane B, Davies S, Mannan K, Sarsam R, Pariente D, Dooley J. Source: Gastroenterology. 1997 May; 112(5): 1707-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9136851
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Fatal overdose of clozapine. Author(s): Keller T, Miki A, Binda S, Dirnhofer R. Source: Forensic Science International. 1997 April 18; 86(1-2): 119-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9153788
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Features and toxicokinetics of clozapine in overdose. Author(s): Reith D, Monteleone JP, Whyte IM, Ebelling W, Holford NH, Carter GL. Source: Therapeutic Drug Monitoring. 1998 February; 20(1): 92-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9485562
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Fishing for a drug: solid-phase microextraction for the assay of clozapine in human plasma. Author(s): Ulrich S, Kruggel S, Weigmann H, Hiemke C. Source: J Chromatogr B Biomed Sci Appl. 1999 August 20; 731(2): 231-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10510776
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Flavin monooxygenase 3 (FMO3) polymorphism in a white population: allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism. Author(s): Sachse C, Ruschen S, Dettling M, Schley J, Bauer S, Muller-Oerlinghausen B, Roots I, Brockmoller J. Source: Clinical Pharmacology and Therapeutics. 1999 October; 66(4): 431-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10546928
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Fluoroquinolone inhibition of clozapine metabolism. Author(s): Markowitz JS, Gill HS, Devane CL, Mintzer JE. Source: The American Journal of Psychiatry. 1997 June; 154(6): 881. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9167522
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Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Author(s): Buchanan RW, Kirkpatrick B, Bryant N, Ball P, Breier A. Source: The American Journal of Psychiatry. 1996 December; 153(12): 1625-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8942462
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Fluvoxamine augmentation in clozapine-resistant schizophrenia: an open pilot study. Author(s): Silver H, Kushnir M, Kaplan A. Source: Biological Psychiatry. 1996 October 1; 40(7): 671-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8886304
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Fluvoxamine increases plasma and urinary levels of clozapine and its major metabolites in a time- and dose-dependent manner. Author(s): Fabrazzo M, La Pia S, Monteleone P, Mennella R, Esposito G, Pinto A, Maj M. Source: Journal of Clinical Psychopharmacology. 2000 December; 20(6): 708-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11106150
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Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients. Author(s): Lu ML, Lane HY, Chen KP, Jann MW, Su MH, Chang WH. Source: The Journal of Clinical Psychiatry. 2000 August; 61(8): 594-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10982203
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Fluvoxamine-clozapine dose-dependent interaction. Author(s): Markowitz JS, Gill HS, Lavia M, Brewerton TD, DeVane CL. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 1996 December; 41(10): 670-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8978949
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Fluvoxamine-Clozapine drug interaction: inhibition in vitro of five cytochrome P450 isoforms involved in clozapine metabolism. Author(s): Olesen OV, Linnet K. Source: Journal of Clinical Psychopharmacology. 2000 February; 20(1): 35-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10653206
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Focus on clozapine. Author(s): Naheed M, Green B. Source: Current Medical Research and Opinion. 2001; 17(3): 223-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11900316
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Frequency of sexual dysfunctions in patients with schizophrenia on haloperidol, clozapine or risperidone. Author(s): Mullen B, Brar JS, Vagnucci AH, Ganguli R. Source: Schizophrenia Research. 2001 March 1; 48(1): 155-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11345946
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From chlorpromazine to clozapine--antipsychotic adverse effects and the clinician's dilemma. Author(s): Abidi S, Bhaskara SM. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2003 December; 48(11): 749-55. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14733456
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Fronto-striato-thalamic perfusion and clozapine response in treatment-refractory schizophrenic patients. A 99mTc-HMPAO study. Author(s): Rodriguez VM, Andree RM, Castejon MJ, Zamora ML, Alvaro PC, Delgado JL, Vila FJ. Source: Psychiatry Research. 1997 November 28; 76(1): 51-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9498309
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Functional antagonistic properties of clozapine at the 5-HT3 receptor. Author(s): Hermann B, Wetzel CH, Pestel E, Zieglgansberger W, Holsboer F, Rupprecht R. Source: Biochemical and Biophysical Research Communications. 1996 August 23; 225(3): 957-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8780717
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Functional effects of antipsychotic drugs: comparing clozapine with haloperidol. Author(s): Lahti AC, Holcomb HH, Weiler MA, Medoff DR, Tamminga CA. Source: Biological Psychiatry. 2003 April 1; 53(7): 601-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679238
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Further evidence of human leukocyte antigen-encoded susceptibility to clozapineinduced agranulocytosis independent of ancestry. Author(s): Dettling M, Schaub RT, Mueller-Oerlinghausen B, Roots I, Cascorbi I. Source: Pharmacogenetics. 2001 March; 11(2): 135-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11266078
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Gabapentin for clozapine-related seizures. Author(s): Landry P. Source: The American Journal of Psychiatry. 2001 November; 158(11): 1930-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11691708
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Gabapentin prophylaxis of clozapine-induced seizures. Author(s): Usiskin SI, Nicolson R, Lenane M, Rapoport JL. Source: The American Journal of Psychiatry. 2000 March; 157(3): 482-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10698845
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Gains in speeded information processing following clozapine treatment of schizophrenia. Author(s): Townsend LA, Manchanda R. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2004 January; 49(1): 77-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14763687
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Gastroesophageal reflux as a possible result of clozapine treatment. Author(s): Baker RW, Chengappa KN. Source: The Journal of Clinical Psychiatry. 1998 May; 59(5): 257. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9632041
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Gating of auditory P50 in schizophrenics: unique effects of clozapine. Author(s): Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R. Source: Biological Psychiatry. 1996 August 1; 40(3): 181-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8830951
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G-CSF plasma levels in clozapine-induced neutropenia. Author(s): Jauss M, Pantel J, Werle E, Schroder J. Source: Biological Psychiatry. 2000 December 1; 48(11): 1113-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11094146
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Gender differences in neuroleptic nonresponsive clozapine-treated schizophrenics. Author(s): Szymanski S, Lieberman J, Pollack S, Kane JM, Safferman A, Munne R, Umbricht D, Woerner M, Masiar S, Kronig M. Source: Biological Psychiatry. 1996 February 15; 39(4): 249-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8645771
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Generalization of clozapine as compared to other antipsychotic agents to a discriminative stimulus elicited by the serotonin (5-HT)2A antagonist, MDL100,907. Author(s): Dekeyne A, Iob L, Millan MJ. Source: Neuropharmacology. 2003 April; 44(5): 604-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12668046
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Generalization of serotonin (5-HT)1A agonists and the antipsychotics, clozapine, ziprasidone and S16924, but not haloperidol, to the discriminative stimuli elicited by PD128,907 and 7-OH-DPAT. Author(s): Dekeyne A, Rivet JM, Gobert A, Millan MJ. Source: Neuropharmacology. 2001 June; 40(7): 899-910. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11378160
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Generic clozapine: a cost-saving alternative to brand name clozapine? Author(s): Tse G, Thompson D, Procyshyn RM. Source: Pharmacoeconomics. 2003; 21(1): 1-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12484800
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Generic replacement of clozapine: a simple decision model from a Canadian perspective. Author(s): Layton S, Barbeau M. Source: Current Medical Research and Opinion. 2004 April; 20(4): 453-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15119982
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Genetic determinants of clozapine-induced agranulocytosis: recent results of HLA subtyping in a non-jewish caucasian sample. Author(s): Dettling M, Cascorbi I, Roots I, Mueller-Oerlinghausen B. Source: Archives of General Psychiatry. 2001 January; 58(1): 93-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11146763
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Genetic factors in clozapine-induced agranulocytosis. Author(s): Reznik I, Mester R. Source: Isr Med Assoc J. 2000 November; 2(11): 857-8. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11344758
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Genetic predictors of therapeutic response to clozapine: current status of research. Author(s): Mancama D, Arranz MJ, Kerwin RW. Source: Cns Drugs. 2002; 16(5): 317-24. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11994021
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Genetic variant of the histamine-1 receptor (glu349asp) and body weight change during clozapine treatment. Author(s): Hong CJ, Lin CH, Yu YW, Chang SC, Wang SY, Tsai SJ. Source: Psychiatric Genetics. 2002 September; 12(3): 169-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12218662
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Genetic variants of the serotonin system and weight change during clozapine treatment. Author(s): Hong CJ, Lin CH, Yu YW, Yang KH, Tsai SJ. Source: Pharmacogenetics. 2001 April; 11(3): 265-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11337942
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Grand mal seizures with liver toxicity in a case of clozapine treatment. Author(s): Panagiotis B. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 1999 Winter; 11(1): 117-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9990571
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Granulocyte colony-stimulating factor plasma levels during clozapine- and olanzapine-induced granulocytopenia. Author(s): Schuld A, Kraus T, Hinze-Selch D, Haack M, Pollmacher T. Source: Acta Psychiatrica Scandinavica. 2000 August; 102(2): 153-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10937789
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Granulocyte colony-stimulating factor treatment of clozapine-induced agranulocytosis. Author(s): Pasquale D, Newton M, Goss JB, Simor G, Lesieur S. Source: The American Journal of Psychiatry. 1996 November; 153(11): 1503-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8890691
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Granulocytopenia with clozapine and quetiapine. Author(s): Diaz P, Hogan TP. Source: The American Journal of Psychiatry. 2001 April; 158(4): 651. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11282709
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Haematological monitoring with clozapine therapy in India. Author(s): Tharyan P. Source: The British Journal of Psychiatry; the Journal of Mental Science. 1998 June; 172: 540. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9828998
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Haloperidol disrupts, clozapine reinstates the circadian rest-activity cycle in a patient with early-onset Alzheimer disease. Author(s): Wirz-Justice A, Werth E, Savaskan E, Knoblauch V, Gasio PF, Muller-Spahn F. Source: Alzheimer Disease and Associated Disorders. 2000 October-December; 14(4): 212-5. Erratum In: Alzheimer Dis Assoc Disord 2001 April-June; 15(2): 101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11186599
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Health care costs of therapy-refractory schizophrenic patients treated with clozapine: a study in a community psychiatric service in Italy. Author(s): Percudani M, Fattore G, Galletta J, Mita PL, Contini A, Altamura AC. Source: Acta Psychiatrica Scandinavica. 1999 April; 99(4): 274-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10223430
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Health status and health care costs for publicly funded patients with schizophrenia started on clozapine. Author(s): Blieden N, Flinders S, Hawkins K, Reid M, Alphs LD, Arfken CL. Source: Psychiatric Services (Washington, D.C.). 1998 December; 49(12): 1590-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9856622
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Heart rate dynamics and their relationship to psychotic symptom severity in clozapine-treated schizophrenic subjects. Author(s): Kim JH, Yi SH, Yoo CS, Yang SA, Yoon SC, Lee KY, Ahn YM, Kang UG, Kim YS. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2004 March; 28(2): 371-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751435
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Heart-rate variability (HRV) in the ECG trace of routine EEGs: fast monitoring for the anticholinergic effects of clozapine and olanzapine? Author(s): Eschweiler GW, Bartels M, Langle G, Wild B, Gaertner I, Nickola M. Source: Pharmacopsychiatry. 2002 May; 35(3): 96-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12107853
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Hepatic encephalopathy associated with combined clozapine and divalproex sodium treatment. Author(s): Wirshing WC, Ames D, Bisheff S, Pierre JM, Mendoza A, Sun A. Source: Journal of Clinical Psychopharmacology. 1997 April; 17(2): 120-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10950478
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Hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria occurring early in clozapine treatment. Author(s): Thompson J, Chengappa KN, Good CB, Baker RW, Kiewe RP, Bezner J, Schooler NR. Source: International Clinical Psychopharmacology. 1998 March; 13(2): 95-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9669191
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High-dose clozapine intoxication. Author(s): Sartorius A, Hewer W, Zink M, Henn FA. Source: Journal of Clinical Psychopharmacology. 2002 February; 22(1): 91-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11799349
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HLA-A2 and B35 are strong predictors of responsiveness to clozapine: preliminary data in Italian schizophrenia patients. Author(s): Marchini M, Scorza R, Antonioli R, Scarone S, Grassi B, Epifani M, Dragoni C. Source: Schizophrenia Research. 2001 March 30; 48(2-3): 363-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11368031
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HLA-B38 and clozapine-induced agranulocytosis in Israeli Jewish schizophrenic patients. Author(s): Valevski A, Klein T, Gazit E, Meged S, Stein D, Elizur A, Narinsky ER, Kutzuk D, Weizman A. Source: European Journal of Immunogenetics : Official Journal of the British Society for Histocompatibility and Immunogenetics. 1998 February; 25(1): 11-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9587740
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Hospital days in clozapine-treated patients. Author(s): Dickson RA, Dalby JT, Williams R, Warden SJ. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 1998 November; 43(9): 945-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9825168
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How does the benzamide antipsychotic amisulpride get into the brain?--An in vitro approach comparing amisulpride with clozapine. Author(s): Hartter S, Huwel S, Lohmann T, Abou El Ela A, Langguth P, Hiemke C, Galla HJ. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2003 November; 28(11): 1916-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865899
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How long to wait for a response to clozapine: a comparison of time course of response to clozapine and conventional antipsychotic medication in refractory schizophrenia. Author(s): Rosenheck R, Evans D, Herz L, Cramer J, Xu W, Thomas J, Henderson W, Charney D. Source: Schizophrenia Bulletin. 1999; 25(4): 709-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10667741
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How reliable are reported plasma clozapine levels? Author(s): Bell R, McLaren A, Copolov D. Source: The Australian and New Zealand Journal of Psychiatry. 2001 August; 35(4): 46873. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11531727
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Human genetic variations in the 5HT2A receptor: a single nucleotide polymorphism identified with altered response to clozapine. Author(s): Harvey L, Reid RE, Ma C, Knight PJ, Pfeifer TA, Grigliatti TA. Source: Pharmacogenetics. 2003 February; 13(2): 107-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12563180
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Human leukocyte antigen typing, response to neuroleptics, and clozapine-induced agranulocytosis in jewish Israeli schizophrenic patients. Author(s): Meged S, Stein D, Sitrota P, Melamed Y, Elizur A, Shmuelian I, Gazit E. Source: International Clinical Psychopharmacology. 1999 September; 14(5): 305-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10529073
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Hyperglycemia, hyperlipemia, and periodic paralysis: a case report of new side effects of clozapine. Author(s): Wu G, Dias P, Chun W, Li G, Kumar S, Singh S. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2000 November; 24(8): 1395-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11125862
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Hypotension associated with clozapine after cardiopulmonary bypass. Author(s): Donnelly JG, MacLeod AD. Source: Journal of Cardiothoracic and Vascular Anesthesia. 1999 October; 13(5): 597-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10527233
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Impact of clozapine on completed suicide. Author(s): Sernyak MJ, Desai R, Stolar M, Rosenheck R. Source: The American Journal of Psychiatry. 2001 June; 158(6): 931-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11384902
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Increase in plasma levels of clozapine and norclozapine after administration of nefazodone. Author(s): Khan AY, Preskorn SH. Source: The Journal of Clinical Psychiatry. 2001 May; 62(5): 375-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11411823
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Increased apoptosis of neutrophils in a case of clozapine-induced agranulocytosis - a case report. Author(s): Loeffler S, Fehsel K, Henning U, Fischer J, Agelink M, Kolb-Bachofen V, Klimke A. Source: Pharmacopsychiatry. 2003 January; 36(1): 37-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12649775
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Increased dopamine d(2) receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine. Author(s): Kapur S, Roy P, Daskalakis J, Remington G, Zipursky R. Source: The American Journal of Psychiatry. 2001 February; 158(2): 311-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11156818
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Increased risk of neutropaenia and agranulocytosis with sodium valproate used adjunctively with clozapine. Author(s): Pantelis C, Adesanya A. Source: The Australian and New Zealand Journal of Psychiatry. 2001 August; 35(4): 5445. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11531743
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Increased risk of side-effects in psychiatric patients treated with clozapine and carbamazepine: a reanalysis. Author(s): Langbehn DR, Alexander B. Source: Pharmacopsychiatry. 2000 September; 33(5): 196. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11071023
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Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Author(s): Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura GJ, Pioli R, Boin F, Kenis G, Bosmans E, de Jongh R, Altamura CA. Source: Schizophrenia Research. 2002 April 1; 54(3): 281-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11950553
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Increased use of antibiotics in clozapine-treated patients. Author(s): Landry P, Benaliouad F, Tessier S. Source: International Clinical Psychopharmacology. 2003 September; 18(5): 297-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12920391
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Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. Author(s): Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Source: Journal of Clinical Psychopharmacology. 2004 February; 24(1): 70-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709950
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Influence of methodology on outcomes of randomised clozapine trials. Author(s): Wahlbeck K, Tuunainen A, Gilbody S, Adams CE. Source: Pharmacopsychiatry. 2000 March; 33(2): 54-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10761820
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Initiation of clozapine therapy in a patient with preexisting leukopenia: a discussion of the rationale of current treatment options. Author(s): Boshes RA, Manschreck TC, Desrosiers J, Candela S, Hanrahan-Boshes M. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 2001 December; 13(4): 233-7. Erratum In: Ann Clin Psychiatry. 2002 June; 14(2): 141. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11958365
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Insulin-resistant hyperglycemia induced by clozapine. Author(s): Isakov I, Klesmer J, Masand PS. Source: Psychosomatics. 2000 July-August; 41(4): 373-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10906368
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Interaction of sertraline with clozapine. Author(s): Pinninti NR, de Leon J. Source: Journal of Clinical Psychopharmacology. 1997 April; 17(2): 119-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10950477
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Interferon-alpha-induced agranulocytosis in a patient on long-term clozapine therapy. Author(s): Hoffmann RM, Ott S, Parhofer KG, Bartl R, Pape GR. Source: Journal of Hepatology. 1998 July; 29(1): 170. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9696507
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Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response. Author(s): Mancama D, Arranz MJ, Munro J, Osborne S, Makoff A, Collier D, Kerwin R. Source: Neuroscience Letters. 2002 November 29; 333(3): 207-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12429384
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Investigation of the potential of clozapine to cause torsade de pointes. Author(s): Warner B, Hoffmann P. Source: Adverse Drug Reactions and Toxicological Reviews. 2002; 21(4): 189-203. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12503253
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Is clozapine useful in schizophrenic patients with concomitant chronic inflammatory disease? Author(s): Schreiner A, Hewer W. Source: Pharmacopsychiatry. 2000 July; 33(4): 153-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10958267
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Is the time course of clozapine response correlated to the time course of clozapine plasma levels? A one-year prospective study in drug-resistant patients with schizophrenia. Author(s): Fabrazzo M, La Pia S, Monteleone P, Esposito G, Pinto A, De Simone L, Bencivenga R, Maj M. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2002 December; 27(6): 1050-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12464462
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Isolation and identification of clozapine metabolites in patient urine. Author(s): Schaber G, Wiatr G, Wachsmuth H, Dachtler M, Albert K, Gaertner I, BreyerPfaff U. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2001 June; 29(6): 923-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11353764
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Jet lag and relapse of schizoaffective psychosis despite maintenance clozapine treatment. Author(s): Oyewumi LK. Source: The British Journal of Psychiatry; the Journal of Mental Science. 1998 September; 173: 268. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9926107
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Ketoacidosis as a side-effect of clozapine: a case report. Author(s): Kostakoglu AE, Yazici KM, Erbas T, Guvener N. Source: Acta Psychiatrica Scandinavica. 1996 March; 93(3): 217-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8739670
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Kindling with clozapine: behavioral and molecular consequences. Author(s): Stevens JR, Denney D, Szot P. Source: Epilepsy Research. 1996 December; 26(1): 295-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8985708
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Lack of a pharmacokinetic interaction between mirtazapine and the newer antipsychotics clozapine, risperidone and olanzapine in patients with chronic schizophrenia. Author(s): Zoccali R, Muscatello MR, Torre DL, Malara G, Canale A, Crucitti D, D'Arrigo C, Spina E. Source: Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 2003 October; 48(4): 411-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12902213
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Lamotrigine and clozapine for bipolar disorder. Author(s): Calabrese JR, Gajwani P. Source: The American Journal of Psychiatry. 2000 September; 157(9): 1523. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10964878
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Lamotrigine--clozapine combination in refractory schizophrenia: three cases. Author(s): Saba G, Dumortier G, Kalalou K, Benadhira R, Degrassat K, Glikman J, Januel D. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2002 Winter; 14(1): 86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11884664
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Late onset neutropenia during clozapine treatment. Author(s): Tamam L, Kulan E, Ozpoyraz N. Source: Psychiatry and Clinical Neurosciences. 2001 October; 55(5): 547-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11555354
