BENZODIAZEPINES A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES
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., 1960Benzodiazepines: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84352-X 1. Benzodiazepines-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 benzodiazepines. 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 BENZODIAZEPINES .................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Benzodiazepines .......................................................................... 14 E-Journals: PubMed Central ....................................................................................................... 48 The National Library of Medicine: PubMed ................................................................................ 51 CHAPTER 2. NUTRITION AND BENZODIAZEPINES .......................................................................... 69 Overview...................................................................................................................................... 69 Finding Nutrition Studies on Benzodiazepines ........................................................................... 69 Federal Resources on Nutrition ................................................................................................... 73 Additional Web Resources ........................................................................................................... 74 CHAPTER 3. ALTERNATIVE MEDICINE AND BENZODIAZEPINES.................................................... 75 Overview...................................................................................................................................... 75 National Center for Complementary and Alternative Medicine.................................................. 75 Additional Web Resources ........................................................................................................... 82 General References ....................................................................................................................... 86 CHAPTER 4. DISSERTATIONS ON BENZODIAZEPINES ..................................................................... 87 Overview...................................................................................................................................... 87 Dissertations on Benzodiazepines ................................................................................................ 87 Keeping Current .......................................................................................................................... 88 CHAPTER 5. PATENTS ON BENZODIAZEPINES ................................................................................ 89 Overview...................................................................................................................................... 89 Patents on Benzodiazepines ......................................................................................................... 89 Patent Applications on Benzodiazepines ................................................................................... 104 Keeping Current ........................................................................................................................ 121 CHAPTER 6. BOOKS ON BENZODIAZEPINES .................................................................................. 123 Overview.................................................................................................................................... 123 Book Summaries: Online Booksellers......................................................................................... 123 Chapters on Benzodiazepines ..................................................................................................... 127 CHAPTER 7. MULTIMEDIA ON BENZODIAZEPINES ....................................................................... 133 Overview.................................................................................................................................... 133 Video Recordings ....................................................................................................................... 133 Audio Recordings....................................................................................................................... 134 CHAPTER 8. PERIODICALS AND NEWS ON BENZODIAZEPINES .................................................... 137 Overview.................................................................................................................................... 137 News Services and Press Releases.............................................................................................. 137 Newsletter Articles .................................................................................................................... 140 Academic Periodicals covering Benzodiazepines........................................................................ 142 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 143 Overview.................................................................................................................................... 143 U.S. Pharmacopeia..................................................................................................................... 143 Commercial Databases ............................................................................................................... 144 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 147 Overview.................................................................................................................................... 147 NIH Guidelines.......................................................................................................................... 147 NIH Databases........................................................................................................................... 149 Other Commercial Databases..................................................................................................... 151 The Genome Project and Benzodiazepines ................................................................................. 151 APPENDIX B. PATIENT RESOURCES ............................................................................................... 155 Overview.................................................................................................................................... 155
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Patient Guideline Sources.......................................................................................................... 155 Finding Associations.................................................................................................................. 159 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 161 Overview.................................................................................................................................... 161 Preparation................................................................................................................................. 161 Finding a Local Medical Library................................................................................................ 161 Medical Libraries in the U.S. and Canada ................................................................................. 161 ONLINE GLOSSARIES................................................................................................................ 167 Online Dictionary Directories ................................................................................................... 169 BENZODIAZEPINES DICTIONARY........................................................................................ 171 INDEX .............................................................................................................................................. 255