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Late-onset agranulocytosis in a patient with schizophrenia after 17 months of clozapine treatment. Author(s): Bhanji NH, Margolese HC, Chouinard G, Turnier L. Source: Journal of Clinical Psychopharmacology. 2003 October; 23(5): 522-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520134
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LC-MS-MS analysis of the neuroleptics clozapine, flupentixol, haloperidol, penfluridol, thioridazine, and zuclopenthixol in hair obtained from psychiatric patients. Author(s): Weinmann W, Muller C, Vogt S, Frei A. Source: Journal of Analytical Toxicology. 2002 July-August; 26(5): 303-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12166818
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Leptin concentrations are increased in subjects treated with clozapine or conventional antipsychotics. Author(s): Hagg S, Soderberg S, Ahren B, Olsson T, Mjorndal T. Source: The Journal of Clinical Psychiatry. 2001 November; 62(11): 843-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11775042
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Lethal gastroenteritis associated with clozapine and loperamide. Author(s): Eronen M, Putkonen H, Hallikainen T, Vartiainen H. Source: The American Journal of Psychiatry. 2003 December; 160(12): 2242-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14638602
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Leucopenia induced by low dose clozapine in Parkinson's disease recedes shortly after drug withdrawal. Clinical case descriptions with commentary on switch-over to olanzapine. Author(s): Onofrj M, Thomas A, Bonanni L, Iacono D, Gambi F. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2000 August; 21(4): 209-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11214659
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Lithium and clozapine-induced neutropenia/agranulocytosis. Author(s): Blier P, Slater S, Measham T, Koch M, Wiviott G. Source: International Clinical Psychopharmacology. 1998 May; 13(3): 137-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9690982
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Long-term combination treatment with clozapine and filgrastim in patients with clozapine-induced agranulocytosis. Author(s): Hagg S, Rosenius S, Spigset O. Source: International Clinical Psychopharmacology. 2003 May; 18(3): 173-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702898
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Long-term outcome with clozapine: comparison of patients continuing and discontinuing treatment. Author(s): Laker MK, Duffett RS, Cookson JC. Source: International Clinical Psychopharmacology. 1998 March; 13(2): 75-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9669187
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Long-term treatment with clozapine in an adult with autistic disorder accompanied by aggressive behaviour. Author(s): Gobbi G, Pulvirenti L. Source: Journal of Psychiatry & Neuroscience : Jpn. 2001 September; 26(4): 340-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11590976
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Low blood selenium concentrations in schizophrenic patients on clozapine. Author(s): Vaddadi KS, Soosai E, Vaddadi G. Source: British Journal of Clinical Pharmacology. 2003 March; 55(3): 307-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12630982
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Low-dose clozapine and diabetic ketoacidosis. Author(s): Lafayette JM, Pirl WF, Henderson DC. Source: Psychosomatics. 2003 May-June; 44(3): 249-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12724507
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Low-dose clozapine for the treatment of Parkinson's disease in a patient with schizophrenia. Author(s): Orr G, Munitz H, Hermesh H. Source: Clinical Neuropharmacology. 2001 March-April; 24(2): 117-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11307050
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Marked clozapine-induced slowing of EEG background over frontal, central, and parietal scalp areas in schizophrenic patients. Author(s): Joutsiniemi SL, Gross A, Appelberg B. Source: Journal of Clinical Neurophysiology : Official Publication of the American Electroencephalographic Society. 2001 January; 18(1): 9-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11290933
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Maternal clozapine treatment and decreased fetal heart rate variability. Author(s): Yogev Y, Ben-Haroush A, Kaplan B. Source: International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. 2002 December; 79(3): 259-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12445996
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Metoclopramide-related pisa syndrome in clozapine treatment. Author(s): Kropp S, Hauser U, Emrich HM, Grohmann R. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2001 Summer; 13(3): 427-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11514658
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Modafinil-associated clozapine toxicity. Author(s): Dequardo JR. Source: The American Journal of Psychiatry. 2002 July; 159(7): 1243-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091210
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Modelling the impact of clozapine on suicide in patients with treatment-resistant schizophrenia in the UK. Author(s): Duggan A, Warner J, Knapp M, Kerwin R. Source: The British Journal of Psychiatry; the Journal of Mental Science. 2003 June; 182: 505-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777341
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Monitoring clozapine: are fingerprick blood and plasma clozapine levels equivalent to arm venipuncture blood and plasma levels? Author(s): Goossen RB, Freeman DJ, Satchell AM, Urquhart BL. Source: Therapeutic Drug Monitoring. 2003 August; 25(4): 469-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883231
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Morning pseudoneutropenia during clozapine treatment. Author(s): Esposito D, Aouille J, Rouillon F, Limosin F. Source: World J Biol Psychiatry. 2003 October; 4(4): 192-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14608591
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Myocarditis and cardiomyopathy associated with clozapine use in the United States. Author(s): La Grenade L, Graham D, Trontell A. Source: The New England Journal of Medicine. 2001 July 19; 345(3): 224-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11463031
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Myocarditis related to clozapine treatment. Author(s): Hagg S, Spigset O, Bate A, Soderstrom TG. Source: Journal of Clinical Psychopharmacology. 2001 August; 21(4): 382-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11476122
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Myoclonic and generalized tonic clonic seizures during combined treatment with low doses of clozapine and haloperidol. Author(s): Haberfellner EM. Source: European Psychiatry : the Journal of the Association of European Psychiatrists. 2002 March; 17(1): 55-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11918994
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Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Author(s): Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, Kunz M, Chakos M, Cooper TB, Horowitz TL, Lieberman JA. Source: The American Journal of Psychiatry. 2002 June; 159(6): 1018-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12042192
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Neuroendocrine responsivities of the pituitary dopamine system in male schizophrenic patients during treatment with clozapine, olanzapine, risperidone, sulpiride, or haloperidol. Author(s): Markianos M, Hatzimanolis J, Lykouras L. Source: European Archives of Psychiatry and Clinical Neuroscience. 2001 June; 251(3): 141-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11697576
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Neuroleptic malignant syndrome associated with long-term clozapine treatment: report of a case and results of a clozapine rechallenge. Author(s): Huang TL. Source: Chang Gung Med J. 2001 August; 24(8): 522-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11601195
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Neutropenia with clozapine and methazolamide. Author(s): Burke WJ, Ranno AE. Source: Journal of Clinical Psychopharmacology. 1994 October; 14(5): 357-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7806694
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Newer atypical antipsychotic medication in comparison to clozapine: a systematic review of randomized trials. Author(s): Tuunainen A, Wahlbeck K, Gilbody S. Source: Schizophrenia Research. 2002 July 1; 56(1-2): 1-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12084413
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No association of tumor necrosis factor alpha gene polymorphisms with schizophrenia or response to clozapine. Author(s): Tsai SJ, Hong CJ, Yu YW, Lin CH, Liu LL. Source: Schizophrenia Research. 2003 December 1; 65(1): 27-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623371
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No effect of reboxetine on plasma concentrations of clozapine, risperidone, and their active metabolites. Author(s): Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Levita A. Source: Therapeutic Drug Monitoring. 2001 December; 23(6): 675-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11802103
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No evidence for a direct effect of clozapine on fat-cell formation and production of leptin and other fat-cell-derived factors. Author(s): Hauner H, Rohrig K, Hebebrand J, Skurk T. Source: Molecular Psychiatry. 2003 March; 8(3): 258-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12660797
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Nothing new under the sun: clozapine rechallenge following a life-threatening medical event in a patient with psychiatric illness and developmental disability. Author(s): Shedlack KJ, Levesque C, Charlot L, Bolduc M, Silka VR, Mikkelsen EJ, Cole JO. Source: Harvard Review of Psychiatry. 2003 November-December; 11(6): 344-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14713570
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Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Author(s): Gutierrez B, Arranz MJ, Huezo-Diaz P, Dempster D, Matthiasson P, Travis M, Munro J, Osborne S, Kerwin RW. Source: Schizophrenia Research. 2002 November 1; 58(1): 93-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12363396
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Obsessive-compulsive symptoms and clozapine. Author(s): Buckley PF, Schulz SC. Source: The British Journal of Psychiatry; the Journal of Mental Science. 1994 September; 165(3): 408. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7994520
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Obsessive-compulsive symptoms during treatment with clozapine in a patient with schizophrenia. Author(s): Cheung EF. Source: The Australian and New Zealand Journal of Psychiatry. 2001 October; 35(5): 6956. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11551293
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Olanzapine and clozapine: comparative effects on motor function in hallucinating PD patients. Author(s): Goetz CG, Blasucci LM, Leurgans S, Pappert EJ. Source: Neurology. 2000 September 26; 55(6): 789-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10993997
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Olanzapine and clozapine: comparative effects on motor function in hallucinating PD patients. Author(s): Leucht S. Source: Neurology. 2001 August 28; 57(4): 747. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11548736
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Olanzapine and clozapine: comparative effects on motor function in hallucinating PD patients. Author(s): Sa DS, Lang AE. Source: Neurology. 2001 August 28; 57(4): 747. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11524507
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Olanzapine appears haematologically safe in patients who developed blood dyscrasia on clozapine and risperidone. Author(s): Dernovsek MZ, Tavcar R. Source: International Clinical Psychopharmacology. 2000 July; 15(4): 237-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10954065
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Olanzapine prolongation of granulocytopenia after clozapine discontinuation. Author(s): Konakanchi R, Grace JJ, Szarowicz R, Pato MT. Source: Journal of Clinical Psychopharmacology. 2000 December; 20(6): 703-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11106146
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Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Author(s): Bitter I, Dossenbach MR, Brook S, Feldman PD, Metcalfe S, Gagiano CA, Furedi J, Bartko G, Janka Z, Banki CM, Kovacs G, Breier A; Olanzapine HGCK Study Group. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2004 January; 28(1): 173-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687871
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Olanzapine-induced neutropenia in patients with history of clozapine treatment: two case reports from a state psychiatric institution. Author(s): Teter CJ, Early JJ, Frachtling RJ. Source: The Journal of Clinical Psychiatry. 2000 November; 61(11): 872-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11105743
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Omeprazole reduces clozapine plasma concentrations. A case report. Author(s): Frick A, Kopitz J, Bergemann N. Source: Pharmacopsychiatry. 2003 May; 36(3): 121-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12806570
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Patterns of concomitant psychotropic medication use during a 2-year study comparing clozapine and olanzapine for the prevention of suicidal behavior. Author(s): Glick ID, Zaninelli R, Hsu C, Young FK, Weiss L, Gunay I, Kumar V. Source: The Journal of Clinical Psychiatry. 2004 May; 65(5): 679-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15163255
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Pericardial and bilateral pleural effusion associated with clozapine treatment. Author(s): Boot E, de Haan L, Guzelcan Y, Scholte WF, Assies H. Source: European Psychiatry : the Journal of the Association of European Psychiatrists. 2004 February; 19(1): 65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14969785
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Pharmacogenetics of the clozapine response. Author(s): Schumacher J, Schulze TG, Wienker TF, Rietschel M, Nothen MM. Source: Lancet. 2000 August 5; 356(9228): 506-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10981913
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Plasma levels of clozapine and desmethylclozapine are unaffected by concomitant ingestion of grapefruit juice. Author(s): Vandel S, Netillard C, Perault MC, Bel AM. Source: European Journal of Clinical Pharmacology. 2000 July; 56(4): 347-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10954351
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Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Author(s): Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT Jr. Source: The American Journal of Psychiatry. 1998 June; 155(6): 751-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9619146
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Postmortem clozapine levels. Author(s): de Leon J, Simpson GM. Source: Journal of Clinical Psychopharmacology. 2004 February; 24(1): 100-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709959
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Potential clozapine target sites on peripheral hematopoietic cells and stromal cells of the bone marrow. Author(s): Pereira A, McLaren A, Bell WR, Copolov D, Dean B. Source: The Pharmacogenomics Journal. 2003; 3(4): 227-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12931136
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Predictors of clinical outcome in schizophrenic patients responding to clozapine. Author(s): Mauri MC, Volonteri LS, Dell'Osso B, Regispani F, Papa P, Baldi M, Bareggi SR. Source: Journal of Clinical Psychopharmacology. 2003 December; 23(6): 660-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624196
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Prevalence of diabetes and impaired glucose tolerance in patients treated with clozapine compared with patients treated with conventional depot neuroleptic medications. Author(s): Hagg S, Joelsson L, Mjorndal T, Spigset O, Oja G, Dahlqvist R. Source: The Journal of Clinical Psychiatry. 1998 June; 59(6): 294-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9671341
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Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. Author(s): Volavka J, Czobor P, Cooper TB, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA. Source: The Journal of Clinical Psychiatry. 2004 January; 65(1): 57-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744169
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Quality of life in schizophrenia: a comparison of instruments. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. Author(s): Cramer JA, Rosenheck R, Xu W, Thomas J, Henderson W, Charney DS. Source: Schizophrenia Bulletin. 2000; 26(3): 659-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10993404
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Quantified EEG changes associated with a positive clinical response to clozapine in schizophrenia. Author(s): Lacroix D, Chaput Y, Rodriguez JP, Filion M, Morrison D, St-Denis P, Albert JM. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1995 September; 19(5): 861-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8539424
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Quantitative EEG in schizophrenia and in response to acute and chronic clozapine treatment. Author(s): Knott V, Labelle A, Jones B, Mahoney C. Source: Schizophrenia Research. 2001 May 30; 50(1-2): 41-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11378313
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Quetiapine as an alternative to clozapine in the treatment of dopamimetic psychosis in patients with Parkinson's disease. Author(s): Menza MM, Palermo B, Mark M. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 1999 September; 11(3): 141-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10482124
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Quetiapine versus clozapine: a preliminary report of comparative effects on dopaminergic psychosis in patients with Parkinson's disease. Author(s): Morgante L, Epifanio A, Spina E, Di Rosa AE, Zappia M, Basile G, La Spina P, Quattrone A. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2002 September; 23 Suppl 2: S89-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12548358
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Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report. Author(s): Sacchetti E, Valsecchi P. Source: International Clinical Psychopharmacology. 2003 November; 18(6): 357-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14571157
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Rapid capillary electrophoretic method for the determination of clozapine and desmethylclozapine in human plasma. Author(s): Raggi MA, Bugamelli F, Mandrioli R, Sabbioni C, Volterra V, Fanali S. Source: J Chromatogr A. 2001 May 4; 916(1-2): 289-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11382303
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Re: Schizophrenia, suicide, and blood count during treatment with clozapine. Author(s): Pompili M, Mancinelli I, Tatarelli R. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2002 December; 47(10): 977. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12553141
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Regional selectivity in clozapine treatment? Author(s): Kessler RM, Meltzer HY. Source: The American Journal of Psychiatry. 2002 June; 159(6): 1064-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12042207
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Reintroduction of clozapine after diagnosis of lymphoma. Author(s): Hundertmark J, Campbell P. Source: The British Journal of Psychiatry; the Journal of Mental Science. 2001 June; 178: 576. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11388983
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Relation of blood counts during clozapine treatment to serum concentrations of clozapine and nor-clozapine. Author(s): Oyewumi LK, Cernovsky ZZ, Freeman DJ, Streiner DL. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2002 April; 47(3): 257-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11987477
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Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses. Author(s): Melkersson KI, Dahl ML. Source: Psychopharmacology. 2003 November; 170(2): 157-66. Epub 2003 July 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851739
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Reversal of pathologic cardiac parameters after transition from clozapine to olanzapine treatment: a case report. Author(s): Cohen H, Loewenthal U, Matar MA, Kotler M. Source: Clinical Neuropharmacology. 2001 March-April; 24(2): 106-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11307047
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Reversible myocarditis in a patient receiving clozapine. Author(s): Kirpekar VC, Deshpande SM, Joshi PP. Source: Indian Heart J. 2001 November-December; 53(6): 779-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11838936
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Rhabdomyolysis associated with clozapine treatment in a patient with decreased calcium-dependent potassium permeability of cell membranes. Author(s): Koren W, Koren E, Nacasch N, Ehrenfeld M, Gur H. Source: Clinical Neuropharmacology. 1998 July-August; 21(4): 262-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9704170
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Risperidone added to clozapine: impact on serum prolactin levels. Author(s): Henderson DC, Goff DC, Connolly CE, Borba CP, Hayden D. Source: The Journal of Clinical Psychiatry. 2001 August; 62(8): 605-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11561931
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Safety and efficacy of combined clozapine-lithium pharmacotherapy. Author(s): Bender S, Linka T, Wolstein J, Gehendges S, Paulus HJ, Schall U, Gastpar M. Source: The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (Cinp). 2004 March; 7(1): 59-63. Epub 2004 January 20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14731311
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Scolpolamine patch for clozapine-induced sialorrhea. Author(s): Gaftanyuk O, Trestman RL. Source: Psychiatric Services (Washington, D.C.). 2004 March; 55(3): 318. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15001737
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Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report. Author(s): de Leon J, Diaz FJ. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2003 September; 27(6): 1059-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14499324
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Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Author(s): Masellis M, Basile V, Meltzer HY, Lieberman JA, Sevy S, Macciardi FM, Cola P, Howard A, Badri F, Nothen MM, Kalow W, Kennedy JL. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 1998 August; 19(2): 123-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9629566
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Serum antimuscarinic activity during clozapine treatment. Author(s): de Leon J, Odom-White A, Josiassen RC, Diaz FJ, Cooper TB, Simpson GM. Source: Journal of Clinical Psychopharmacology. 2003 August; 23(4): 336-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12920408
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Serum clozapine levels: a review of their clinical utility. Author(s): Greenwood-Smith C, Lubman DI, Castle DJ. Source: Journal of Psychopharmacology (Oxford, England). 2003 June; 17(2): 234-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12870573
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Serum concentrations of clozapine and N-desmethylclozapine are unaffected by the potent CYP3A4 inhibitor itraconazole. Author(s): Raaska K, Neuvonen PJ. Source: European Journal of Clinical Pharmacology. 1998 April; 54(2): 167-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9626923
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Severe hyperglycemia associated with high doses of clozapine. Author(s): Kamran A, Doraiswamy PM, Jane JL, Hammett EB, Dunn L. Source: The American Journal of Psychiatry. 1994 September; 151(9): 1395. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8067501
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Six-month review of weight and metabolic parameters in patients receiving clozapine, risperidone, olanzapine, or quetiapine. Author(s): Kelly DL, Kreyenbuhl J, Love RC, Van-Duong Q, Conley RR. Source: The Journal of Clinical Psychiatry. 2003 September; 64(9): 1133-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14628994
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Successful treatment with clozapine at higher doses after clozapine-induced priapism. Author(s): de Nesnera A. Source: The Journal of Clinical Psychiatry. 2003 November; 64(11): 1394-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14658959
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The adjunctive use of a centralised database in the monitoring of clozapine-related neutropenia. Author(s): Pascoe SJ. Source: Pharmacoepidemiology and Drug Safety. 2003 July-August; 12(5): 395-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899114
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The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study. Author(s): Zoccali R, Muscatello MR, Cedro C, Neri P, La Torre D, Spina E, Di Rosa AE, Meduri M. Source: International Clinical Psychopharmacology. 2004 March; 19(2): 71-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15076014
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The effects of clozapine on the GSK-3-mediated signaling pathway. Author(s): Kang UG, Seo MS, Roh MS, Kim Y, Yoon SC, Kim YS. Source: Febs Letters. 2004 February 27; 560(1-3): 115-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14988008
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The effects of clozapine versus haloperidol on measures of impulsive aggression and suicidality in chronic schizophrenia patients: an open, nonrandomized, 6-month study. Author(s): Spivak B, Shabash E, Sheitman B, Weizman A, Mester R. Source: The Journal of Clinical Psychiatry. 2003 July; 64(7): 755-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12934974
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The efficacy of high-dose olanzapine versus clozapine in treatment-resistant schizophrenia: a double-blind crossover study. Author(s): Conley RR, Kelly DL, Richardson CM, Tamminga CA, Carpenter WT Jr. Source: Journal of Clinical Psychopharmacology. 2003 December; 23(6): 668-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624201
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The relationship of clozapine and haloperidol treatment response to prefrontal, hippocampal, and caudate brain volumes. Author(s): Arango C, Breier A, McMahon R, Carpenter WT Jr, Buchanan RW. Source: The American Journal of Psychiatry. 2003 August; 160(8): 1421-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12900303
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Three case reports of emergent dyskinesia with clozapine. Author(s): Gafoor R, Brophy J. Source: European Psychiatry : the Journal of the Association of European Psychiatrists. 2003 August; 18(5): 260-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12927329
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Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder. Author(s): Small JG, Klapper MH, Malloy FW, Steadman TM. Source: Journal of Clinical Psychopharmacology. 2003 June; 23(3): 223-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826983
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Topiramate leukopenia on clozapine. Author(s): Behar D, Schaller JL. Source: European Child & Adolescent Psychiatry. 2004 February; 13(1): 51-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14991432
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Toxic rise of clozapine plasma concentrations in relation to inflammation. Author(s): Haack MJ, Bak ML, Beurskens R, Maes M, Stolk LM, Delespaul PA. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 2003 October; 13(5): 381-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12957337
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Unanticipated plasma concentrations in two clozapine-treated patients. Author(s): Alfaro CL, McClure RK, Vertrees JE, Benavides R. Source: The Annals of Pharmacotherapy. 2001 September; 35(9): 1028-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11573850
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Undiagnosed hyperglycemia in clozapine-treated patients with schizophrenia. Author(s): Sernyak MJ, Gulanski B, Leslie DL, Rosenheck R. Source: The Journal of Clinical Psychiatry. 2003 May; 64(5): 605-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12755666
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Unsuccessful reexposure to clozapine. Author(s): Szarek BL, Goethe JW, Pentz PG. Source: Journal of Clinical Psychopharmacology. 1997 February; 17(1): 71-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9004074
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Uptake of clozapine into HL-60 promyelocytic leukaemia cells. Author(s): Henning U, Loffler S, Krieger K, Klimke A. Source: Pharmacopsychiatry. 2002 May; 35(3): 90-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12107852
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Use of atropine eye drops for clozapine induced hypersalivation. Author(s): Comley C, Galletly C, Ash D. Source: The Australian and New Zealand Journal of Psychiatry. 2000 December; 34(6): 1033-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11127617
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Use of clozapine in 10 mentally retarded adults. Author(s): Buzan RD, Dubovsky SL, Firestone D, Dal Pozzo E. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 1998 Winter; 10(1): 93-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9547472
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Use of clozapine to treat levodopa-induced psychosis in Parkinson's disease: retrospective review. Author(s): Widman LP, Burke WJ, Pfeiffer RF, McArthur-Campbell D. Source: Journal of Geriatric Psychiatry and Neurology. 1997 April; 10(2): 63-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9188021
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Use of clozapine with nonresponsive patients. Author(s): Markowitz JS, Jackson CW. Source: Psychiatric Services (Washington, D.C.). 1996 December; 47(12): 1392. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9117483
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Usefulness of heart rate variability (HRV) for monitoring clozapine plasma levels. Author(s): Agelink MW, Sayar K, Klieser E. Source: Pharmacopsychiatry. 2003 July; 36(4): 166-7; Authors Reply 168. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12905104
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Uses of clozapine in nonschizophrenic patients. Author(s): Frankenburg FR, Zanarini MC. Source: Harvard Review of Psychiatry. 1994 September-October; 2(3): 142-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9384895
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Valproic acid effects on serum concentrations of clozapine and norclozapine. Author(s): Longo LP, Salzman C. Source: The American Journal of Psychiatry. 1995 April; 152(4): 650. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7694927
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Valproic acid treatment of clozapine-induced myoclonus. Author(s): Meltzer HY, Ranjan R. Source: The American Journal of Psychiatry. 1994 August; 151(8): 1246-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8080553
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Venous thromboembolism and clozapine: an association unresolved. Author(s): Anil AE, Ozkan B, Ulusahin A. Source: General Hospital Psychiatry. 2003 January-February; 25(1): 59-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12583935
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Very high cytochrome P4501A2 activity and nonresponse to clozapine. Author(s): Bender S, Eap CB. Source: Archives of General Psychiatry. 1998 November; 55(11): 1048-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9819075
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Violence and schizophrenia: clozapine as a specific antiaggressive agent. Author(s): Buckley P, Bartell J, Donenwirth K, Lee S, Torigoe F, Schulz SC. Source: Bull Am Acad Psychiatry Law. 1995; 23(4): 607-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8639988
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Weight and blood pressure change during clozapine treatment. Author(s): Baymiller SP, Ball P, McMahon RP, Buchanan RW. Source: Clinical Neuropharmacology. 2002 July-August; 25(4): 202-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12151907
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Weight changes during clozapine treatment. Author(s): Briffa D, Meehan T. Source: The Australian and New Zealand Journal of Psychiatry. 1998 October; 32(5): 71821. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9805596
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Weight gain among patients on clozapine. Author(s): Bai YM, Lin CC, Chen JY, Lin CY. Source: Psychiatric Services (Washington, D.C.). 1999 May; 50(5): 704-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10332914
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What is an adequate trial with clozapine?: therapeutic drug monitoring and time to response in treatment-refractory schizophrenia. Author(s): Schulte P. Source: Clinical Pharmacokinetics. 2003; 42(7): 607-18. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12844323
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What is the clinical significance of the discontinuation syndrome seen with clozapine? Author(s): Goudie AJ. Source: Journal of Psychopharmacology (Oxford, England). 2000 June; 14(2): 188-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10890315
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When symptoms persist: clozapine augmentation strategies. Author(s): Buckley P, Miller A, Olsen J, Garver D, Miller DD, Csernansky J. Source: Schizophrenia Bulletin. 2001; 27(4): 615-28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11824488
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When treating patients with schizophrenia, what clinical points should be considered if lamotrigine is chosen to augment clozapine? Author(s): Dursun SM, Devarajan S. Source: Journal of Psychiatry & Neuroscience : Jpn. 2001 March; 26(2): 168. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11496920
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Whole saliva and plasma levels of clozapine and desmethylclozapine. Author(s): Dumortier G, Lochu A, Zerrouk A, Van Nieuwenhuyse V, Colen de Melo P, Roche Rabreau D, Degrassat K. Source: Journal of Clinical Pharmacy and Therapeutics. 1998 February; 23(1): 35-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9756110
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Will routine therapeutic drug monitoring have a place in clozapine therapy? Author(s): Freeman DJ, Oyewumi LK. Source: Clinical Pharmacokinetics. 1997 February; 32(2): 93-100. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9068925
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Withdrawal from clozapine: the "rebound phenomenon". Author(s): Durst R, Teitelbaum A, Katz G, Knobler HY. Source: The Israel Journal of Psychiatry and Related Sciences. 1999; 36(2): 122-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10472746
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Ziprasidone augmentation of clozapine in 11 patients. Author(s): Kaye NS. Source: The Journal of Clinical Psychiatry. 2003 February; 64(2): 215-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12633133
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Ziprasidone-induced Pisa syndrome after clozapine treatment. Author(s): Ziegenbein M, Schomerus G, Kropp S. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2003 Fall; 15(4): 458-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627778
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CHAPTER 2. NUTRITION AND CLOZAPINE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and clozapine.
Finding Nutrition Studies on Clozapine 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 “clozapine” (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.
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The following information is typical of that found when using the “Full IBIDS Database” to search for “clozapine” (or a synonym): •
A case of pharmacokinetic interference in comedication of clozapine and valproic acid. Author(s): Department of Psychiatry I, Regional Hospital Rankweil, Austria. Source: Conca, A Beraus, W Konig, P Waschgler, R Pharmacopsychiatry. 2000 November; 33(6): 234-5 0176-3679
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Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D3 preferring antagonist PNU-99194a: an analysis of possible mechanisms. Author(s): Psychology Department, Liverpool University, UK.
[email protected] Source: Goudie, A J Baker, L E Smith, J A Prus, A J Svensson, K A Cortes Burgos, L A Wong, E H Haadsma Svensson, S Behav-Pharmacol. 2001 September; 12(5): 303-15 09558810
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Computerized EEG profiles of haloperidol, chlorpromazine, clozapine and placebo in treatment resistant schizophrenia. Author(s): Indiana University School of Medicine, Department of Psychiatry, Larue D. Carter Memorial Hospital, Indianapolis 46202. Source: Small, J G Milstein, V Small, I F Miller, M J Kellams, J J Corsaro, C J ClinElectroencephalogr. 1987 July; 18(3): 124-35 0009-9155
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Discriminative stimulus properties of the atypical neuroleptic clozapine in rats: tests with subtype selective receptor ligands. Author(s): Psychology Department, Liverpool University, UK.
[email protected] Source: Goudie, A J Smith, J A Taylor, A Taylor, M A Tricklebank, M D BehavPharmacol. 1998 December; 9(8): 699-710 0955-8810
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Effects of chronic haloperidol and clozapine on vacuous chewing and dopaminemediated jaw movements in rats: evaluation of a revised animal model of tardive dyskinesia. Author(s): Department of Pharmacology, Nihon University School of Dentistry, Tokyo, Japan. Source: Ikeda, H Adachi, K Hasegawa, M Sato, M Hirose, N Koshikawa, N Cools, A R JNeural-Transm. 1999; 106(11-12): 1205-16
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Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat. Author(s): Department of Psychiatry, University of California, San Diego, La Jolla. Source: Swerdlow, N R Keith, V A Braff, D L Geyer, M A J-Pharmacol-Exp-Ther. 1991 February; 256(2): 530-6 0022-3565
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Lack of CYP3A4 inhibition by grapefruit juice and ketoconazole upon clozapine administration in vivo. Author(s): Department of Psychiatry, Tzi-Chi General Hospital and Tzu Chi University School of Medicine, Hualien City, Taiwan. Source: Lane, H Y Chiu, C C Kazmi, Y Desai, H Lam, Y W Jann, M W Chang, W H DrugMetabol-Drug-Interact. 2001; 18(3-4): 263-78 0792-5077
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Lack of effects of apomorphine, haloperidol and clozapine on the synthesis and utilization of brain GABA. Source: Lindgren, S J-Neural-Transm. 1987; 69(1-2): 47-57 0300-9564
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Long-term treatment with chlorpromazine and haloperidol but not with sulpiride and clozapine markedly elevates neuropeptide Y-like immunoreactivity in the rat hypothalamus. Author(s): Department of Clinical Pharmacology, Silesian University School of Medicine, Katowice, Poland. Source: Obuchowicz, E Neuropeptides. 1996 October; 30(5): 471-8 0143-4179
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Low dosage clozapine effects on L-dopa induced dyskinesias in parkinsonian patients. Author(s): Istituto di Clinica delle Malattie Nervose e Mentali, Universita La Sapienza, Rome, Italy. Source: Pierelli, F Adipietro, A Soldati, G Fattapposta, F Pozzessere, G Scoppetta, C Acta-Neurol-Scand. 1998 May; 97(5): 295-9 0001-6314
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Metabolism and bioactivation of clozapine by human liver in vitro. Author(s): Department of Pharmacology and Therapeutics, University of Liverpool, UK. Source: Pirmohamed, M Williams, D Madden, S Templeton, E Park, B K J-PharmacolExp-Ther. 1995 March; 272(3): 984-90 0022-3565
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Modulatory effect of clozapine on levodopa response in Parkinson's disease: a preliminary study. Author(s): Seccion Enfermedades Extrapiramidales, Hospital Frances, Bueons Aires, Argentina. Source: Arevalo, G J Gershanik, O S Mov-Disord. 1993 July; 8(3): 349-54 0885-3185
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Myoclonus during treatment with clozapine and lithium: the role of serotonin. Author(s): Hillside Hospital, Research Department, Glen Oaks, NY 11004. Source: Lemus, C Z Lieberman, J A Johns, C A Hillside-J-Clin-Psychiatry. 1989; 11(2): 127-30 0193-5216
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Nicotine interactions with haloperidol, clozapine and risperidone and working memory function in rats. Author(s): Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. Source: Addy, N Levin, E D Neuropsychopharmacology. 2002 October; 27(4): 534-41 0893-133X
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One year of continuous treatment with haloperidol or clozapine fails to induce a hypersensitive response of caudate putamen neurons to dopamine D1 and D2 receptor agonists. Author(s): Department of Psychiatry and Behavioral Sciences, State University of New York, Stony Brook. Source: Jiang, L H Kasser, R J Altar, C A Wang, R Y J-Pharmacol-Exp-Ther. 1990 June; 253(3): 1198-205 0022-3565
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Response to clozapine in acute mania is more rapid than that of chlorpromazine. Author(s): I.R.C.C.S. Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, University of Milan, School of Medicine, Italy. Source: Barbini, B Scherillo, P Benedetti, F Crespi, G Colombo, C Smeraldi, E Int-ClinPsychopharmacol. 1997 March; 12(2): 109-12 0268-1315
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Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Author(s): Institute of Pharmacology, University of Messina, Italy. Source: Facciola, G Avenoso, A Scordo, M G Madia, A G Ventimiglia, A Perucca, E Spina, E Ther-Drug-Monit. 1999 June; 21(3): 341-5 0163-4356
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The group II metabotropic glutamate receptor agonist (-)-2-oxa-4aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) and clozapine reverse phencyclidine-induced behaviors in monoamine-depleted rats. Author(s): Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA. Source: Swanson, C J Schoepp, D D J-Pharmacol-Exp-Ther. 2002 December; 303(3): 91927 0022-3565
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
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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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/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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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
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
Nutrition
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WebMD®Health: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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The following is a specific Web list relating to clozapine; 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 C Source: Healthnotes, Inc.; www.healthnotes.com
•
Minerals Selenium Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND CLOZAPINE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to clozapine. At the conclusion of this chapter, we will provide additional sources.
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 clozapine 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 “clozapine” (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 clozapine: •
A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. Author(s): Peet M, Horrobin DF; E-E Multicentre Study Group. Source: Journal of Psychiatric Research. 2002 January-February; 36(1): 7-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11755456
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Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone. Author(s): Green AI, Burgess ES, Dawson R, Zimmet SV, Strous RD. Source: Schizophrenia Research. 2003 March 1; 60(1): 81-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12505141
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Altered consciousness states and endogenous psychoses: a common molecular pathway? Author(s): Ciprian-Ollivier J, Cetkovich-Bakmas MG.
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Source: Schizophrenia Research. 1997 December 19; 28(2-3): 257-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9468359 •
Alternatives to lithium and divalproex in the maintenance treatment of bipolar disorder. Author(s): Gnanadesikan M, Freeman MP, Gelenberg AJ. Source: Bipolar Disorders. 2003 June; 5(3): 203-16. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12780874
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An algorithm for the treatment of schizophrenia in the correctional setting: the Forensic Algorithm Project. Author(s): Buscema CA, Abbasi QA, Barry DJ, Lauve TH. Source: The Journal of Clinical Psychiatry. 2000 October; 61(10): 767-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11078038
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Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. Author(s): Bakshi VP, Geyer MA. Source: Psychopharmacology. 1995 November; 122(2): 198-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8848537
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Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Author(s): Swerdlow NR, Braff DL, Taaid N, Geyer MA. Source: Archives of General Psychiatry. 1994 February; 51(2): 139-54. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8297213
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Blockade of drug-induced deficits in prepulse inhibition of acoustic startle by ziprasidone. Author(s): Mansbach RS, Carver J, Zorn SH. Source: Pharmacology, Biochemistry, and Behavior. 2001 July-August; 69(3-4): 535-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11509214
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Body weight changes associated with psychopharmacology. Author(s): Vanina Y, Podolskaya A, Sedky K, Shahab H, Siddiqui A, Munshi F, Lippmann S. Source: Psychiatric Services (Washington, D.C.). 2002 July; 53(7): 842-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12096167
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Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. Author(s): Bakshi VP, Swerdlow NR, Geyer MA.
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Source: The Journal of Pharmacology and Experimental Therapeutics. 1994 November; 271(2): 787-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7965797 •
Clozapine but not haloperidol Re-establishes normal task-activated rCBF patterns in schizophrenia within the anterior cingulate cortex. Author(s): Lahti AC, Holcomb HH, Weiler MA, Medoff DR, Frey KN, Hardin M, Tamminga CA. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2004 January; 29(1): 171-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14520337
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Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism. Author(s): Simosky JK, Stevens KE, Adler LE, Freedman R. Source: Psychopharmacology. 2003 February; 165(4): 386-96. Epub 2002 November 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12459928
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Clozapine therapy in refractory affective disorders: polarity predicts response in longterm follow-up. Author(s): Banov MD, Zarate CA Jr, Tohen M, Scialabba D, Wines JD Jr, Kolbrener M, Kim JW, Cole JO. Source: The Journal of Clinical Psychiatry. 1994 July; 55(7): 295-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8071290
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Clozapine, but not typical antipsychotics, correct P50 suppression deficit in patients with schizophrenia. Author(s): Becker J, Gomes I, Ghisolfi ES, Schuch A, Ramos FL, Ehlers JA, Nora DB, Lara DR, da Costa JC. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2004 February; 115(2): 396-401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744582
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Clozapine's effects on phencyclidine-induced disruption of prepulse inhibition of the acoustic startle response. Author(s): Wiley JL. Source: Pharmacology, Biochemistry, and Behavior. 1994 December; 49(4): 1025-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7886071
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Cognitive behavior therapy for weight gain. Author(s): Umbricht D, Flury H, Bridler R.
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Source: The American Journal of Psychiatry. 2001 June; 158(6): 971. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11384925 •
Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. Author(s): Parikh V, Khan MM, Mahadik SP. Source: Journal of Psychiatric Research. 2003 January-February; 37(1): 43-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12482469
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Disruption of prepulse inhibition following N-methyl-D-aspartate infusion into the ventral hippocampus is antagonized by clozapine but not by haloperidol: a possible model for the screening of atypical antipsychotics. Author(s): Zhang W, Pouzet B, Jongen-Relo AL, Weiner I, Feldon J. Source: Neuroreport. 1999 August 20; 10(12): 2533-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10574365
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Drug-induced potentiation of prepulse inhibition of acoustic startle reflex in mice: a model for detecting antipsychotic activity? Author(s): Ouagazzal AM, Jenck F, Moreau JL. Source: Psychopharmacology. 2001 July; 156(2-3): 273-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11549229
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Effect of dopamine agonists and antagonists on the lorazepam withdrawal syndrome in rats. Author(s): Nath C, Saxena RC, Gupta MB. Source: Clinical and Experimental Pharmacology & Physiology. 2000 March; 27(3): 16771. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10744342
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Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder: a retrospective survey. Author(s): Zimmet SV, Strous RD, Burgess ES, Kohnstamm S, Green AI. Source: Journal of Clinical Psychopharmacology. 2000 February; 20(1): 94-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10653215
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Effects of haloperidol and clozapine on prepulse inhibition of the acoustic startle response and the N1/P2 auditory evoked potential in man. Author(s): Graham SJ, Langley RW, Bradshaw CM, Szabadi E. Source: Journal of Psychopharmacology (Oxford, England). 2001 December; 15(4): 24350. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11769817
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Effects of LU-111995 in three models of disrupted prepulse inhibition in rats. Author(s): Geyer MA, Swerdlow NR, Lehmann-Masten V, Teschendorf HJ, Traut M, Gross G. Source: The Journal of Pharmacology and Experimental Therapeutics. 1999 August; 290(2): 716-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10411583
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Effects of phencyclidine (PCP) and (+)MK-801 on sensorimotor gating in CD-1 mice. Author(s): Curzon P, Decker MW. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1998 January; 22(1): 129-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9533171
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Effects of typical and atypical antipsychotics on the prepulse inhibition of the startle reflex in patients with schizophrenia. Author(s): Oranje B, Van Oel CJ, Gispen-De Wied CC, Verbaten MN, Kahn RS. Source: Journal of Clinical Psychopharmacology. 2002 August; 22(4): 359-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172334
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Electrodermal activity in schizophrenia: a quantitative study using a short interstimulus paradigm. Author(s): Lim CL, Gordon E, Harris A, Bahramali H, Li WM, Manor B, Rennie C. Source: Biological Psychiatry. 1999 January 1; 45(1): 127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9894584
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Elevated plasma level of apolipoprotein D in schizophrenia and its treatment and outcome. Author(s): Mahadik SP, Khan MM, Evans DR, Parikh VV. Source: Schizophrenia Research. 2002 November 1; 58(1): 55-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12363390
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Fatty acid derivatives of clozapine: prolonged antidopaminergic activity of docosahexaenoylclozapine in the rat. Author(s): Baldessarini RJ, Campbell A, Webb NL, Swindell CS, Flood JG, Shashoua VE, Kula NS, Hemamalini S, Bradley MO. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2001 January; 24(1): 55-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11106876
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Genetics, haloperidol-induced catalepsy and haloperidol-induced changes in acoustic startle and prepulse inhibition. Author(s): McCaughran J Jr, Mahjubi E, Decena E, Hitzemann R.