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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 benzodiazepines 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 benzodiazepines, 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 benzodiazepines, 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 benzodiazepines. 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 benzodiazepines, 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 benzodiazepines. 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 BENZODIAZEPINES Overview In this chapter, we will show you how to locate peer-reviewed references and studies on benzodiazepines.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and benzodiazepines, 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 “benzodiazepines” (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: •
Identifying a Neurobiological Basis for Drug Therapy in TMDs Source: JADA. Journal of American Dental Association. 127(5): 581-593. May 1996. Summary: Emerging results from clinical and basic research indicate that persistent pain results in changes in the central nervous system. This article reviews data that support the use of tricyclic antidepressants for neurogenic or atypical pain, and benzodiazepines for musculoskeletal pain. Other topics covered include the pathophysiology of persistent pain and the pharmacological management of temporomandibular disorders (TMDs) with antidepressants, benzodiazepines, muscle relaxants, non-opioid analgesics, corticosteroids, and opioids. The authors stress that dentists must weigh the benefits of the chronic administration of a drug for the management of TMDs against the equivocal scientific support for the use of many drug
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classes and the potential for serious toxicity with prolonged administration. 3 figures. 80 references. (AA-M). •
Flexible Sigmoidoscopy Source: American Family Physician. 63(7): 1375-1380. April 1, 2001. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: Flexible sigmoidoscopy remains a common tool used for the periodic screening of colorectal cancer. This article reminds family care physicians of the recommendations for the use of flexible sigmoidoscopy. Most organizations recommend screening at three to five year intervals beginning at age 50 for persons with average risk. Extensive training in endoscopic maneuvering, colorectal anatomy, and pathologic recognition is required. Most physicians report comfort performing the procedure unsupervised after 10 to 25 supervised sessions. The procedure itself involves the insertion of the sigmoidoscope through the anus and distal rectum and advancement of the scope tip to an average depth of 48 to 55 centimeters in the sigmoid colon. Once the sigmoidoscope has been appropriately advanced, the scope is slowly withdrawn, allowing for the inspection of colon mucosa during withdrawal. Polyps less than 5 millimeters in diameter should be biopsied. Polyps 5 to 10 millimeters or greater can be assumed to be adenomatous, and follow up colonoscopy for complete polypectomy is required. Diverticulosis, hemorrhoids, nonspecific colitis and pseudomembranes may also be encountered during inspection. Use of preprocedural benzodiazepines can be helpful in reducing patient discomfort. 2 figures. 10 references.
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Sleep Disorders: A Common Problem Among Kidney Patients? Source: For Patients Only. 8(1): 8-10, 24. January-February 1995. Contact: Available from Contemporary Dialysis, Inc. 6300 Variel Avenue, Suite I, Woodland Hills, CA 91367. Summary: In this article, the author provides readers with information about an oftenencountered, but little-discussed complication of dialysis, insomnia. Topics include the adequacy of dialysis and its impact on the sleep habits of patients; restless leg syndrome (RLS) and the role of peripheral neuropathy in its development; the use of Sinemet to treat RLS; using conventional sleep aids, including Ambien; the use of muscle relaxants, or benzodiazepines, for milder forms of RLS; psychological sleep disturbances; and adjunctive therapies, including Qigong, biofeedback, and meditation. The author encourages readers to become more self-aware and to participate as an active member of their own health care team. The article includes a short list of references and organizations that may provide additional information about sleep disorders and their therapy.
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Pathogenesis and Treatment of Portal-Systemic Encephalopathy: An Update Source: Digestive Diseases and Sciences. 37(3): 321-327. March 1992. Summary: Portal-systemic encephalopathy (PSE) remains a serious complication of chronic liver disease. Impairment of intellectual function, deterioration of personality, altered levels of consciousness, and neuromuscular incoordinations dominate the clinical presentation of PSE. This review covers the pathogenesis and treatment of PSE. The author makes reference, where appropriate, to studies in human material as well as to work in experimental animal models of PSE and to clinical studies with new
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therapeutic agents. Topics include the ammonia hypothesis; the GABA theory; endogenous benzodiazepines; and other neurotransmitter systems. 2 figures. 2 tables. 55 references. •
Restless Legs Syndrome: Detection and Management in Primary Care Source: American Family Physician. 62(1): 108-114. July 1, 2000. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: Restless legs syndrome (RLS) is a neurologic movement disorder that is often associated with a sleep complaint. This article explores the role of the primary care physician in the diagnosis and management of RLS. Patients with RLS have an irresistible urge to move their legs, usually due to disagreeable sensations that are worse during periods of inactivity and often interfere with sleep. The authors estimate that between 2 and 15 percent of the population may experience symptoms of RLS. Primary RLS likely has a genetic origin. Secondary causes of RLS include iron deficiency, neurologic lesions, pregnancy, and uremia (urea in the blood). RLS also may occur secondarily to certain medications. The diagnosis of RLS is based primarily on the patient's history. A list of questions to assess the likelihood of RLS is included in the article. Drug therapy includes dopaminergic agents, opioids, benzodiazepines, and anticonvulsants. The primary care physician can incorporate sleep and RLS related questions into the general review of systems as a useful step in diagnosing RLS. Most patients with RLS can obtain symptomatic relief with commonly prescribed medications and support. 5 tables. 30 references.