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Source: Psychopharmacology. 1997 November; 134(2): 131-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9399376 •
Haloperidol- and clozapine-induced enhancement of latent inhibition with extended conditioning: implications for the mechanism of action of neuroleptic drugs. Author(s): Weiner I, Shadach E, Barkai R, Feldon J. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 1997 January; 16(1): 42-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8981387
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Helping clozapine help: a role for support groups. Author(s): Zita DF, Goethe J. Source: Schizophrenia Bulletin. 2002; 28(1): 123-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12047011
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Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine. Author(s): Williams DP, Pirmohamed M, Naisbitt DJ, Uetrecht JP, Park BK. Source: Molecular Pharmacology. 2000 July; 58(1): 207-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10860943
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Lack of CYP3A4 inhibition by grapefruit juice and ketoconazole upon clozapine administration in vivo. Author(s): Lane HY, Chiu CC, Kazmi Y, Desai H, Lam YW, Jann MW, Chang WH. Source: Drug Metabol Drug Interact. 2001; 18(3-4): 263-78. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11791889
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Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse inhibition in mice. Author(s): Brody SA, Geyer MA, Large CH. Source: Psychopharmacology. 2003 September; 169(3-4): 240-6. Epub 2003 April 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698229
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Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats. Author(s): Cilia J, Reavill C, Hagan JJ, Jones DN. Source: Psychopharmacology. 2001 July; 156(2-3): 327-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11549233
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Normalization of information processing deficits in schizophrenia with clozapine. Author(s): Kumari V, Soni W, Sharma T.
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Source: The American Journal of Psychiatry. 1999 July; 156(7): 1046-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10401450 •
Plasma clozapine and desmethylclozapine levels in clozapine-induced agranulocytosis. Author(s): Hasegawa M, Cola PA, Meltzer HY. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 1994 August; 11(1): 45-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7945743
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Protein binding study of clozapine by capillary electrophoresis in the frontal analysis mode. Author(s): Zhou D, Li F. Source: Journal of Pharmaceutical and Biomedical Analysis. 2004 June 29; 35(4): 879-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15193732
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Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability. Author(s): Lane HY, Jann MW, Chang YC, Chiu CC, Huang MC, Lee SH, Chang WH. Source: The Journal of Clinical Psychiatry. 2001 October; 62(10): 812-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11816871
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Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys. Author(s): Linn GS, Negi SS, Gerum SV, Javitt DC. Source: Psychopharmacology. 2003 September; 169(3-4): 234-9. Epub 2003 July 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12845408
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Seroquel (ICI 204,636) restores prepulse inhibition of acoustic startle in apomorphinetreated rats: Similarities to clozapine. Author(s): Swerdlow NR, Zisook D, Taaid N. Source: Psychopharmacology. 1994 May; 114(4): 675-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7855231
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The effect of clozapine on the speed and accuracy of information processing in schizophrenia. Author(s): Galletly CA, Clark CR, McFarlane AC, Weber DL. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2000 November; 24(8): 1329-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11125857
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The effects of haloperidol and clozapine on the disruption of sensorimotor gating induced by the noncompetitive glutamate antagonist MK-801. Author(s): Hoffman DC, Donovan H, Cassella JV. Source: Psychopharmacology. 1993; 111(3): 339-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7870972
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The latent inhibition model dissociates between clozapine, haloperidol, and ritanserin. Author(s): Shadach E, Gaisler I, Schiller D, Weiner I. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2000 August; 23(2): 151-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10882841
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/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMD®Health: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to clozapine; 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 Schizophrenia Source: Healthnotes, Inc.; www.healthnotes.com
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•
Herbs and Supplements Clozapine Source: Healthnotes, Inc.; www.healthnotes.com Glycine Source: Healthnotes, Inc.; www.healthnotes.com N-Acetyl Cysteine Source: Healthnotes, Inc.; www.healthnotes.com
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.
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CHAPTER 4. PATENTS ON CLOZAPINE 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.8 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 “clozapine” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on clozapine, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Clozapine By performing a patent search focusing on clozapine, 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
8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on clozapine: •
Agranolocytosis screening procedure Inventor(s): Lieberman; Jeffrey A. (New York, NY), Yunis; Edmond J. (Concord, MA) Assignee(s): Dana-Farber Cancer Institute (Boston, MA), Long Island Jewish Medical Center (New Hyde Park, NY) Patent Number: 5,223,399 Date filed: March 19, 1991 Abstract: Certain patients undergoing clozapine drug therapy may be vulnerable to agranulocytosis. It has been found that agranulocytosis vulnerability is correlated with the presence of HLA antigens B38, DR4 and DQw3. Accordingly, a method is provided for detecting such patients, and an HLA kit is provided. Excerpt(s): This invention relates to a method of screening patients undergoing drug therapy for vulnerability to drug induced agranulocytosis. In particular it relates to a screening procedure to determine before drug therapy is initiated, whether a patient is susceptible to drug induced agranulocytosis. Agranulocytosis is an infrequent but potentially fatal complication associated with certain drugs, that otherwise have less serious side effects and ordinarily are harmless to most patients. The complication is characterized by leukopenia (white blood count less than 2000/cu.mm.), a total absence of polymorphonuclear leukocytes and relative lymphopenia. If the disorder goes unrecognized and treatment with the drug is not discontinued, agranulocytois will run a progressive course of increasing severity culminating in death from infection. If treatment with the drug is discontinued, complete recovery usually occurs. The period of greatest risk of agranulocytosis developing is in the first 3 to 12 weeks of treatment. Psychotic drugs such as neuroleptics, trycyclic antidepressants and the benzodiazepines, have been implicated in producing agranulocytosis. The most significant of these is the atypical neuroleptic drug, clozapine, whose chemical name is 8-chloro-11-(4-methyl-1piperazinyl)-5H-dibenzo[b,e][1,4]diazepine. Clinical studies have shown that clozapine is effective as an antipsychotic agent in patients who are refractory and/or intolerant to classical antipsychotic drug treatment. The compound was found to be superior to standard neuroleptics; and approximately 30% of the patients conservatively defined as being refractory to these neuroleptics significantly improved with clozapine treatment. At the same time, it was found that clozapine does not cause parkinsonism or tardive dyskinesia to the same extent as classical neuroleptics and that it does not elevate prolactin secretion. With regard to tardive dyskinesia, long term treatment with clozapine appears to have a therapeutic effect against this neuroleptic side-effect, particularly the more severe form, tardive dystonia. Web site: http://www.delphion.com/details?pn=US05223399__
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Hypotensive intraocular pressure activity of clozapine and sulpiride Inventor(s): Chen; Ing-Jun (Kaohsiung, TW), Lin; Tong-Ho (7F-1, No.200, Sec.1, FuHsing S.Rd., Taipei, TW) Assignee(s): Lin; Tong-Ho (Taipei, TW) Patent Number: 5,744,468 Date filed: October 23, 1996 Abstract: This invention introduces a novel anti-glaucoma solution which comprises of Clozapine or Sulpiride and a pharmaceutical vehicle. This is the first time all the above agents have been prepared in ophthalmologic solutions, which will be able to decrease the IOP in animals. Excerpt(s): In C. Y. George's 1989 experiment, it was discovered that some dopamine receptor antagonists belonging to an antipsychotic drug were found to be able to reduce intraocular pressure(IOP) and increase the blood flow to the retina, choroid, iris and ciliary body in rabbits. According to Schizophrenia Bull, vol. 17, pp.263-309, 1991 by Meltzer H. Y., antipsychotic drugs can be generally divided into two categories. One is a typical antipsychotic drug which will produce side effects of parkinsonism and tarditive dyskinesia, the other an atypical antipsychotic which won't produce the above side effects. Antipsychotic drugs are usually categorized to be dopamine receptor antagonist. In 1979 Drugs vol. 17 pp. 38-55, reported that a non selective.beta.-adrenergic receptors L-timolol could treat patients with glaucoma in clinics. Therefore it was thought that.beta. blocker drugs could lower the IOP in treating patients with glaucoma. Then in 1986 Inv. Ophthalmol. Vis. Sci. Vol. 27 reported that L-timolol couldn't improve parcipitation of retinopathy. This fact has led many investigators to search for a newer anti-glaucoma agent. Recently subtype D.sub.1A, D.sub.1B, D.sub.2A, D.sub.2B, D.sub.3, D.sub.4 and D.sub.5 have been separated out from a number of dopamine receptors with molecular cloning techniques in 1992 by Sibley D. R.(reported in Sci. Trends Pharmac. Vol. 13, pp. 61-69). Web site: http://www.delphion.com/details?pn=US05744468__
•
Pharmaceutical compositions comprising clozapine and a radical scavenger Inventor(s): Fischer; Volker (Lorrach-Brombach, DE), Mason; Ronald P. (Cary, NC) Assignee(s): Sandoz Ltd. (Basle, CH) Patent Number: 5,312,819 Date filed: August 2, 1991 Abstract: The invention concerns pharmaceutical compositions comprising clozapine and a radical scavenger. Excerpt(s): The present invention relates to novel pharmaceutical compositions comprising clozapine and a radical scavenger preferably L-ascorbic acid. Clozapine, having the chemical name 8-chloro-11-(4-methyl-1-piperazinyl)-5Hdibenzo[b,e][1,4]diazepine, is a neuroleptic drug. Clinical studies have shown that clozapine is effective as an antipsychotic agent in patients who are refractory and/or intolerant to classical antipsychotic drug treatment. The compound was found to be superior in antipsychotic efficacy to standard neuroleptics; and approximately 30% of patients conservatively defined as being refractory to these neuroleptics significantly improved with clozapine treatment.
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Web site: http://www.delphion.com/details?pn=US05312819__ •
Screening method for controlling agranulocytosis Inventor(s): Gerson; Stanton L. (Pepper Pike, OH), Meltzer; Herbert (Shaker Heights, OH) Assignee(s): Case Western Reserve University (Cleveland, OH) Patent Number: 5,300,422 Date filed: December 4, 1991 Abstract: A screening method for detecting the vulnerability of patients on clozapine therapy to developing agranulocytosis which comprises establishing the concentration of N-desmethylclozapine in the blood or bone marrow of said patient. In addition, a method of determining patient sensitivity to N-desmethylclozapine is provided which comprises collecting heparinized blood and assaying it for stem cell sensitivity to Ndesmethylclozapine. Excerpt(s): This invention relates to a method of screening patients undergoing drug therapy for vulnerability to drug-induced agranulocytosis. More particularly, it relates to a screening method for detecting the vulnerability of patients on clozapine therapy to developing agranulocytosis which comprises establishing the concentration of Ndesmethylclozapine in the blood or bone marrow of said patients. Agranulocytosis is an infrequent but potentially fatal complication associated with certain drugs that otherwise have less serious side effects and ordinarily are harmless to most patients. The complication is characterized by leukopenia (white blood count less than 2000/cu.mm.), a total absence of polymorphonuclear leukocytes (defined as less than 500/cu.mm.) and relative lymphopenia. If the disorder goes unrecognized and treatment with the drug is not discontinued, agranulocytosis will run a progressive course of increasing severity culminating in death from infection. If treatment with the drug is discontinued, complete recovery usually occurs. The period of greatest risk of agranulocytosis developing is in the first 3 to 12 weeks of treatment. Antipsychotic drugs such as neuroleptics, tricyclic antidepressants and the benzodiazepines have been implicated in producing agranulocytosis. The most significant of these is the atypical neuroleptic drug, clozapine, whose chemical name is 8-chloro-11-(4-methyl-1-piperazinyl)-5Hdibenzo[b,e]-[1,4]diazepine. Clinical studies have shown that clozapine is effective as an antipsychotic agent in patients who are refractory and/or intolerant to classical antipsychotic drug treatment. The compound was found to be superior to standard neuroleptics; and approximately 30% of the patients conservatively defined as being refractory to these neuroleptics significantly improved with clozapine treatment. At the same time, it was found that clozapine does not cause parkinsonism or tardive dyskinesia to the same extent as classical neuroleptics and that it does not elevate prolactin secretion. With regard to tardive dyskinesia, long term treatment with clozapine appears to have a therapeutic effect against this neuroleptic side-effect, particularly the more severe form, tardive dystonia. Web site: http://www.delphion.com/details?pn=US05300422__
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Treatment of dyskinesias Inventor(s): Sayers; Anthony Campbell (Koniz, CH) Assignee(s): Sandoz Ltd. (Basel, CH) Patent Number: 3,983,234 Date filed: June 25, 1975 Abstract: Clozapine is useful in the treatment of dyskinesias. Excerpt(s): The present invention relates to a new therapeutic use of the compound 8chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine (clozapine) in the suppression of dyskinesias induced by dopaminergic substancies, such as DOPA [3-(3,4dihydroxyphenyl)-L-alanine] used for the treatment of Parkinson's disease, as indicated by a suppression of the hypersensitiveness of DA receptors, but without any blocking of these receptors, in the following tests in rats on administration of from 0.4 to 80 mg/kg animal body weight daily. The favourable effect of clozapine is indicated inter ali in tests conducted with rats in which a unilaterial lesion of the corpus striatum has been performed. Apomorphine (0.4 mg/kg s.c.) was administered 3 hours after the last treatment. n.s. = insignificant; *p <0.05; **p<0.01; ***p<0.001. Web site: http://www.delphion.com/details?pn=US03983234__
Patent Applications on Clozapine As of December 2000, U.S. patent applications are open to public viewing.9 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 clozapine: •
SUBSTANCE TO PREVENT OR REVERSE WEIGHT GAIN INDUCED BY PSYCHOACTIVE AGENTS Inventor(s): MILLER, JON M.; (LOUISVILLE, KY) Correspondence: Donald L. Cox; Lynch, Cox, Gilman & Mahan; Aegon Center- Suite 2200; 400 W. Market; Louisville; KY; 40202; US Patent Application Number: 20030096808 Date filed: March 29, 1999 Abstract: A substance to prevent or reverse weight gain induced by psychoactive agents (10) having an antipsychotic drug (12) or mood stabilizing drug (14) in a concentration from 0.01% to 99.99% in combination with a histamine H2-receptor antagonist (16) in a concentration from 99.99% to 0.01%. The antipsychotic drug (12) is selected from a group consisting of olanzapine (12A), clozapine (12B), risperidone (12C), and quetiapine (12D). The antipsychotic drug (12) is typically in a concentration of 10% to 90%, 30% to 60% and 50%. The mood stabilizing drug (14) is selected from a group consisting of divalproex sodium (14A), valproic acid (14B), and mirtazapine (14C). The mood stabilizing drug (14) is typically in a concentration of 10% to 90%, 30% to 60% and 50%. The histamine H2-receptor antagonist (16) is selected from a group consisting of nizatidine (16A), famotidine (16B), cimetidine (16C) and ranitidine (16D). The histamine
9
This has been a common practice outside the United States prior to December 2000.
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H2-receptor antagonist (16) is in a concentration of 90% to 10%. The histamine H2receptor antagonist (16) is typically in a concentration of 60% to 30% and 50%. Excerpt(s): The present invention relates to medications used for weight control. More particularly, the present invention relates to the use of a histamine H.sub.2-receptor antagonist with antipsychotic and mood stabilizing drugs to control weight. Numerous innovations for substances to prevent or reverse weight gain have been provided in the past. Even though these innovations may be suitable for the specific individual purposes to which they address, they differ from the present invention because they fail to describe or claim at least one combination of the features depicted in the present invention. Even though these innovations may be suitable for the specific individual purposes to which they address, they would not be suitable for the purposes of the present invention as heretofore described. The present invention prevents and reverses weight gain associated with the use of olanzapine and other antipsychotic drugs. The combination of psychoactive drugs and histamine H.sub.2-receptor antagonists may represent a combined single dose delivery system or multiple drug regimen taken at preselected times. The psychoactive drugs are dosed as recommended by the manufacturer and the histamine H.sub.2-receptor antagonists are dosed as for use in maintenance treatment of duodenal ulcer. 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 clozapine, 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 “clozapine” (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 clozapine. You can also use this procedure to view pending patent applications concerning clozapine. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 5. BOOKS ON CLOZAPINE Overview This chapter provides bibliographic book references relating to clozapine. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on clozapine include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
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 “clozapine” (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:10 •
10
Pharmacoeconomic evaluation in schizophrenia: clozapine in treatment-resistant schizophrenia and risperidone in chronic schizophrenia. Author: Paul Oh. [et al.]; Year: 1997
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. 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. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.
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CHAPTER 6. PERIODICALS AND NEWS ON CLOZAPINE Overview In this chapter, we suggest a number of news sources and present various periodicals that cover clozapine.
News Services and Press Releases One of the simplest ways of tracking press releases on clozapine 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 “clozapine” (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 clozapine. 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 “clozapine” (or synonyms). The following was recently listed in this archive for clozapine: •
Patients with schizophrenia tolerate switch from Clozaril to generic clozapine: study Source: Reuters Industry Breifing Date: May 21, 2003
•
FDA approves clozapine for suicide prevention Source: Reuters Medical News Date: December 19, 2002
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FDA advisors back Novartis' Clozaril for suicide prevention in schizophrenics Source: Reuters Industry Breifing Date: November 04, 2002
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Arrest rates, high among psychotic patients, decline after clozapine treatment Source: Reuters Industry Breifing Date: February 20, 2001
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GPhA asks FDA to respond to Wall Street Journal clozapine article Source: Reuters Industry Breifing Date: November 03, 2000
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Ivax beats estimates for Q3, responds to Wall Street Journal clozapine article Source: Reuters Industry Breifing Date: October 25, 2000
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Thromboembolism, five deaths associated with clozapine use Source: Reuters Medical News Date: March 31, 2000
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Five deaths associated with short-term clozapine use Source: Reuters Health eLine Date: March 31, 2000
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Addition of clozapine stabilizes mood in treatment-resistant patients with mania Source: Reuters Medical News Date: August 20, 1999
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FDA to study whether clozapine can cause diabetes Source: Reuters Medical News Date: July 14, 1999
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Use of antipsychotic agents risperidone and clozapine linked to low rehospitalization rates Source: Reuters Medical News Date: July 05, 1999
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Caution urged when substituting olanzapine for clozapine in Parkinson's patients Source: Reuters Medical News Date: October 19, 1998
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Risperidone As Effective As Clozapine For Treatment-Resistant Schizophrenia Source: Reuters Medical News Date: April 29, 1998
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Low-Dose Clozapine Effective For Severe Borderline Personality Disorder Source: Reuters Medical News Date: April 06, 1998
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Data On Time To Clozapine Response In Treatment Refractory Schizophrenics Published Source: Reuters Medical News Date: September 10, 1997
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Low-Dose Clozapine Reduces Psychotic Symptoms In Parkinson's Patients Source: Reuters Medical News Date: June 12, 1997
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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 “clozapine” (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 “clozapine” (or synonyms). If you know the name of a company that is relevant to clozapine, you can go to any stock trading Web site (such as http://www.etrade.com/) and 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 “clozapine” (or synonyms).
Academic Periodicals covering Clozapine Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to clozapine. In addition to
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these sources, you can search for articles covering clozapine 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.”
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CHAPTER 7. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for clozapine. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI® Advice for the Patient® can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with clozapine. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The
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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to clozapine: Clozapine •
Systemic - U.S. Brands: Clozaril http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202157.html
Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.
Mosby’s Drug Consult™ Mosby’s Drug Consult™ database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.
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APPENDICES
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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 Institute11: •
Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
11
These publications are typically written by one or more of the various NIH Institutes.
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•
National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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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
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 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:13 •
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
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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
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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
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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/
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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
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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
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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/
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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
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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
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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
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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
12
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). 13 See http://www.nlm.nih.gov/databases/databases.html.
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•
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 Gateway14 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.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “clozapine” (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 6195 29 273 19 26 6542
HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 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.18 Simply search by “clozapine” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
14
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
15
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). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18
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.
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Coffee Break: Tutorials for Biologists19 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.20 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.21 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/.
19 Adapted 20
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. 21 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.
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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 clozapine 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 clozapine. 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 clozapine. 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 “clozapine”:
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Bipolar Disorder http://www.nlm.nih.gov/medlineplus/bipolardisorder.html Child Mental Health http://www.nlm.nih.gov/medlineplus/childmentalhealth.html Marijuana Abuse http://www.nlm.nih.gov/medlineplus/marijuanaabuse.html Mental Health http://www.nlm.nih.gov/medlineplus/mentalhealth.html Schizophrenia http://www.nlm.nih.gov/medlineplus/schizophrenia.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 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 clozapine. 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
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
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Med Help International: http://www.medhelp.org/HealthTopics/A.html
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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMD®Health: http://my.webmd.com/health_topics
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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to clozapine. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with clozapine. 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 clozapine. 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 “clozapine” (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 “clozapine”. 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 publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “clozapine” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months.
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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 “clozapine” (or a synonym) into the search box, and click “Submit Query.”
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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.22
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
22
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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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)23: •
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
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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
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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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/
23
Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.
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•
Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml
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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
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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html
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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm
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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp
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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/
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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm
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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html
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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/
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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm
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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/
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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/
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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
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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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/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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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/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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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
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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/
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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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/
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•
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
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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
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CLOZAPINE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 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] Aberrant: Wandering or deviating from the usual or normal course. [EU] 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] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] 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] Acoustic: Having to do with sound or hearing. [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] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine 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] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [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] 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 Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH]
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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] Adverse Effect: An unwanted side effect of treatment. [NIH] 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] Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] 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 substances. [EU] Agranulocytosis: A decrease in the number of granulocytes (basophils, eosinophils, and neutrophils). [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] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] 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] 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] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity
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(allergy). [EU] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [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] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] 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] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [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]
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Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] 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] 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] 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] 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 chamber: The space in front of the iris and behind the cornea. [NIH] Anti-Anxiety Agents: Agents that alleviate anxiety, tension, and neurotic symptoms, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. Some are also effective as anticonvulsants, muscle relaxants, or anesthesia adjuvants. Adrenergic beta-antagonists are commonly used in the symptomatic treatment of anxiety but are not included here. [NIH] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [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 the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticholinergic: An agent that blocks the parasympathetic nerves. Called also parasympatholytic. [EU] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antidepressant: A drug used to treat depression. [NIH] Antidepressive Agents: Mood-stimulating drugs used primarily in the treatment of
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affective disorders and related conditions. Several monoamine oxidase inhibitors are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents also appear to act through brain catecholamine systems. A third group (antidepressive agents, secondgeneration) is a diverse group of drugs including some that act specifically on serotonergic systems. [NIH] Antidopaminergic: Preventing or counteracting (the effects of) dopamine. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]
Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [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] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] 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] 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 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] Antipsychotic Agents: Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in schizophrenia, senile dementia, transient psychosis following surgery or myocardial infarction, etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. [NIH] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiseptic: A substance that inhibits the growth and development of microorganisms
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without necessarily killing them. [EU] Anuria: Inability to form or excrete urine. [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] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [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] 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] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [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 phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] 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] 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] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aspartate: A synthetic amino acid. [NIH] Aspergillosis: Infections with fungi of the genus Aspergillus. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU]
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Astringent: Causing contraction, usually locally after topical application. [EU] 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] 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] Atrial: Pertaining to an atrium. [EU] 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] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [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] 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] Autoreceptors: Transmitter receptors on or near presynaptic terminals (or varicosities) which are sensitive to the transmitter(s) released by the terminal itself. Receptors for the hormones released by hormone-releasing cells are also included. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [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] 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]
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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] Behavior Therapy: The application of modern theories of learning and conditioning in the treatment of behavior disorders. [NIH] Belladonna: A species of very poisonous Solanaceous plants yielding atropine (hyoscyamine), scopolamine, and other belladonna alkaloids, used to block the muscarinic autonomic nervous system. [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-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] 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] Binaural: Used of the two ears functioning together. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biofilms: Films of bacteria or other microbial organisms, usually embedded in extracellular polymers such as implanted medical devices, which adhere to surfaces submerged in, or subjected to, aquatic environments (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). Biofilms consist of multilayers of microbial cells glued together to form microbial communities which are highly resistant to both phagocytes and antibiotics. [NIH] Biogenic Amines: A group of naturally occurring amines derived by enzymatic decarboxylation of the natural amino acids. Many have powerful physiological effects (e.g., histamine, serotonin, epinephrine, tyramine). Those derived from aromatic amino acids, and also their synthetic analogs (e.g., amphetamine), are of use in pharmacology. [NIH] Biogenic Monoamines: Biogenic amines having only one amine moiety. Included in this group are all natural monoamines formed by the enzymatic decarboxylation of natural amino acids. [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 Psychiatry: An interdisciplinary science concerned with studies of the biological
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bases of behavior - biochemical, genetic, physiological, and neurological - and applying these to the understanding and treatment of mental illness. [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] 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] Bipolar Disorder: A major affective disorder marked by severe mood swings (manic or major depressive episodes) and a tendency to remission and recurrence. [NIH] Bladder: The organ that stores urine. [NIH] Blastomycosis: A fungal infection that may appear in two forms: 1) a primary lesion characterized by the formation of a small cutaneous nodule and small nodules along the lymphatics that may heal within several months; and 2) chronic granulomatous lesions characterized by thick crusts, warty growths, and unusual vascularity and infection in the middle or upper lobes of the lung. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [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-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [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
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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] 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] Bradykinesia: Abnormal slowness of movement; sluggishness of physical and mental responses. [EU] 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] 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] Buccal mucosa: The inner lining of the cheeks and lips. [NIH] Bupropion: A unicyclic, aminoketone antidepressant. The mechanism of its therapeutic actions is not well understood, but it does appear to block dopamine uptake. The hydrochloride is available as an aid to smoking cessation treatment. [NIH] Buspirone: An anxiolytic agent and a serotonin receptor agonist belonging to the azaspirodecanedione class of compounds. Its structure is unrelated to those of the benzodiazepines, but it has an efficacy comparable to diazepam. [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] 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] Cannabis: The hemp plant Cannabis sativa. Products prepared from the dried flowering tops of the plant include marijuana, hashish, bhang, and ganja. [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] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [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-, poly-
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and heterosaccharides. [EU] Carcinogenic: Producing carcinoma. [EU] Cardiac: Having to do with the heart. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardiopulmonary Bypass: Diversion of the flow of blood from the entrance of the right atrium directly to the aorta (or femoral artery) via an oxygenator thus bypassing both the heart and lungs. [NIH] 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] 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] Catalepsy: A condition characterized by inactivity, decreased responsiveness to stimuli, and a tendency to maintain an immobile posture. The limbs tend to remain in whatever position they are placed (waxy flexibility). Catalepsy may be associated with psychotic disorders (e.g., schizophrenia, catatonic), nervous system drug toxicity, and other conditions. [NIH] Catechol: A chemical originally isolated from a type of mimosa tree. Catechol is used as an astringent, an antiseptic, and in photography, electroplating, and making other chemicals. It can also be man-made. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] 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] 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 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]
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Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellar Diseases: Diseases that affect the structure or function of the cerebellum. Cardinal manifestations of cerebellar dysfunction include dysmetria, gait ataxia, and muscle hypotonia. [NIH] 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 Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [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] 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] Chemoreceptor: A receptor adapted for excitation by chemical substances, e.g., olfactory and gustatory receptors, or a sense organ, as the carotid body or the aortic (supracardial) bodies, which is sensitive to chemical changes in the blood stream, especially reduced oxygen content, and reflexly increases both respiration and blood pressure. [EU] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Chlorpromazine: The prototypical phenothiazine antipsychotic drug. Like the other drugs in this class chlorpromazine's antipsychotic actions are thought to be due to long-term adaptation by the brain to blocking dopamine receptors. Chlorpromazine has several other actions and therapeutic uses, including as an antiemetic and in the treatment of intractable hiccup. [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
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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] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [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] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [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] Cimetidine: A histamine congener, it competitively inhibits histamine binding to H2 receptors. Cimetidine has a range of pharmacological actions. It inhibits gastric acid secretion, as well as pepsin and gastrin output. It also blocks the activity of cytochrome P450. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour 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] 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] Clonic: Pertaining to or of the nature of clonus. [EU] 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] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaine: An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is
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thought to involve inhibition of dopamine uptake. [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] Colloidal: Of the nature of a colloid. [EU] 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, 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] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Compulsions: In psychology, an irresistible urge, sometimes amounting to obsession to perform a particular act which usually is carried out against the performer's will or better judgment. [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
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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] Concomitant: Accompanying; accessory; joined with another. [EU] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [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] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connexins: A group of homologous proteins which form the intermembrane channels of gap junctions. The connexins are the products of an identified gene family which has both highly conserved and highly divergent regions. The variety contributes to the wide range of functional properties of gap junctions. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] 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] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [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] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments,
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etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] 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] Corpus: The body of the uterus. [NIH] Corpus Striatum: Striped gray and white matter consisting of the neostriatum and paleostriatum (globus pallidus). It is located in front of and lateral to the thalamus in each cerebral hemisphere. The gray substance is made up of the caudate nucleus and the lentiform nucleus (the latter consisting of the globus pallidus and putamen). The white matter is the internal capsule. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Curative: Tending to overcome disease and promote recovery. [EU] 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] 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 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] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]
Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH]
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Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] 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, 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] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] 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] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [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] 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] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Dextroamphetamine: The d-form of amphetamine. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic. [NIH] Diabetes Insipidus: A metabolic disorder due to disorders in the production or release of vasopressin. It is characterized by the chronic excretion of large amounts of low specific gravity urine and great thirst. [NIH]
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Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Ketoacidosis: Complication of diabetes resulting from severe insulin deficiency coupled with an absolute or relative increase in glucagon concentration. The metabolic acidosis is caused by the breakdown of adipose stores and resulting increased levels of free fatty acids. Glucagon accelerates the oxidation of the free fatty acids producing excess ketone bodies (ketosis). [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] 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] 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] Diuretic: A drug that increases the production of urine. [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]
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Dopamine Agonists: Drugs that bind to and activate dopamine receptors. [NIH] Dopamine Antagonists: Drugs that bind to but do not activate dopamine receptors, thereby blocking the actions of dopamine or exogenous agonists. Many drugs used in the treatment of psychotic disorders (antipsychotic agents) are dopamine antagonists, although their therapeutic effects may be due to long-term adjustments of the brain rather than to the acute effects of blocking dopamine receptors. Dopamine antagonists have been used for several other clinical purposes including as antiemetics, in the treatment of Tourette syndrome, and for hiccup. [NIH] Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] 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] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] 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 Monitoring: The process of observing, recording, or detecting the effects of a chemical substance administered to an individual therapeutically or diagnostically. [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] Drug Toxicity: Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning for which specific headings are available. [NIH] Duodenal Ulcer: An ulcer in the lining of the first part of the small intestine (duodenum). [NIH]
Duodenum: The first part of the small intestine. [NIH] Dyscrasia: A term formerly used to indicate an abnormal mixture of the four humours; in surviving usages it now is roughly synonymous with 'disease' or 'pathologic condition'. [EU] 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] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] Dystonia: Disordered tonicity of muscle. [EU] Effector: It is often an enzyme that converts an inactive precursor molecule into an active
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second messenger. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [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] Electroconvulsive Therapy: Electrically induced convulsions primarily used in the treatment of severe affective disorders and schizophrenia. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] 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]
Electroplating: Coating with a metal or alloy by electrolysis. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]
Emetic: An agent that causes vomiting. [EU] 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] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [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] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH]
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Endotoxin: Toxin from cell walls of bacteria. [NIH] 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] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Enuresis: Involuntary discharge of urine after the age at which urinary control should have been achieved; often used alone with specific reference to involuntary discharge of urine occurring during sleep at night (bed-wetting, nocturnal enuresis). [EU] 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] Eosinophilia: Abnormal increase in eosinophils in the blood, tissues or organs. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [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] Epithalamus: The dorsal posterior subdivision of the diencephalon. The epithalamus is generally considered to include the habenular nuclei (habenula) and associated fiber bundles, the pineal body, and the epithelial roof of the third ventricle. The anterior and posterior paraventricular nuclei of the thalamus are included with the thalamic nuclei although they develop from the same pronuclear mass as the epithalamic nuclei and are sometimes considered part of the epithalamus. [NIH] Epithelial: Refers to the cells that line the internal and external 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] 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] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Estrogen: One of the two female sex hormones. [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] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a
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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] 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] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excitatory Amino Acid Agonists: Drugs that bind to and activate excitatory amino acid receptors. [NIH] Excrete: To get rid of waste from the body. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Extracellular: Outside a cell or cells. [EU] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extrapyramidal: Outside of the pyramidal tracts. [EU] Extravasation: A discharge or escape, as of blood, from a vessel into the tissues. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Famotidine: A competitive histamine H2-receptor antagonist. Its main pharmacodynamic effect is the inhibition of gastric secretion. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femoral Artery: The main artery of the thigh, a continuation of the external iliac artery. [NIH] Fetal Heart: The heart of the fetus of any viviparous animal. It refers to the heart in the postembryonic period and is differentiated from the embryonic heart (heart/embryology) only on the basis of time. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Filgrastim: A colony-stimulating factor that stimulates the production of neutrophils (a type of white blood cell). It is a cytokine that belongs to the family of drugs called hematopoietic (blood-forming) agents. Also called granulocyte colony-stimulating factor (G-CSF). [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] 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]
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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] Fluphenazine: A phenothiazine used in the treatment of psychoses. Its properties and uses are generally similar to those of chlorpromazine. [NIH] Fluvoxamine: A selective serotonin reuptake inhibitor. It is effective in the treatment of depression, obsessive-compulsive disorders, anxiety, panic disorders, and alcohol amnestic disorders. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] 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 Acid: Hydrochloric acid present in gastric juice. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]
Gastroenteritis: An acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhoea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Called also enterogastritis. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [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 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,
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transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [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] Globus Pallidus: The representation of the phylogenetically oldest part of the corpus striatum called the paleostriatum. It forms the smaller, more medial part of the lentiform nucleus. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [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] 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]
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]
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] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granulocyte Colony-Stimulating Factor: A glycoprotein of MW 25 kDa containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. [NIH]
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Granulocytopenia: A deficiency in the number of granulocytes, a type of white blood cell. [NIH]
Gyrus Cinguli: One of the convolutions on the medial surface of the cerebral hemisphere. It surrounds the rostral part of the brain and interhemispheric commissure and forms part of the limbic system. [NIH] Hallucination: A sense perception without a source in the external world; a perception of an external stimulus object in the absence of such an object. [EU] Hallucinogen: A hallucination-producing drug, a category of drugs producing this effect. The user of a hallucinogenic drug is almost invariably aware that what he is seeing are hallucinations. [NIH] Haloperidol: Butyrophenone derivative. [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] Harmaline: Alkaloid isolated from seeds of Peganum harmala L., Zygophyllaceae. A CNS stimulant acting as a monoamine oxidase inhibitor. [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] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Hematoma: An extravasation of blood localized in an organ, space, or tissue. [NIH] Hematuria: Presence of blood in the urine. [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] 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] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [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.