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Considerations for the Use of Oral Sedation in the Institutionalized Geriatric Patient During Dental Interventions: A Review of the Literature Source: SCD. Special Care in Dentistry. 19(2): 56-63. March-April 1999. Contact: Available from Special Care Dentistry. 211 East Chicago Avenue, Chicago, IL 60611. (312) 440-2660. Fax (312) 440-2824. Summary: Some institutionalized elderly persons need a sedative prior to a dental examination or treatment because they have a disturbance due to physical illnesses, degenerative changes in the brain, or psychiatric disorders, associated with advanced aging. Oral administration is one of the safest methods of delivery of a sedative drug. It is almost universally acceptable, easy to administer, costs little, has a low incidence and severity of adverse reactions, and requires no additional formal specialized training for the dentist. However, theoretical and practical knowledge of sedation is essential. This article reviews the literature on oral sedation for the geriatric patient. Benzodiazepines are most often used for oral sedation of geriatric patients. The properties of these drugs are reviewed, and recommendations are made with respect to the drugs of choice and their dosage. Generally, fast acting benzodiazepines of short duration, with rapid rate of elimination and no active metabolites, are recommended. The authors note that the drug of choice, and the dosage, will vary according to the medical history and physical condition of the patient. 6 tables. 48 references.
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Behavioral Problems in Nursing Home Residents: Safe Ways To Manage Dementia Source: Postgraduate Medicine. 97(5): 189-191, 195-196. May 1995. Summary: This article addresses behavioral problems in nursing home residents and the use of patient assessment and treatment options, both pharmacological and non-
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pharmacological, that can help control these behaviors. Non-pharmacological treatment options include environmental changes, bright-light treatment, and restraints and behavior modification. Pharmacological options involve the use of neuroleptics, benzodiazepines, and other agents such as beta-blocker therapy, carbamazepine, lithium, trazodone hydrochloride, and buspirone hydrochloride. According to the authors, patients should be assessed to differentiate delirium from dementia, and possible precipitants of disturbed behavior should be investigated. The authors suggest that ultimately, long-term success with patients with dementia may depend in part on realistic expectations. 21 references. •
Causes and Treatment of Behavioral Changes Source: Consultant. 28(1): 43-45, 48. January 1988. Summary: This article describes Alzheimer's disease as an increasingly common management concern for primary care physicians. Although little can be done for the primary symptoms of the dementing process, the secondary behavioral complications of this illness may be amenable to behavioral or pharmacologic manipulation. Agitation may be responsive to environmental or psychosocial intervention. Treatment with low doses of antidepressants can improve depressive symptoms. Mild anxiety is best treated with emotional support from the family and caregiver. Benzodiazepines can be used with caution. Insomnia can be reduced by encouraging a routine that prevents daytime napping and keeping the patient busy during the day. Pharmacotherapy for disturbed sleep often causes more harm than good and should be avoided if possible. 3 references. (AA-M).
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Burning Mouth Syndrome Source: American Family Physician. 65(4): 615-620. February 15, 2002. Contact: Available from American Academy of Family Physicians. Publications Division, 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 944-0000. Website: www.aafp.org/afp. Summary: This article discusses burning mouth syndrome (BMS), a condition that is characterized by a burning sensation in the tongue or other oral sites, usually in the absence of clinical and laboratory findings. Affected patients often present with multiple oral complaints, including burning, dryness, and taste alterations. Burning mouth complaints are reported more often in women, especially after menopause. Typically, patients awaken without pain but note increasing symptoms through the day and into the evening. Conditions that have been reported in association with BMS include chronic anxiety or depression, various nutritional deficiencies, type 2 diabetes, and changes in salivary function. However, these conditions have not been consistently linked with the syndrome, and their treatment has had little impact on BMS symptoms. Recent studies have pointed to dysfunction of several cranial nerves associated with taste sensation as a possible cause of BMS. Given in low dosages, benzodiazepines, tricyclic antidepressants, or anticonvulsants may be effective in patients with BMS. Topical capsaicin has also been used in some patients. 1 table. 31 references.
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Pharmacologic Treatments for Temporomandibular Disorders Source: Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 83(1, Supplement): 134-142. January 1997.
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Summary: This article on pharmacologic treatments for temporomandibular disorders is from a special supplement issue on the NIH Technology Assessment Conference on the management of temporomandibular disorders (TMDs), held in April 1996. The author notes that drugs are widely used in the management of acute and chronic orofacial pain. Whereas the use of analgesics for acute orofacial pain is well documented, the use of a broad spectrum of drugs for chronic pain is based on few studies. In the absence of data supporting a therapeutic benefit for a drug used chronically for pain, toxicity associated with the drug can still occur. It is critical, therefore, to assess the balance between therapeutic benefit and safety. The author reviews current evidence supporting the use of several drug classes for TMD and identifies therapeutic controversies in need of further research. Drug classes discussed include nonopioid analgesics, opioids, corticosteroids, antidepressants, benzodiazepines, and muscle relaxants. Assuming that a reliable differential diagnosis can be performed, pain with a neuropathic or atypical component would recommend a trial with a tricyclic antidepressant. Pain of musculoskeletal origin is probably best managed by physical medicine procedures, possibly supplemented with a short trial of a benzodiazepine or an NSAID. Patients with manifestations of psychosocial dysfunction may not benefit from drug therapy aimed at pain and should be considered as candidates for physical medicine modalities and behavioral methods. 3 figures. 1 table. 55 references. (AA-M). •
Pharmacologic Management of Myofascial Pain and Dysfunction Source: Oral and Maxillofacial Surgery Clinics of North America. 7(1): 87-97. February 1995. Summary: This article on the pharmacologic management of myofascial pain and dysfunction is from an issue of Oral and Maxillofacial Clinics on the medical management of temporomandibular disorders (TMD). The authors discuss the most frequently used classes of drugs, providing information about their mechanism of action, indications and contraindications, methods of use, and possible adverse side effects. Specific drugs discussed include anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs, and corticosteroids; muscle relaxants (other than benzodiazepines); antianxiety medications; antidepressant medication; opiate narcotic analgesics; and local anesthetics. A final section covers the placebo effect. The author emphasizes the importance of understanding the patient in terms of compliance and tolerance of side effects in order to achieve successful management with pharmacologic therapy. 2 figures. 6 tables. 25 references. (AA-M).
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Practical Considerations in Managing Alzheimer's Disease Source: Geriatrics. 42(10): 55-61. October 1987. Summary: This article presents a panel discussion on the role of the physician in the treatment of Alzheimer's, including handling the patient's response to the diagnosis, managing behavioral aspects of the illness, treatment of depression and other emotional symptoms, treatment of other medical conditions, and helping patients live with cognitive impairment. The panelists also considered such drug therapy as THA, Hydergine neuroleptics for agitation, and benzodiazepines for sleep disorders.
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Current Perspectives on Drug Therapies for Anorexia Nervosa and Bulimia Nervosa Source: Drugs. 41(3): 367-377. March 1991. Contact: Available from ADIS International. Suite B-30, Oxford Court Business Center, 582 Middletown Boulevard, Langhorne, PA 19047. (215) 752-4500. ISSN: 0012-6667.