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[NIH]
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] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [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] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormonal therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called hormone therapy or endocrine therapy. [NIH] 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 therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [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 unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrogenation: Specific method of reduction in which hydrogen is added to a substance by the direct use of gaseous hydrogen. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperlipidemia: An excess of lipids in the blood. [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
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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] Hypokinesia: Slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other conditions. [NIH] Hypophyseal: Hypophysial. [EU] Hypotension: Abnormally low blood pressure. [NIH] 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] Hypotonia: A condition of diminished tone of the skeletal muscles; diminished resistance of muscles to passive stretching. [EU] Ileum: The lower end of the small intestine. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
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] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific 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] 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 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] 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]
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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] 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] Infant, Newborn: An infant during the first month after birth. [NIH] 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]
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] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [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] 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] 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] 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] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are
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distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-10: Factor that is a coregulator of mast cell growth. It is produced by T-cells and B-cells and shows extensive homology with the Epstein-Barr virus BCRFI gene. [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] Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] Internal Capsule: White matter pathway, flanked by nuclear masses, consisting of both afferent and efferent fibers projecting between the cerebral cortex and the brainstem. It consists of three distinct parts: an anterior limb, posterior limb, and genu. [NIH] Interneurons: Most generally any neurons which are not motor or sensory. Interneurons may also refer to neurons whose axons remain within a particular brain region as contrasted with projection neurons which have axons projecting to other brain regions. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestines: The section of the alimentary canal from the stomach to the anus. It includes the large intestine and small intestine. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intraocular: Within the eye. [EU] Intraocular pressure: Pressure of the fluid inside the eye; normal IOP varies among individuals. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] 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]
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] Ipratropium: A muscarinic antagonist structurally related to atropine but often considered safer and more effective for inhalation use. It is used for various bronchial disorders, in rhinitis, and as an antiarrhythmic. [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] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction
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of a blood vessel. [EU] Itraconazole: An antifungal agent that has been used in the treatment of histoplasmosis, blastomycosis, cryptococcal meningitis, and aspergillosis. [NIH] Kainate: Glutamate receptor. [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] 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] Ketamine: A cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (receptors, NMethyl-D-Aspartate) and may interact with sigma receptors. [NIH] Ketoconazole: Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. [NIH] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketosis: A condition of having ketone bodies build up in body tissues and fluids. The signs of ketosis are nausea, vomiting, and stomach pain. Ketosis can lead to ketoacidosis. [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 by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Kinetic: Pertaining to or producing motion. [EU] Lactation: The period of the secretion of milk. [EU] Lag: The time elapsing between application of a stimulus and the resulting reaction. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [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
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fat cells in the feedback system that controls body fat stores. [NIH] Lesion: An area of abnormal tissue change. [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]
Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [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] Ligands: A RNA simulation method developed by the MIT. [NIH] Limbic: Pertaining to a limbus, or margin; forming a border around. [EU] Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] 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] Lipid: Fat. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipolysis: The hydrolysis of lipids. [NIH] 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,
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and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] 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]
Lithium Carbonate: A lithium salt, classified as a mood-stabilizing agent. Lithium ion alters the metabolism of biogenic monoamines in the central nervous system, and affects multiple neurotransmission systems. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] 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] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Loperamide: 4-(p-Chlorophenyl)-4-hydroxy-N.N-dimethyl-alpha,alpha-diphenyl-1piperidine butyramide hydrochloride. Synthetic anti-diarrheal agent with a long duration of action; it is not significantly absorbed from the gut, has no effect on the adrenergic system or central nervous system, but may antagonize histamine and interfere with acetylcholine release locally. [NIH] Lorazepam: An anti-anxiety agent with few side effects. It also has hypnotic, anticonvulsant, and considerable sedative properties and has been proposed as a preanesthetic agent. [NIH] 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] 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] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale
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blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [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] Lymphopenia: Reduction in the number of lymphocytes. [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] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [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] Man-made: Ionizing radiation emitted by artificial or concentrated natural, radioactive material or resulting from the operation of high voltage apparatus, such as X-ray apparatus or particle accelerators, of nuclear reactors, or from nuclear explosions. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Median Eminence: Raised area on the infundibular hypothalamus at the floor of the third ventricle of the brain which contains the primary capillary network of the hypophyseal portal system. [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] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [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] 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
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immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] 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 Health: The state wherein the person is well adjusted. [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]
Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesolimbic: Inner brain region governing emotion and drives. [NIH] Metabolic acidosis: (met-ah-BOL-ik as-id-O-sis): A condition in which the blood is too acidic. It may be caused by severe illness or sepsis (bacteria in the bloodstream). [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metabotropic: A glutamate receptor which triggers an increase in production of 2 intracellular messengers: diacylglycerol and inositol 1, 4, 5-triphosphate. [NIH] Methazolamide: A carbonic anhydrase inhibitor that is used as a diuretic and in the treatment of glaucoma. [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] 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] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] Micturition: The passage of urine; urination. [EU] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] 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]
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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] Monoamine: Enzyme that breaks down dopamine in the astrocytes and microglia. [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] Monotherapy: A therapy which uses only one drug. [EU] 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] 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] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH] Movement Disorders: Syndromes which feature dyskinesias as a cardinal manifestation of the disease process. Included in this category are degenerative, hereditary, post-infectious, medication-induced, post-inflammatory, and post-traumatic conditions. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Muscarinic Antagonists: Drugs that bind to but do not activate muscarinic cholinergic receptors (receptors, muscarinic), thereby blocking the actions of endogenous acetycholine or exogenous agonists. Muscarinic antagonists have widespread effects including actions on the iris and ciliary muscle of the eye, the heart and blood vessels, secretions of the respiratory tract, GI system, and salivary glands, GI motility, urinary bladder tone, and the central nervous system. Antagonists that discriminate among the various muscarinic receptor subtypes and might allow better control of peripheral and central actions are under development. [NIH] Mutate: To change the genetic material of a cell. Then changes (mutations) can be harmful, beneficial, or have no effect. [NIH] Myocarditis: Inflammation of the myocardium; inflammation of the muscular walls of the heart. [EU] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH]
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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] 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] 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] Neocortex: The largest portion of the cerebral cortex. It is composed of neurons arranged in six layers. [NIH] Neostriatum: The phylogenetically newer part of the corpus striatum consisting of the caudate nucleus and putamen. It is often called simply the striatum. [NIH] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nerve Growth Factor: Nerve growth factor is the first of a series of neurotrophic factors that were found to influence the growth and differentiation of sympathetic and sensory neurons. It is comprised of alpha, beta, and gamma subunits. The beta subunit is responsible for its growth stimulating activity. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [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] 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] Neuromuscular: Pertaining to muscles and nerves. [EU] 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] 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] Neuropharmacology: The branch of pharmacology dealing especially with the action of drugs upon various parts of the nervous system. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neurosciences: The scientific disciplines concerned with the embryology, anatomy, physiology, biochemistry, pharmacology, etc., of the nervous sytem. [NIH] Neurotensin: A biologically active tridecapeptide isolated from the hypothalamus. It has been shown to induce hypotension in the rat, to stimulate contraction of guinea pig ileum
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and rat uterus, and to cause relaxation of rat duodenum. There is also evidence that it acts as both a peripheral and a central nervous system neurotransmitter. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophil: A type of white blood cell. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nicotinic Antagonists: Drugs that bind to nicotinic cholinergic receptors (receptors, nicotinic) and block the actions of acetylcholine or cholinergic agonists. Nicotinic antagonists block synaptic transmission at autonomic ganglia, the skeletal neuromuscular junction, and at central nervous system nicotinic synapses. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. 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] Nizatidine: A histamine H2 receptor antagonist with low toxicity that inhibits gastric acid secretion. The drug is used for the treatment of duodenal ulcers. [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] 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] Nucleus Accumbens: Collection of pleomorphic cells in the caudal part of the anterior horn of the lateral ventricle, in the region of the olfactory tubercle, lying between the head of the caudate nucleus and the anterior perforated substance. It is part of the so-called ventral striatum, a composite structure considered part of the basal ganglia. [NIH] Obsession: A recurrent, persistent thought, image, or impulse that is unwanted and distressing (ego-dystonic) and comes involuntarily to mind despite attempts to ignore or
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suppress it. Common obsessions involve thoughts of violence, contamination, and selfdoubt. [EU] Obsessive-Compulsive Disorder: An anxiety disorder characterized by recurrent, persistent obsessions or compulsions. Obsessions are the intrusive ideas, thoughts, or images that are experienced as senseless or repugnant. Compulsions are repetitive and seemingly purposeful behavior which the individual generally recognizes as senseless and from which the individual does not derive pleasure although it may provide a release from tension. [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] Odds Ratio: The ratio of two odds. The exposure-odds ratio for case control data is the ratio of the odds in favor of exposure among cases to the odds in favor of exposure among noncases. The disease-odds ratio for a cohort or cross section is the ratio of the odds in favor of disease among the exposed to the odds in favor of disease among the unexposed. The prevalence-odds ratio refers to an odds ratio derived cross-sectionally from studies of prevalent cases. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Omeprazole: A highly effective inhibitor of gastric acid secretion used in the therapy of gastric ulcers and Zollinger-Ellison syndrome. The drug inhibits the H(+)-K(+)-ATPase (H(+)-K(+)-exchanging ATPase) in a pH-dependent manner. This ATPase is considered the proton pump in the secretory membrane of the parietal cell. [NIH] 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] 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 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] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [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] Orofacial: Of or relating to the mouth and face. [EU]
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Orthostatic: Pertaining to or caused by standing erect. [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] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overdose: An accidental or deliberate dose of a medication or street drug that is in excess of what is normally used. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [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]
Oxygenator: An apparatus by which oxygen is introduced into the blood during circulation outside the body, as during open heart surgery. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] 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] 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] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [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] 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
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tissues and organs. [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]
Penfluridol: A long-acting antipsychotic used for maintenance or long-term therapy of schizophrenia and other psychoses. [NIH] 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] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Pepsin A: Formed from pig pepsinogen by cleavage of one peptide bond. The enzyme is a single polypeptide chain and is inhibited by methyl 2-diaazoacetamidohexanoate. It cleaves peptides preferentially at the carbonyl linkages of phenylalanine or leucine and acts as the principal digestive enzyme of gastric juice. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [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] 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] Perphenazine: An antipsychotic phenothiazine derivative with actions and uses similar to those of chlorpromazine. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacogenetics: A branch of genetics which deals with the genetic components of variability in individual responses to and metabolism (biotransformation) of drugs. [NIH] 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] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Phencyclidine: A hallucinogen formerly used as a veterinary anesthetic, and briefly as a general anesthetic for humans. Phencyclidine is similar to ketamine in structure and in many of its effects. Like ketamine, it can produce a dissociative state. It exerts its pharmacological action through inhibition of NMDA receptors (receptors, N-methyl-Daspartate). As a drug of abuse, it is known as PCP and Angel Dust. [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
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phenotype, characteristic of yeasts. [NIH] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an antiarrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [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] Phototherapy: Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. [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] Physostigmine: A cholinesterase inhibitor that is rapidly absorbed through membranes. It can be applied topically to the conjunctiva. It also can cross the blood-brain barrier and is used when central nervous system effects are desired, as in the treatment of severe anticholinergic toxicity. [NIH] Pilot study: The initial study examining a new method or treatment. [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] 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] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [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 Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is
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released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [NIH]
Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Pleura: The thin serous membrane enveloping the lungs and lining the thoracic cavity. [NIH] Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pleural cavity: A space enclosed by the pleura (thin tissue covering the lungs and lining the interior wall of the chest cavity). It is bound by thin membranes. [NIH] Pleural Effusion: Presence of fluid in the pleural cavity resulting from excessive transudation or exudation from the pleural surfaces. It is a sign of disease and not a diagnosis in itself. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polydipsia: Chronic excessive thirst, as in diabetes mellitus or diabetes insipidus. [EU] 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] Polymorphism: The occurrence together of two or more distinct forms in the same population. [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] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Pontine: A brain region involved in the detection and processing of taste. [NIH] Portal Pressure: The venous pressure measured in the portal vein. [NIH] Portal System: A system of vessels in which blood, after passing through one capillary bed, is conveyed through a second set of capillaries before it returns to the systemic circulation. It pertains especially to the hepatic portal system. [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] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] 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
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the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiates: 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] 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] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Prefrontal Cortex: The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the mediodorsal nucleus of the thalamus. The prefrontal cortex receives afferent fibers from numerous structures of the diencephalon, mesencephalon, and limbic system as well as cortical afferents of visual, auditory, and somatic origin. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Presynaptic Terminals: The distal terminations of axons which are specialized for the release of neurotransmitters. Also included are varicosities along the course of axons which have similar specializations and also release transmitters. Presynaptic terminals in both the central and peripheral nervous systems are included. [NIH] Preventive Medicine: A medical specialty primarily concerned with prevention of disease and the promotion and preservation of health in the individual. [NIH] Priapism: Persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. [EU] 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] Problem Solving: A learning situation involving more than one alternative from which a selection is made in order to attain a specific goal. [NIH] Progeny: The offspring produced in any generation. [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
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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] Promoter: A chemical substance that increases the activity of a carcinogenic process. [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] Propranolol: A widely used non-cardioselective beta-adrenergic antagonist. Propranolol is used in the treatment or prevention of many disorders including acute myocardial infarction, arrhythmias, angina pectoris, hypertension, hypertensive emergencies, hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [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] 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 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] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proton Pump: Integral membrane proteins that transport protons across a membrane against a concentration gradient. This transport is driven by hydrolysis of ATP by H(+)transporting ATP synthase. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pruritus: An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. [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] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychogenic: Produced or caused by psychic or mental factors rather than organic factors. [EU]
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Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychopathology: The study of significant causes and processes in the development of mental illness. [NIH] Psychopharmacology: The study of the effects of drugs on mental and behavioral activity. [NIH]
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] Psychotomimetic: Psychosis miming. [NIH] Psychotropic: Exerting an effect upon the mind; capable of modifying mental activity; usually applied to drugs that effect the mental state. [EU] Psychotropic Drugs: A loosely defined grouping of drugs that have effects on psychological function. Here the psychotropic agents include the antidepressive agents, hallucinogens, and tranquilizing agents (including the antipsychotics and anti-anxiety agents). [NIH] 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 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 Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary Embolism: Embolism in the pulmonary artery or one of its branches. [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]
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] Putamen: The largest and most lateral of the basal ganglia lying between the lateral medullary lamina of the globus pallidus and the external capsule. It is part of the neostriatum and forms part of the lentiform nucleus along with the globus pallidus. [NIH]
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Pyramidal Cells: Projection neurons in the cerebral cortex and the hippocampus. Pyramidal cells have a pyramid-shaped soma with the apex and an apical dendrite pointed toward the pial surface and other dendrites and an axon emerging from the base. The axons may have local collaterals but also project outside their cortical region. [NIH] Pyramidal Tracts: Fibers that arise from cells within the cerebral cortex, pass through the medullary pyramid, and descend in the spinal cord. Many authorities say the pyramidal tracts include both the corticospinal and corticobulbar tracts. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [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] Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] Raclopride: A substituted benzamide that has antipsychotic properties. It is a dopamine D2 receptor antagonist. [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] Radioactive: Giving off radiation. [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [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] Ranitidine: A non-imidazole blocker of those histamine receptors that mediate gastric secretion (H2 receptors). It is used to treat gastrointestinal ulcers. [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] 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, Muscarinic: One of the two major classes of cholinergic receptors. Muscarinic receptors were originally defined by their preference for muscarine over nicotine. There are several subtypes (usually M1, M2, M3.) that are characterized by their cellular actions, pharmacology, and molecular biology. [NIH] Receptors, Nicotinic: One of the two major classes of cholinergic receptors. Nicotinic receptors were originally distinguished by their preference for nicotine over muscarine. They are generally divided into muscle-type and neuronal-type (previously ganglionic)
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based on pharmacology, molecular biology, and biophysical properties of the channels. [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] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [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] 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] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Refractory: Not readily yielding to treatment. [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] Relative risk: The ratio of the incidence rate of a disease among individuals exposed to a specific risk factor to the incidence rate among unexposed individuals; synonymous with risk ratio. Alternatively, the ratio of the cumulative incidence rate in the exposed to the cumulative incidence rate in the unexposed (cumulative incidence ratio). The term relative risk has also been used synonymously with odds ratio. This is because the odds ratio and relative risk approach each other if the disease is rare ( 5 percent of population) and the number of subjects is large. [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] 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] 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]
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Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retrograde: 1. Moving backward or against the usual direction of flow. 2. Degenerating, deteriorating, or catabolic. [EU] Retrospective: Looking back at events that have already taken place. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [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] Ritanserin: A selective and potent serotonin-2 antagonist that is effective in the treatment of a variety of syndromes related to anxiety and depression. The drug also improves the subjective quality of sleep and decreases portal pressure. [NIH] Rod: A reception for vision, located in the retina. [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] 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] Schizophrenia, Catatonic: A type of schizophrenia characterized by abnormality of motor behavior which may involve particular forms of stupor, rigidity, excitement or inappropriate posture. [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] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Screening: Checking for disease when there are no symptoms. [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
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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] Selegiline: A selective, irreversible inhibitor of Type B monoamine oxidase. It is used in newly diagnosed patients with Parkinson's disease. It may slow progression of the clinical disease and delay the requirement for levodopa therapy. It also may be given with levodopa upon onset of disability. (From AMA Drug Evaluations Annual, 1994, p385) The compound without isomeric designation is Deprenyl. [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] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Septal: An abscess occurring at the root of the tooth on the proximal surface. [NIH] Septal Nuclei: Neural nuclei situated in the septal region. They have afferent and cholinergic efferent connections with a variety of forebrain and brainstem areas including the hippocampus, the lateral hypothalamus, the tegmentum, and the amygdala. Included are the dorsal, lateral, medial, and triangular septal nuclei, septofimbrial nucleus, nucleus of diagonal band, nucleus of anterior commissure, and the nucleus of stria terminalis. [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] Serrata: The serrated anterior border of the retina located approximately 8.5 mm from the limbus and adjacent to the pars plana of the ciliary body. [NIH] Sertraline: A selective serotonin uptake inhibitor that is used in the treatment of depression. [NIH]
Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [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] 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.
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[NIH]
Sialorrhea: Increased salivary flow. [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] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoking Cessation: Discontinuation of the habit of smoking, the inhaling and exhaling of tobacco smoke. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [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] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall
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in contrast to the viscera. [EU] 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] Spiperone: A spiro butyrophenone analog similar to haloperidol and other related compounds. It has been recommended in the treatment of schizophrenia. [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] 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 specialized and take the place of those that die or are lost. [NIH] 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] 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] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [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]
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Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] Sublingual: Located beneath the tongue. [EU] 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 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] Support group: A group of people with similar disease who meet to discuss how better to cope with their cancer and treatment. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [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] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [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 Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] 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] 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]
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Tacrine: A cholinesterase inhibitor that crosses the blood-brain barrier. Tacrine has been used to counter the effects of muscle relaxants, as a respiratory stimulant, and in the treatment of Alzheimer's disease and other central nervous system disorders. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] 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] Temporal Lobe: Lower lateral part of the cerebral hemisphere. [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] Thalamic Nuclei: Several groups of nuclei in the thalamus that serve as the major relay centers for sensory impulses in the brain. [NIH] Thalamus: Paired bodies containing mostly gray substance and forming part of the lateral wall of the third ventricle of the brain. The thalamus represents the major portion of the diencephalon and is commonly divided into cellular aggregates known as nuclear groups. [NIH]
Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] 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] 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] Thromboembolism: Obstruction of a vessel by a blood clot that has been transported from a distant site by the blood stream. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [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
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of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Tic: An involuntary compulsive, repetitive, stereotyped movement, resembling a purposeful movement because it is coordinated and involves muscles in their normal synergistic relationships; tics usually involve the face and shoulders. [EU] Timolol: A beta-adrenergic antagonist similar in action to propranolol. The levo-isomer is the more active. Timolol has been proposed as an antihypertensive, antiarrhythmic, antiangina, and antiglaucoma agent. It is also used in the treatment of migraine and tremor. [NIH]
Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [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] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Tonicity: The normal state of muscular tension. [NIH] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] 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] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Traction: The act of pulling. [NIH] Tranquilizing Agents: A traditional grouping of drugs said to have a soothing or calming effect on mood, thought, or behavior. Included here are the anti-anxiety agents (minor tranquilizers), antimanic agents, and the antipsychotic agents (major tranquilizers). These drugs act by different mechanisms and are used for different therapeutic purposes. [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
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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] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [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] Trigger zone: Dolorogenic zone (= producing or causing pain). [EU] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trophic: Of or pertaining to nutrition. [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] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyramine: An indirect sympathomimetic. Tyramine does not directly activate adrenergic receptors, but it can serve as a substrate for adrenergic uptake systems and monoamine oxidase so it prolongs the actions of adrenergic transmitters. It also provokes transmitter release from adrenergic terminals. Tyramine may be a neurotransmitter in some invertebrate nervous systems. [NIH] 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] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH]
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Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [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] 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] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Valproic Acid: A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GABA levels in the brain or by altering the properties of voltage dependent sodium channels. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasodilator: An agent that widens blood vessels. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venter: Belly. [NIH] 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] Ventral Tegmental Area: A region in the mesencephalon which is dorsomedial to the substantia nigra and ventral to the red nucleus. The mesocortical and mesolimbic dopaminergic systems originate here, including an important projection to the nucleus accumbens. Overactivity of the cells in this area has been suspected to contribute to the positive symptoms of schizophrenia. [NIH] 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] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or 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] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye
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(corpus vitreum). [EU] 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] 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]
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 cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] 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] 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] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
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INDEX A Abdominal, 8, 139, 156, 161, 177 Aberrant, 35, 139 Acceptor, 139, 169, 177 Acetaminophen, 5, 139 Acetylcholine, 16, 34, 139, 150, 170, 175 Acoustic, 96, 97, 98, 99, 101, 139 Adaptation, 139, 150 Adenosine, 139, 148, 179 Adipocytes, 139, 168 Adipose Tissue, 8, 139 Adjunctive Therapy, 50, 139 Adjustment, 68, 139 Adolescence, 42, 139 Adrenal Medulla, 139, 149, 159, 175 Adrenergic, 107, 140, 142, 143, 156, 159, 170, 182, 190, 192, 193 Adverse Effect, 42, 61, 140, 144, 157, 179, 188 Afferent, 140, 167, 168, 181, 187 Affinity, 39, 140, 145, 188 Age Groups, 12, 140 Age of Onset, 140, 193 Aged, 80 and Over, 140 Agonist, 19, 34, 39, 43, 92, 140, 144, 148, 156, 175 Agranulocytosis, 29, 61, 63, 64, 66, 67, 68, 69, 71, 72, 101, 106, 108, 140 Akathisia, 7, 140, 143 Alanine, 109, 140 Alertness, 140, 148 Algorithms, 9, 25, 140, 147 Alkaline, 140, 141, 148 Alkaloid, 140, 145, 151, 163, 173, 175 Alleles, 52, 140, 164 Allergen, 140, 155 Allylamine, 141 Alternative medicine, 115, 141 Ameliorated, 21, 141 Ameliorating, 21, 141 Amine, 36, 141, 146, 164 Amino Acid Sequence, 141, 142 Amino Acids, 141, 146, 174, 178, 180, 182, 186, 187, 193 Ammonia, 141 Amnestic, 141, 161 Amphetamine, 22, 100, 141, 146, 155 Amygdala, 22, 141, 145, 169, 187, 191
Anaesthesia, 141, 166 Anal, 141, 170 Analgesic, 139, 141, 169, 173 Analog, 141, 176, 189 Analogous, 42, 142, 193 Anatomical, 21, 22, 29, 31, 46, 142, 145, 150, 165, 172 Anemia, 142 Anesthesia, 67, 142, 168 Anesthetics, 5, 32, 142, 159 Animal model, 10, 15, 21, 25, 90, 96, 142 Anorexia, 142, 161 Antagonism, 30, 38, 96, 142, 148 Anterior chamber, 142, 167 Anti-Anxiety Agents, 142, 183, 192 Antiarrhythmic, 142, 167, 192 Antibiotic, 142, 178, 189 Antibodies, 42, 142, 163, 165, 179 Antibody, 42, 140, 142, 143, 152, 163, 164, 165, 166, 171, 189 Anticholinergic, 30, 65, 142, 179 Anticoagulant, 142, 182 Anticonvulsant, 5, 142, 148, 170, 179, 194 Antidepressant, 42, 142, 148, 151, 161 Antidepressive Agents, 142, 183 Antidopaminergic, 39, 99, 143 Antiemetic, 143, 150 Antifungal, 143, 168 Antigen, 61, 67, 140, 142, 143, 152, 164, 165, 166, 171, 172 Antihypertensive, 143, 192 Anti-inflammatory, 139, 143 Antioxidant, 98, 143, 144 Antipsychotic Agents, 4, 24, 39, 62, 114, 143, 157, 192 Antipyretic, 139, 143 Antiseptic, 143, 149 Anuria, 144, 168 Anxiety, 7, 25, 58, 140, 142, 144, 161, 170, 176, 177, 182, 186 Anxiety Disorders, 25, 144, 177 Anxiolytic, 5, 144, 148 Aorta, 144, 149, 194 Apathy, 7, 144, 174 Aplastic anemia, 52, 144 Apomorphine, 90, 101, 109, 144 Apoptosis, 67, 100, 144 Applicability, 14, 144
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Arachidonic Acid, 39, 144, 169, 182 Arrestin, 10, 144 Arterial, 141, 144, 153, 164, 182, 190 Arteries, 144, 147, 154, 170, 183, 191 Arterioles, 144, 147, 148 Artery, 144, 160, 183 Ascorbic Acid, 107, 144 Aspartate, 98, 144, 168, 178 Aspergillosis, 144, 168 Assay, 36, 59, 144, 165 Astringent, 145, 149 Astrocytes, 43, 145, 172, 173 Ataxia, 14, 145, 150, 191 Atrial, 145, 153, 193 Atrioventricular, 145, 153 Atrium, 145, 149, 153, 193, 194 Atropine, 84, 145, 146, 167 Auditory, 13, 16, 62, 97, 98, 145, 181 Autoradiography, 11, 20, 27, 145 Autoreceptors, 39, 145 Axons, 145, 155, 167, 176, 181, 184 B Bacteria, 142, 143, 145, 146, 159, 160, 172, 184, 189, 192 Basal Ganglia, 30, 143, 145, 151, 165, 169, 175, 183 Basal Ganglia Diseases, 145, 151, 165 Base, 145, 155, 168, 184, 191 Basophils, 140, 146, 162 Behavior Therapy, 97, 146 Belladonna, 145, 146 Benzodiazepines, 4, 5, 106, 108, 146, 148 Beta-Thromboglobulin, 146, 167 Bilateral, 23, 48, 77, 146 Bile, 146, 161, 170 Binaural, 14, 146 Binding Sites, 27, 46, 146 Bioavailability, 40, 49, 146 Bioavailable, 7, 146 Biochemical, 10, 12, 29, 41, 61, 140, 146, 147, 168, 187 Biofilms, 43, 146 Biogenic Amines, 49, 146 Biogenic Monoamines, 146, 170 Biological Factors, 9, 146 Biological Psychiatry, 12, 46, 51, 56, 57, 60, 61, 62, 65, 67, 77, 79, 81, 99, 101, 146 Biosynthesis, 144, 147, 187 Biotechnology, 43, 44, 111, 115, 123, 147 Biotransformation, 48, 147, 178 Bipolar Disorder, 71, 96, 128, 147 Bladder, 49, 147, 152, 173, 194
Blastomycosis, 147, 168 Blood Coagulation, 147, 148, 191 Blood Platelets, 147, 180, 187 Blood pressure, 6, 86, 143, 147, 149, 150, 164, 165, 173, 183, 188 Blood vessel, 147, 149, 150, 153, 158, 162, 168, 173, 178, 188, 189, 191, 194 Blood-Brain Barrier, 147, 169, 179, 191 Blot, 31, 147 Body Composition, 8, 147 Body Fluids, 147, 188 Body Mass Index, 12, 147 Bone Marrow, 46, 78, 108, 144, 147, 170, 173, 189 Bowel, 141, 148, 176 Bradykinesia, 13, 148 Brain Stem, 148, 150 Bronchial, 148, 164, 167 Buccal, 40, 148 Buccal mucosa, 40, 148 Bupropion, 37, 148 Buspirone, 5, 148 C Caffeine, 56, 57, 59, 148, 183 Calcium, 36, 81, 148, 152, 188 Cannabis, 15, 95, 148 Capillary, 79, 101, 148, 171, 180, 194 Carbamazepine, 5, 68, 148 Carbohydrate, 148, 162, 180 Carcinogenic, 149, 166, 182 Cardiac, 80, 141, 142, 148, 149, 153, 159, 173 Cardiomyopathy, 74, 149 Cardiopulmonary, 67, 149 Cardiopulmonary Bypass, 67, 149 Cardiovascular, 8, 44, 141, 149, 169, 187 Cardiovascular disease, 8, 149 Case report, 5, 53, 59, 67, 70, 77, 79, 80, 81, 83, 149, 151 Case series, 22, 52, 149, 151 Catalepsy, 20, 99, 149 Catechol, 25, 149 Catecholamine, 143, 149, 156, 178 Caudal, 149, 165, 175, 180 Caudate Nucleus, 145, 149, 154, 174, 175 Cell Death, 144, 149, 174 Cell Differentiation, 149, 188 Cell membrane, 81, 149, 155, 161, 179, 188 Cell proliferation, 150, 188 Cerebellar, 145, 150, 185, 193 Cerebellar Diseases, 145, 150, 193 Cerebellum, 14, 27, 150, 180, 185
199
Cerebral, 24, 31, 145, 147, 148, 150, 153, 154, 155, 159, 160, 161, 163, 167, 174, 177, 184, 191 Cerebral Cortex, 145, 150, 160, 167, 174, 184 Cerebrovascular, 145, 149, 150, 191 Cerebrum, 150, 191 Cervical, 45, 150 Cervix, 150 Chemoreceptor, 143, 150 Chin, 44, 150, 172 Chlorpromazine, 47, 48, 61, 90, 91, 150, 161, 178 Cholesterol, 146, 150, 154, 157, 164, 169, 170 Choline, 10, 150 Cholinergic, 5, 10, 16, 97, 143, 150, 173, 175, 184, 187 Chorea, 143, 150 Choroid, 107, 151, 185 Chromatin, 144, 151, 159, 170 Chromosome, 151, 169 Chronic Disease, 151, 169 Ciliary, 107, 151, 173, 187 Ciliary Body, 107, 151, 187 Ciliary processes, 151 Cimetidine, 109, 151 Circadian, 64, 151 Citalopram, 5, 151 Clamp, 29, 151 Clinical study, 32, 39, 151 Clinical trial, 5, 8, 9, 17, 32, 33, 41, 46, 123, 151, 153, 157, 184 Clonic, 74, 151 Cloning, 107, 147, 151 Coca, 151 Cocaine, 12, 151 Coenzyme, 144, 152 Cofactor, 152, 182, 191 Cognition, 7, 20, 21, 152, 174 Colloidal, 152, 158 Complement, 152, 161 Complementary and alternative medicine, 95, 103, 152 Complementary medicine, 95, 152 Compliance, 3, 24, 55, 68, 152 Compulsions, 47, 152, 176 Computational Biology, 123, 152 Concomitant, 12, 69, 77, 153 Confusion, 153, 174, 193 Congestion, 143, 153 Conjugated, 153, 154