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Summary: This article presents current perspectives on drug therapies for anorexia nervosa and bulimia nervosa. Topics include diagnostic considerations, drug treatment for anorexia nervosa, and drug treatment for bulimia nervosa. The authors maintain that there is little if any role for pharmacotherapy in anorexia nervosa. Drugs used to promote food intake and weight gain in bulimia nervosa have provided disappointing results. Newer antidepressants, anticonvulsants, benzodiazepines, lithium, fenfluramine, and opiate antagonists may prove useful, although all require further research. 1 table. 85 references. •
Burning Mouth Syndrome: An Update Source: JADA. Journal of the American Dental Association. 126(7): 842-853. July 1995. Contact: Available from ADA (American Dental Association) Publishing Company. 211 East Chicago Avenue, Chicago, Ill 60611. (312) 440-2867. Summary: This article provides an overview of burning mouth syndrome (BMS), a chronic oral-facial pain condition that affects many U.S. adults. The authors provide an update on what is known about the epidemiology, etiology, and treatment of BMS. Specific topics include the clinical presentation of BMS; statistics on the incidence and prevalence of BMS; oral disorders that can result in BMS, such as denture allergy, salivary dysfunction, or taste disturbances; systemic conditions that can result in BMS, such as hematological disorders, nutritional disorders, anemias, central nervous system disorders, psychological disorders, diabetes mellitus, or Sjogren's syndrome; and treatment options, including the use of antidepressants and benzodiazepines. The authors conclude that the dental profession should formulate standardized symptom and diagnostic criteria so that multidisciplinary investigations can identify effective and reliable treatment strategies. 2 figures. 2 tables. 65 references. (AA-M).
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Tinnitus: Keeping Up to Date Source: Hearing Health. 12(6): 40-42. November-December 1996. Contact: Available from Voice International Publications, Inc. P.O. Drawer V, Ingleside, TX 78362-0500. Voice/TTY (361) 776-7240. Fax (361) 776-3278. Website: www.hearinghealthmag.com. Summary: This article reviews some recent research on tinnitus and its management. Topics include tinnitus in children, benefits or detriments of alcohol use in people with tinnitus, drug treatment and tinnitus, psychological factors, and future research, particularly that on children with tinnitus. Drugs discussed include carbamazepine, betahistine hydrochloride, benzodiazepines, propranol, pitzotifen, and antidepressants. The author notes that most children with tinnitus believe it is normal, a regular aspect of every day life. The author stresses that children must be educated about avoiding loud noise.
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Use of Psychotropic Medication in the Management of Problem Behaviors in the Patient With Alzheimer's Disease Source: Medical Clinics of North America. 78(4): 811-822. July 1994. Summary: This article reviews the literature on alternatives to neuroleptics in the treatment of the agitated patient with progressive dementia. Specific neuroleptics discussed are the following: serotoninergic agents (trazodone), azapirones (buspirone), benzodiazepines, beta-blockers, anticonvulsants, and lithium. The authors state that, although a variety of potential alternatives to the neuroleptics in the management of
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agitated behavior in Alzheimer's disease exist, more large, well-controlled studies are needed. At present, neuroleptics remain the standard treatment for this problem. 2 tables, 59 references. •
Management of the Psychotic Patient Source: Oral and Maxillofacial Clinics of North America. 10(3): 457-464. August 1998. Contact: Available from W.B. Saunders. Periodicals Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.wbsaunders.com. Summary: This article reviews the pharmacologic management of the psychotic patient, to familiarize oral and maxillofacial surgeons with the care of these patients. The author notes that the trend to outpatient care extends to the psychiatric patient and more health care providers will be faced with the care of this patient population. The author reviews potential drug interactions and clinical considerations for patients already under maintenance therapy. The article covers antipsychotic agents, mood disorders, HCAs (including tricyclic drugs), MAOIs (derivatives of hydrazine or amphetamine), SSRIs (antidepressants), bipolar disorder, and antianxiety agents, specifically benzodiazepines, barbiturates, and buspirone. The emphasis in each section is on pharmacodynamics, drug interactions, and anesthetic concerns. 3 tables. 25 references.
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Pharmacologic Approach to Management of Agitation Associated With Dementia Source: Journal of Clinical Psychiatry. 55(Suppl):13-17. February 1994. Summary: This article reviews the phenomenology of agitation and its pharmacologic treatment in patients with dementia, including the use of benzodiazepines, neuroleptics, beta-adrenergic-blocking agents, serotonergic agents, carbamazepine, and lithium. Persistent and acute agitation may be treated through sedation with neuroleptics or benzodiazepines. However, care should be taken to not maintain patients on these medications for protracted period of time, i.e., beyond 4 to 6 weeks. For chronic agitation, the severe side effects and limited efficacy of neuroleptics and benzodiazepines diminish their usefulness. The authors recommend a trial of the serotonergic agents, including buspirone, trazodone, and serotonin selective reuptake inhibitor antidepressants, as first-line treatment for chronic agitation in patients with dementia. Second-line treatment includes beta-blockers, carbamazepine and lithium when agitation is associated with manic affects. The authors suggests the usage of neuroleptics when agitation is derived from psychotic ideation. The authors state that no gold standard exists for the treatment of chronic agitation in older patients with dementia. They recommend more placebo-controlled, double-blind studies to assess therapeutic efficacy, and these should utilize valid scales to define and rate agitation. 1 table, 58 references.