Conjunctiva, 153, 179 Connective Tissue, 144, 148, 153, 161, 170, 189 Connexins, 153, 161 Consciousness, 95, 141, 142, 153, 155, 156, 182 Constipation, 53, 143, 153 Constriction, 153, 167 Contraindications, ii, 153 Controlled study, 51, 82, 153 Convulsions, 142, 153, 158 Coordination, 150, 153 Cor, 28, 153 Coronary, 149, 153, 154 Coronary heart disease, 149, 154 Corpus, 109, 154, 162, 170, 174, 178, 181, 191, 195 Corpus Striatum, 109, 154, 162, 174 Cortex, 7, 18, 27, 29, 32, 97, 154, 159, 181, 185 Cortical, 21, 27, 31, 32, 37, 38, 41, 43, 48, 57, 154, 160, 181, 184, 187, 191 Cranial, 150, 154, 163, 176, 178 Curative, 154, 191 Cutaneous, 43, 147, 154 Cyclic, 15, 36, 148, 154 Cytochrome, 60, 85, 151, 154 Cytokine, 154, 160, 167 Cytoplasm, 144, 146, 149, 154, 159, 170, 173, 186, 190 Cytoskeletal Proteins, 31, 154 Cytoskeleton, 154 Cytotoxic, 154, 188 D Decarboxylation, 146, 154, 164 Degenerative, 155, 173, 186 Deletion, 144, 155 Delirium, 53, 143, 155 Delivery of Health Care, 155, 163 Delusions, 7, 39, 155, 183 Dementia, 4, 143, 155 Dendrites, 35, 155, 174, 184 Dentate Gyrus, 155, 164 Depolarization, 31, 155, 188 Depressive Disorder, 41, 155, 170 Desensitization, 9, 39, 155 Dextroamphetamine, 141, 155 Diabetes Insipidus, 155, 180 Diabetes Mellitus, 8, 156, 162, 176, 180 Diabetic Ketoacidosis, 8, 53, 72, 156 Diagnostic procedure, 105, 115, 156 Diaphragm, 156, 180
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Clozapine
Diarrhoea, 156, 161 Diastolic, 156, 164 Digestion, 146, 148, 156, 170, 189, 194 Dilated cardiomyopathy, 50, 156 Dimethyl, 156, 170 Direct, iii, 14, 29, 34, 54, 75, 117, 156, 164, 185, 190 Discrimination, 18, 156 Dissociation, 140, 156 Distal, 35, 156, 181, 182 Diuresis, 148, 156 Diuretic, 156, 172 Dominance, 57, 156 Dopa, 91, 156, 169 Dopamine, 6, 8, 9, 16, 18, 20, 21, 22, 24, 25, 27, 29, 30, 32, 35, 36, 37, 38, 39, 40, 48, 67, 74, 90, 91, 98, 107, 141, 143, 144, 148, 150, 152, 155, 156, 157, 169, 173, 175, 184, 186 Dopamine Agonists, 20, 98, 157 Dopamine Antagonists, 20, 157 Dorsal, 157, 159, 180, 187 Dose-dependent, 60, 157 Double-blind, 4, 16, 17, 19, 38, 42, 82, 83, 157 Drive, ii, vi, 26, 89, 157 Drug Interactions, 118, 157 Drug Monitoring, 59, 73, 75, 86, 87, 157 Drug Tolerance, 157, 192 Drug Toxicity, 149, 157 Duodenal Ulcer, 110, 157, 175 Duodenum, 146, 157, 175, 189 Dyscrasia, 76, 157 Dyskinesia, 7, 8, 10, 40, 79, 83, 90, 106, 107, 108, 143, 151, 157 Dyslipidemia, 8, 157 Dysphoric, 155, 157 Dystonia, 8, 45, 106, 108, 143, 157 E Effector, 139, 152, 157 Efferent, 22, 158, 167, 187 Efficacy, 4, 7, 10, 12, 13, 16, 17, 18, 20, 24, 29, 32, 36, 39, 42, 58, 81, 83, 107, 148, 158 Electroconvulsive Therapy, 5, 22, 158 Electrolyte, 155, 158, 168, 180, 188 Electrons, 143, 145, 158, 177, 184 Electrophoresis, 101, 158 Electroplating, 149, 158 Embryo, 149, 158, 166 Embryology, 158, 160, 174 Emesis, 143, 158 Emetic, 144, 158
Empirical, 19, 21, 158 Emulsion, 145, 158 Encephalopathy, 65, 158 Endogenous, 10, 26, 35, 95, 156, 158, 159, 173 Endorphins, 158, 175 Endothelial cell, 147, 158, 167, 191 Endotoxin, 159, 193 Energy balance, 159, 168 Enkephalins, 159, 175 Entorhinal Cortex, 159, 164 Enuresis, 58, 159 Environmental Health, 122, 124, 159 Enzymatic, 146, 148, 152, 159, 164, 185 Enzyme, 10, 26, 152, 157, 159, 162, 173, 178, 188, 190, 191, 195 Eosinophilia, 65, 159 Eosinophils, 140, 159, 162 Epinephrine, 140, 146, 156, 159, 175, 193 Epithalamus, 159, 169 Epithelial, 151, 159 Epithelium, 159, 167 Erection, 159, 181 Erythrocytes, 142, 148, 159 Esophagus, 159, 185, 189 Estrogen, 159, 182 Ethanol, 151, 159 Eukaryotic Cells, 154, 159, 165, 176 Evacuation, 153, 160 Evoke, 22, 160, 189 Excitation, 150, 160, 175 Excitatory, 22, 26, 43, 160, 162 Excitatory Amino Acid Agonists, 22, 160 Excrete, 144, 160, 168 Exhaustion, 142, 160 Exogenous, 10, 147, 157, 158, 160, 173, 193 Extracellular, 18, 36, 38, 145, 146, 153, 160, 172, 188 Extracellular Space, 160, 172 Extrapyramidal, 7, 13, 20, 30, 37, 46, 140, 143, 156, 160 Extravasation, 160, 163 F Family Planning, 123, 160 Famotidine, 109, 160 Fat, 8, 75, 139, 144, 147, 153, 154, 160, 168, 169, 188, 193 Fatty acids, 156, 160, 182, 192 Feces, 153, 160 Femoral, 149, 160 Femoral Artery, 149, 160 Fetal Heart, 73, 160
201
Fetus, 160, 194 Fibroblasts, 160, 167 Filgrastim, 72, 160 Fissure, 155, 160, 181 Fistula, 160, 176 Flatus, 160, 161 Fluoxetine, 5, 12, 56, 59, 161 Fluphenazine, 11, 24, 57, 161 Fluvoxamine, 5, 45, 49, 55, 60, 161 Forearm, 147, 161 Fossa, 150, 161 Free Radicals, 143, 156, 161 Frontal Lobe, 161, 181 G Gallbladder, 139, 161 Ganglia, 31, 139, 145, 161, 174, 175, 178 Gap Junctions, 43, 153, 161, 190 Gas, 32, 141, 160, 161, 164, 175 Gastric, 151, 160, 161, 164, 175, 176, 178, 184 Gastric Acid, 151, 161, 175, 176 Gastrin, 151, 161, 164 Gastroenteritis, 71, 161 Gastrointestinal, 159, 161, 169, 184, 187, 190 Gastrointestinal tract, 159, 161, 169, 187 Gene, 6, 17, 18, 22, 25, 26, 43, 46, 47, 75, 140, 147, 153, 156, 161, 164, 167 Gene Expression, 18, 22, 43, 161 Genetic Engineering, 147, 151, 161 Genetics, 33, 43, 63, 99, 156, 162, 178 Genotype, 162, 178 Gland, 139, 162, 170, 177, 186, 189 Globus Pallidus, 38, 145, 154, 162, 183 Glomerulus, 162, 174 Glucose, 8, 45, 78, 144, 156, 162, 166 Glucose Intolerance, 156, 162 Glucose tolerance, 8, 78, 162 Glucose Tolerance Test, 162 Glutamate, 7, 18, 26, 32, 33, 36, 92, 102, 162, 168, 172 Glutamic Acid, 162, 175 Glutathione Peroxidase, 162, 187 Glycine, 103, 162, 175, 187 Glycoprotein, 162, 191, 193 Governing Board, 162, 181 Granulocyte, 64, 160, 162 Granulocyte Colony-Stimulating Factor, 160, 162 Granulocytopenia, 64, 76, 163 Gyrus Cinguli, 163, 169
H Hallucination, 163 Hallucinogen, 12, 163, 178 Haptens, 140, 163 Harmaline, 13, 163 Headache, 148, 163 Health Care Costs, 65, 163 Health Expenditures, 163 Heart attack, 149, 163 Hematoma, 52, 163 Hematuria, 65, 163 Hemodialysis, 163, 168 Hemorrhage, 163, 189 Hemostasis, 163, 187 Hepatic, 65, 155, 162, 163, 180 Hepatotoxicity, 5, 59, 163 Heredity, 161, 162, 163 Heterogeneity, 27, 140, 163 Heterozygotes, 156, 164 Hippocampus, 14, 16, 26, 27, 34, 35, 98, 155, 164, 169, 184, 187, 190 Histamine, 7, 63, 69, 109, 110, 143, 146, 151, 160, 164, 170, 175, 184 Histidine, 164 Homeostasis, 6, 164 Homologous, 9, 140, 153, 164, 190 Homozygotes, 156, 164 Hormonal, 5, 164 Hormonal therapy, 5, 164 Hormone, 28, 145, 159, 161, 164, 166, 168, 176, 181, 182, 188 Hormone therapy, 164 Hydrogen, 139, 141, 145, 148, 162, 164, 169, 173, 177 Hydrogen Peroxide, 162, 164, 169 Hydrogenation, 146, 164 Hydrolysis, 147, 164, 169, 179, 180, 182 Hypercholesterolemia, 157, 164 Hyperglycemia, 8, 65, 67, 69, 82, 84, 164 Hyperlipidemia, 157, 164 Hypersensitivity, 140, 155, 164, 169 Hypertension, 50, 149, 163, 164, 176, 182 Hypertriglyceridemia, 157, 164 Hypertrophy, 153, 165, 193 Hypnotic, 165, 170 Hypokinesia, 165, 177 Hypophyseal, 165, 171 Hypotension, 67, 143, 153, 165, 174 Hypothalamic, 28, 165 Hypothalamus, 27, 91, 165, 169, 171, 174, 187, 191 Hypotonia, 13, 150, 165
202
Clozapine
I Ileum, 165, 174 Imaging procedures, 165, 192 Imidazole, 164, 165, 184 Immune response, 143, 163, 165, 190, 194 Immunity, 140, 165 Immunoassay, 36, 165 Immunofluorescence, 11, 43, 165 Immunohistochemistry, 22, 41, 165 Immunologic, 165 Immunology, 140, 165 Immunotherapy, 155, 165 Impairment, 10, 17, 21, 34, 42, 45, 145, 155, 157, 165, 172, 183 In situ, 11, 28, 31, 165 In Situ Hybridization, 11, 31, 165 In vitro, 12, 26, 39, 44, 57, 60, 66, 91, 166 In vivo, 12, 16, 21, 22, 25, 44, 90, 100, 166, 172, 191 Induction, 32, 100, 143, 166, 168, 182 Infant, Newborn, 140, 166 Infarction, 143, 146, 166, 182 Infection, 106, 108, 147, 151, 155, 161, 162, 166, 170, 178, 189, 195 Inflammation, 84, 143, 151, 161, 166, 169, 172, 173, 174, 180, 186, 194 Infusion, 28, 35, 98, 166 Ingestion, 26, 77, 101, 162, 166, 180 Inhalation, 166, 167, 180 Initiation, 6, 7, 69, 166 Innervation, 22, 34, 43, 166 Inositol, 166, 172 Inotropic, 156, 166 Insight, 5, 166 Insulin, 6, 8, 45, 56, 69, 80, 156, 162, 166, 168, 193 Insulin-dependent diabetes mellitus, 166 Interleukin-1, 68, 166, 167 Interleukin-10, 68, 167 Interleukin-2, 167 Interleukin-8, 68, 167 Internal Capsule, 154, 167 Interneurons, 21, 26, 167 Interstitial, 44, 160, 167, 174 Intestinal, 162, 167 Intestines, 139, 160, 161, 167 Intoxication, 45, 65, 155, 167, 195 Intracellular, 15, 148, 166, 167, 172, 180, 185, 187, 188 Intraocular, 107, 167 Intraocular pressure, 107, 167 Intravenous, 166, 167
Intrinsic, 36, 39, 140, 167 Invasive, 165, 167, 171 Involuntary, 145, 150, 159, 167, 173, 174, 185, 192 Ion Channels, 145, 167, 179, 190 Ipratropium, 52, 167 Iris, 107, 142, 167, 173 Ischemia, 43, 167 Itraconazole, 82, 168 K Kainate, 32, 168 Kb, 122, 168 Keratinocytes, 167, 168 Ketamine, 26, 32, 100, 168, 178 Ketoconazole, 5, 90, 100, 168 Ketone Bodies, 156, 168 Ketosis, 156, 168 Kidney Failure, 6, 168 Kidney Failure, Acute, 168 Kidney Failure, Chronic, 168 Kinetic, 36, 168 L Lactation, 168, 182 Lag, 70, 168 Latent, 100, 102, 168, 181 Leptin, 56, 71, 75, 168 Lesion, 31, 109, 147, 169, 170, 191, 193 Leucocyte, 169 Leukaemia, 84, 169 Leukemia, 68, 169 Leukopenia, 69, 83, 106, 108, 169 Leukotrienes, 144, 169 Levo, 156, 169, 192 Levodopa, 51, 85, 91, 156, 169, 187 Ligands, 17, 90, 169 Limbic, 26, 32, 37, 38, 141, 163, 169, 181 Limbic System, 26, 141, 163, 169, 181 Linkage, 59, 169 Lipid, 8, 98, 150, 166, 169, 193 Lipid Peroxidation, 98, 169 Lipolysis, 8, 169 Lipoprotein, 157, 169, 170 Lithium, 52, 72, 81, 83, 91, 96, 143, 170 Lithium Carbonate, 52, 170 Liver, 5, 8, 59, 64, 91, 139, 144, 146, 158, 160, 161, 162, 163, 170 Lobe, 14, 170 Localization, 27, 43, 165, 170 Localized, 15, 163, 166, 170, 179, 193 Locomotion, 20, 170, 179 Longitudinal study, 57, 170 Loperamide, 71, 170
203
Lorazepam, 98, 170 Low-density lipoprotein, 157, 170 Lutein Cells, 170, 182 Lymph, 150, 158, 170 Lymph node, 150, 170 Lymphatic, 166, 170 Lymphocytes, 143, 166, 167, 169, 170, 171, 195 Lymphoid, 142, 169, 170, 171 Lymphoma, 80, 171 Lymphopenia, 106, 108, 171 M Macrophage, 167, 171 Magnetic Resonance Imaging, 8, 171 Maintenance therapy, 51, 171 Malignant, 47, 52, 74, 171 Mania, 91, 114, 171 Manic, 143, 147, 170, 171, 183 Manic-depressive psychosis, 171, 183 Man-made, 149, 171 Medial, 14, 27, 162, 163, 171, 176, 187 Median Eminence, 27, 171 Mediate, 32, 38, 39, 156, 171, 184 Mediator, 156, 167, 171, 180, 187 MEDLINE, 123, 171 Medullary, 171, 183, 184 Meiosis, 171, 190 Melanin, 167, 171, 193 Memory, 7, 10, 20, 31, 34, 91, 142, 155, 171 Meninges, 150, 172 Meningitis, 168, 172 Mental Disorders, 14, 38, 41, 165, 172, 182, 183 Mental Health, iv, 5, 9, 23, 33, 53, 55, 122, 124, 128, 172, 183 Mental Retardation, 50, 172 Mentors, 9, 172 Mesolimbic, 18, 143, 172, 194 Metabolic acidosis, 156, 172 Metabolite, 6, 54, 147, 156, 172 Metabotropic, 32, 92, 172 Methazolamide, 75, 172 Microbe, 172, 192 Microbiology, 139, 145, 146, 172 Microdialysis, 16, 18, 22, 172 Microglia, 42, 145, 172, 173 Micturition, 44, 172 Mitochondria, 172, 176 Mitosis, 144, 172 Modification, 161, 173, 184 Molecular Structure, 173, 193
Molecule, 7, 143, 145, 146, 152, 156, 157, 160, 164, 173, 177, 180, 184, 188 Monitor, 36, 47, 173, 175 Monoamine, 92, 141, 143, 155, 163, 173, 187, 193 Monocytes, 53, 166, 167, 173 Mononuclear, 54, 173, 193 Monotherapy, 22, 37, 173 Morphine, 144, 173 Morphological, 14, 31, 158, 173 Morphology, 14, 30, 173 Motility, 173, 187 Motor Activity, 20, 26, 38, 153, 173 Movement Disorders, 143, 173, 191 Mucins, 173, 186 Mucosa, 173, 182, 189 Muscarinic Antagonists, 90, 173 Mutate, 19, 173 Myocarditis, 44, 74, 80, 173 Myocardium, 173 Myoclonus, 85, 91, 174 N Nausea, 143, 161, 168, 174, 177, 193 Necrosis, 144, 166, 174 Neocortex, 14, 174 Neostriatum, 149, 154, 174, 183 Nephritis, 44, 174 Nerve Growth Factor, 10, 174 Nervous System, 15, 43, 139, 140, 141, 146, 148, 149, 150, 151, 155, 158, 161, 162, 163, 169, 170, 171, 172, 173, 174, 175, 176, 178, 179, 180, 187, 190, 191, 193 Neural, 21, 29, 34, 43, 49, 90, 140, 172, 174, 187, 188 Neuromuscular, 139, 174, 175 Neuromuscular Junction, 139, 174, 175 Neuronal, 6, 10, 25, 29, 31, 39, 41, 151, 174, 184 Neurons, 6, 10, 15, 16, 18, 22, 26, 28, 29, 30, 31, 32, 39, 41, 43, 91, 151, 155, 160, 161, 167, 169, 174, 175, 184, 190 Neuropeptide, 28, 91, 174 Neuropharmacology, 14, 32, 54, 62, 73, 80, 81, 86, 174 Neurophysiology, 72, 73, 79, 97, 155, 174 Neurosciences, 33, 52, 64, 71, 73, 84, 87, 174 Neurotensin, 46, 174 Neurotoxic, 32, 175 Neurotransmitter, 9, 18, 21, 34, 39, 40, 139, 156, 162, 164, 167, 175, 188, 190, 193
204
Clozapine
Neutropenia, 52, 58, 62, 71, 72, 75, 77, 82, 175 Neutrophil, 100, 175 Nicotine, 34, 37, 91, 175, 184 Nicotinic Antagonists, 16, 175 Nitrogen, 140, 141, 168, 175, 193 Nizatidine, 109, 175 Norepinephrine, 54, 140, 156, 175 Nuclear, 15, 145, 158, 160, 167, 169, 171, 174, 175, 191 Nuclei, 22, 27, 141, 158, 159, 162, 171, 172, 175, 176, 180, 187, 191 Nucleic acid, 165, 175, 183, 184 Nucleus, 10, 18, 22, 27, 43, 144, 146, 151, 154, 159, 162, 170, 171, 173, 175, 181, 182, 183, 187, 191, 194 Nucleus Accumbens, 10, 18, 22, 43, 175, 194 O Obsession, 152, 175 Obsessive-Compulsive Disorder, 161, 176 Octreotide, 5, 176 Odds Ratio, 176, 185 Oliguria, 168, 176 Omeprazole, 5, 77, 176 Ophthalmologic, 107, 176 Ophthalmology, 176 Optic Chiasm, 165, 176 Optic Nerve, 176, 185, 186 Oral Health, 3, 176 Oral Hygiene, 3, 176 Organelles, 31, 154, 173, 176, 179 Orofacial, 3, 176 Orthostatic, 143, 176, 177 Outpatient, 38, 177 Ovary, 177, 189 Overdose, 53, 59, 177 Overexpress, 15, 177 Ovum, 177, 181, 182 Oxidation, 45, 139, 143, 147, 154, 156, 162, 169, 177 Oxygenator, 149, 177 P Palliative, 177, 191 Pancreas, 139, 166, 177 Panic, 161, 177 Panic Disorder, 161, 177 Paralysis, 67, 177 Parietal, 32, 73, 176, 177, 180 Parietal Lobe, 177 Parkinsonism, 7, 52, 106, 107, 108, 143, 144, 169, 177
Parturition, 177, 182 Patch, 37, 81, 177 Pathologic, 43, 80, 144, 154, 157, 164, 177 Pathologic Processes, 144, 177 Pathophysiology, 6, 22, 24, 29, 30, 31, 34, 178 Patient Education, 55, 132, 134, 137, 178 Penfluridol, 71, 178 Penicillin, 142, 178 Penis, 178, 181 Pepsin, 151, 178 Pepsin A, 151, 178 Peptide, 168, 178, 180, 182 Perfusion, 61, 178 Peripheral Nervous System, 159, 175, 178, 181, 190 Perphenazine, 11, 178 Pharmacodynamic, 160, 178 Pharmacogenetics, 24, 61, 63, 66, 77, 178 Pharmacokinetic, 11, 70, 90, 178 Pharmacologic, 4, 40, 142, 178, 192 Pharmacotherapy, 12, 38, 40, 45, 49, 58, 81, 84, 178 Phencyclidine, 21, 26, 32, 92, 96, 97, 99, 101, 178 Phenotype, 7, 14, 22, 178 Phenytoin, 148, 179 Phospholipases, 179, 188 Phospholipids, 160, 166, 169, 179 Phosphorus, 148, 179 Phosphorylated, 144, 152, 179 Phototherapy, 5, 179 Physiologic, 140, 147, 156, 165, 174, 179, 184, 193 Physiology, 6, 29, 38, 43, 98, 139, 174, 179 Physostigmine, 13, 179 Pilot study, 58, 60, 179 Plants, 140, 145, 146, 150, 151, 162, 173, 175, 179, 192 Plasma cells, 142, 179 Plastids, 176, 179 Platelet Activation, 179, 188 Platelet Factor 4, 167, 179 Pleomorphic, 175, 180 Pleura, 180 Pleural, 65, 77, 180 Pleural cavity, 180 Pleural Effusion, 65, 77, 180 Pneumonia, 47, 153, 180 Poisoning, 144, 155, 157, 161, 167, 174, 180 Polydipsia, 58, 180 Polymers, 146, 180, 182
205
Polymorphism, 9, 46, 47, 59, 66, 180 Polypeptide, 141, 178, 180, 182, 195 Polysaccharide, 143, 180 Pons, 27, 148, 180 Pontine, 58, 180 Portal Pressure, 180, 186 Portal System, 171, 180 Posterior, 27, 32, 141, 145, 150, 151, 157, 159, 167, 177, 180, 186 Postnatal, 20, 180, 189 Postsynaptic, 35, 180, 188, 190 Potassium, 81, 180 Potentiates, 166, 181 Potentiation, 12, 98, 181, 188 Practice Guidelines, 124, 181 Preclinical, 17, 32, 181 Precursor, 144, 150, 156, 157, 158, 159, 162, 169, 175, 181, 193 Predisposition, 6, 181 Prefrontal Cortex, 6, 16, 18, 21, 22, 27, 29, 181 Presynaptic, 35, 38, 145, 175, 181, 190 Presynaptic Terminals, 145, 181, 190 Preventive Medicine, 9, 133, 181 Priapism, 82, 181 Probe, 27, 172, 181 Problem Solving, 54, 181 Progeny, 43, 181 Progesterone, 181, 182 Progression, 142, 181, 187 Progressive, 106, 108, 149, 155, 157, 168, 174, 179, 181 Projection, 26, 167, 175, 176, 181, 184, 185, 194 Prolactin, 67, 78, 81, 106, 108, 182 Promoter, 69, 182 Prophase, 182, 190 Prophylaxis, 61, 182 Propranolol, 182, 192 Prospective study, 45, 70, 170, 182 Prostaglandins, 144, 182 Protein C, 19, 141, 169, 182 Protein S, 147, 182, 186 Proteins, 10, 32, 42, 43, 141, 143, 147, 149, 151, 152, 153, 161, 167, 173, 175, 178, 179, 180, 182, 184, 185, 187, 191 Proteinuria, 65, 182 Proton Pump, 176, 182 Proximal, 156, 181, 182, 187 Pruritus, 143, 182 Psychic, 172, 182, 187 Psychoactive, 109, 110, 182, 195
Psychogenic, 58, 182 Psychology, 17, 29, 54, 90, 152, 156, 183 Psychopathology, 4, 47, 53, 183 Psychosis, 4, 12, 17, 25, 26, 32, 38, 39, 40, 51, 58, 70, 79, 85, 143, 183 Psychotomimetic, 141, 155, 183 Psychotropic, 42, 77, 183 Psychotropic Drugs, 42, 183 Public Health, 12, 16, 24, 124, 183 Public Policy, 123, 183 Publishing, 44, 183 Pulmonary, 48, 147, 153, 168, 169, 183, 194 Pulmonary Artery, 147, 183, 194 Pulmonary Edema, 168, 183 Pulmonary Embolism, 48, 183 Pulmonary hypertension, 153, 183 Pulse, 35, 58, 173, 183 Purines, 183, 187 Putamen, 27, 91, 145, 154, 174, 183 Pyramidal Cells, 26, 35, 155, 184 Pyramidal Tracts, 160, 184 Pyrimidines, 184, 187 Q Quality of Life, 16, 184 R Race, 12, 41, 156, 184 Racemic, 156, 184 Raclopride, 90, 184 Radiation, 145, 161, 171, 184, 195 Radioactive, 145, 164, 171, 175, 184 Radioisotope, 184, 192 Randomized, 4, 17, 19, 23, 38, 47, 75, 158, 184 Ranitidine, 109, 184 Reaction Time, 13, 57, 184 Reactive Oxygen Species, 53, 184 Reality Testing, 183, 184 Receptors, Muscarinic, 173, 184 Receptors, Nicotinic, 175, 184 Receptors, Serotonin, 185, 187 Rectum, 160, 161, 185 Recurrence, 147, 171, 185 Red Nucleus, 145, 185, 194 Refer, 1, 148, 152, 158, 167, 170, 174, 183, 185, 192 Reflex, 98, 99, 185 Reflux, 62, 185 Refractory, 9, 13, 22, 42, 51, 53, 55, 58, 60, 61, 64, 66, 71, 78, 86, 97, 106, 107, 108, 114, 185 Regimen, 110, 158, 178, 185 Relapse, 70, 185
206
Clozapine
Relative risk, 23, 185 Remission, 147, 171, 185 Respiration, 150, 172, 173, 185 Retina, 107, 151, 176, 185, 186, 187, 194, 195 Retinal, 144, 176, 185, 186 Retinopathy, 107, 186 Retrograde, 18, 29, 186 Retrospective, 85, 98, 186 Rhinitis, 167, 186 Rhodopsin, 144, 185, 186 Ribosome, 186, 193 Rigidity, 177, 179, 186 Risk factor, 53, 182, 185, 186 Ritanserin, 102, 186 Rod, 151, 186 S Saliva, 87, 186 Salivary, 173, 186, 188 Salivary glands, 173, 186 Schizoid, 186, 195 Schizophrenia, Catatonic, 149, 186 Schizotypal Personality Disorder, 186, 195 Sclera, 151, 153, 186, 194 Screening, 24, 25, 98, 106, 108, 151, 186 Secretion, 106, 108, 151, 160, 164, 166, 168, 172, 173, 175, 176, 184, 186, 187, 194 Secretory, 176, 187, 190 Sedative, 170, 187 Seizures, 61, 64, 74, 148, 155, 179, 187 Selegiline, 5, 187 Selenium, 72, 93, 187 Senile, 143, 187 Septal, 169, 187 Septal Nuclei, 169, 187 Serine, 33, 187 Serologic, 165, 187 Serrata, 151, 187 Sertraline, 5, 69, 187 Serum, 32, 47, 53, 54, 56, 68, 80, 81, 82, 85, 152, 168, 170, 187, 193 Sex Characteristics, 139, 187 Shock, 32, 174, 187 Sialorrhea, 52, 81, 188 Side effect, 3, 4, 5, 7, 10, 13, 17, 19, 21, 23, 24, 30, 37, 38, 39, 40, 42, 49, 67, 81, 106, 107, 108, 117, 140, 143, 151, 170, 188, 192 Signal Transduction, 10, 166, 188 Signs and Symptoms, 185, 188 Skeletal, 8, 151, 165, 175, 188 Skeleton, 188 Skull, 188, 191
Small intestine, 157, 164, 165, 167, 188 Smoking Cessation, 37, 148, 188 Smooth muscle, 141, 148, 164, 173, 188, 190 Social Environment, 184, 188 Sodium, 65, 68, 109, 188, 194 Sodium Channels, 188, 194 Soft tissue, 147, 188 Soma, 184, 188 Somatic, 139, 169, 171, 172, 178, 181, 188 Specialist, 129, 189 Species, 27, 28, 146, 159, 161, 171, 172, 184, 189, 190, 194, 195 Specificity, 21, 22, 140, 189 Spectrum, 168, 172, 189 Spinal cord, 145, 148, 150, 172, 174, 178, 181, 184, 185, 189 Spiperone, 90, 189 Steel, 151, 189 Stem Cells, 43, 189 Stimulant, 141, 148, 155, 163, 164, 189, 191 Stimulus, 12, 13, 18, 62, 90, 157, 160, 163, 166, 167, 168, 184, 185, 189, 191 Stomach, 139, 159, 161, 162, 164, 167, 168, 174, 178, 185, 188, 189 Stress, 5, 20, 149, 161, 174, 181, 189 Striatum, 10, 31, 37, 174, 175, 189 Stroke, 6, 32, 122, 149, 189 Stroma, 167, 189 Stromal, 78, 189 Stromal Cells, 78, 189 Subacute, 166, 189 Subclinical, 166, 187, 189 Subiculum, 27, 164, 190 Sublingual, 52, 190 Subspecies, 189, 190 Substance P, 172, 187, 190 Substrate, 28, 190, 193 Support group, 100, 190 Suppression, 30, 97, 109, 190 Sympathomimetic, 141, 155, 156, 159, 175, 190, 193 Symptomatic, 23, 142, 190 Symptomatology, 41, 42, 190 Synapse, 140, 174, 181, 190, 193 Synapsis, 190 Synaptic, 26, 31, 35, 175, 188, 190 Synaptic Transmission, 35, 175, 190 Synaptic Vesicles, 190 Synergistic, 182, 190, 192 Systemic, 3, 26, 32, 35, 118, 144, 147, 155, 159, 166, 180, 190, 193
207
Systolic, 164, 190 T Tacrine, 30, 191 Tardive, 7, 8, 10, 79, 90, 106, 108, 143, 151, 191 Telencephalon, 145, 150, 191 Temporal, 11, 13, 25, 27, 141, 164, 191 Temporal Lobe, 13, 141, 191 Thalamic, 22, 32, 61, 145, 159, 191 Thalamic Diseases, 145, 191 Thalamic Nuclei, 22, 159, 191 Thalamus, 27, 32, 154, 159, 169, 181, 191 Therapeutics, 24, 31, 59, 87, 91, 97, 99, 118, 191 Third Ventricle, 159, 165, 171, 191 Threonine, 187, 191 Threshold, 164, 191 Thrombin, 180, 182, 191 Thromboembolism, 85, 114, 191 Thrombomodulin, 182, 191 Thrombosis, 146, 182, 189, 191 Thromboxanes, 144, 191 Tic, 40, 192 Timolol, 107, 192 Tissue, 8, 24, 27, 30, 41, 43, 56, 139, 140, 143, 146, 147, 148, 151, 153, 157, 159, 160, 161, 163, 167, 169, 170, 171, 173, 174, 175, 176, 178, 179, 180, 185, 188, 189, 192, 193 Tolerance, 8, 24, 39, 162, 192 Tone, 13, 165, 173, 176, 192 Tonic, 74, 192 Tonicity, 157, 192 Tonus, 192 Toxic, iv, 84, 145, 165, 175, 187, 192 Toxicity, 44, 45, 64, 73, 157, 175, 179, 192 Toxicokinetics, 59, 192 Toxicology, 12, 20, 71, 124, 192 Toxin, 159, 192 Tracer, 18, 192 Traction, 151, 192 Tranquilizing Agents, 183, 192 Transduction, 188, 192 Transfection, 147, 192 Translation, 32, 193 Translational, 31, 193 Transmitter, 139, 145, 156, 167, 171, 175, 190, 193 Tremor, 13, 48, 177, 192, 193 Tricuspid Atresia, 153, 193 Tricyclic, 108, 143, 151, 193 Trigger zone, 143, 193
Triglyceride, 54, 164, 193 Trophic, 41, 193 Tryptophan, 187, 193 Tubercle, 175, 193 Tumor Necrosis Factor, 75, 193 Type 2 diabetes, 8, 54, 193 Tyramine, 146, 193 Tyrosine, 156, 193 U Ulcer, 157, 193 Unconscious, 142, 193 Uremia, 168, 193 Urethra, 178, 194 Urinary, 60, 159, 173, 176, 194 Urine, 70, 144, 147, 155, 156, 159, 163, 168, 172, 176, 182, 194 Uterus, 150, 154, 175, 181, 194 Uveitis, 144, 194 V Vacuoles, 32, 176, 194 Valproic Acid, 5, 90, 91, 109, 194 Vascular, 67, 141, 151, 166, 194 Vasodilator, 156, 164, 194 Vein, 167, 175, 180, 194 Venous, 85, 146, 180, 182, 193, 194 Venter, 194 Ventral, 31, 32, 38, 98, 165, 175, 180, 194 Ventral Tegmental Area, 31, 32, 194 Ventricle, 141, 145, 149, 153, 164, 175, 183, 190, 191, 193, 194 Ventricular, 43, 153, 193, 194 Venules, 147, 148, 194 Veterinary Medicine, 123, 194 Virulence, 192, 194 Virus, 161, 167, 192, 194 Visceral, 169, 194 Vitreous, 185, 194, 195 Vitreous Body, 185, 194, 195 Vitro, 195 Vivo, 21, 25, 195 W White blood cell, 142, 160, 162, 163, 169, 170, 171, 175, 179, 195 Withdrawal, 7, 13, 56, 57, 72, 87, 98, 155, 195 X Xenograft, 142, 195 X-ray, 8, 171, 175, 195 Y Yeasts, 179, 195 Z Zymogen, 182, 195
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