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Pharmacologic Treatment of Behavioral Symptoms of Alzheimer's Dementia - A Review and a Possible Strategy Source: Clinical Gerontologist. 16(1): 3-16. 1995. Summary: This article reviews the use of both neuroleptics and nonneuroleptics in the treatment of behavioral symptoms of Alzheimer's disease. The author suggests that using current knowledge about the possible neurobiological basis of behavioral symptoms in Alzheimer's disease and the actions of medications may make possible a pharmacologic strategy for the treatment of aggression and agitation in Alzheimer's disease. This strategy may need to consider the specific neural network dysfunction as
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determined by neuroradiologic, electroencephalographic, and neuropsychological testing. The author suggests that proposed strategy is an empirical one that has not been validated through appropriate scientific study, but has been used clinically. The treatment strategy for acute agitation usually depends on antipsychotics for psychotic behaviors and benzodiazepines for nonpsychotic behavior. For chronic psychotic agitation, the strategy suggests use of neuroleptics as a first step, with appropriate drugs added according to patient response. The strategy for chronic nonpsychotic agitation calls for the treatment of specific psychiatric syndromes and neural dysfunctions, with specific suggestions for drug types for use in neural dysfunction. Symptoms other than agitation that may be amenable to a pharmacologic approach are emotional lability, abulia, sleep disturbances, decreased food intake, and inappropriate sexual behavior. 52 references. •
Guidelines for Prescribing Psychoactive Drugs in the Elderly: Part 1 Source: Geriatrics. 46(9): 40-47. September 1991. Summary: This journal article describes guidelines for prescribing psychoactive drugs in the elderly. Primary care physicians are usually the first to see elderly patients with emotional problems secondary to dementia and other psychiatric disorders. Because these problems often can be treated effectively, physicians should have a working knowledge of the guidelines for optimal use of psychoactive medications. This article provides an up-to-date compendium of prescribing information on benzodiazepines and antidepressants for use by primary care physicians in treating elderly patients with cognitive or behavioral dysfunction. Included is practical information on the half-life of drugs, time to steady state, and other data geriatricians need for effective prescribing and dosing.
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Effect of a Program of Diverse Activities on Disturbed Behavior in Three Severely Demented Patients Source: International Psychogeriatrics. 9(4): 423-430. December 1997. Summary: This journal article describes the effects of a daily program of diverse activities on the disturbed behavior of three patients with severe dementia, aged 76, 81, and 82 years. The patients were on a Dutch psychogeriatric ward and had severe disturbed behavior that had not responded to benzodiazepines or antipsychotic drugs. The Behavioral Rating Scale for Psychogeriatric Inpatients, Social Dysfunction and Aggression Scale, and Clinical Global Impression/Improvement Scale were used to assess behavior during baseline, intervention, and followup periods of 4 weeks each. During the intervention period, the patients participated in a twice-daily program of various group, musical, physical, and social activities off the ward. During baseline and followup, they followed the regular ward activities. The patients had different responses to the intervention. One patient worsened during intervention but improved during followup. The second patient improved on global functioning during intervention, and then worsened during followup. The third patient exhibited aggressive behavior which worsened during intervention; during followup, the aggressive behavior improved but global functioning declined. The authors explore possible implications for practice and further research. 3 figures, 2 tables, 25 references.
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Donepezil Improves Symptoms of Delirium in Dementia: Implications for Future Research Source: Journal of Geriatric Psychiatry and Neurology. 11: 159-161. Fall 1998.
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Summary: This journal article discusses a case study of delirium, complicated by preexisting dementia, that was resolved rapidly following initiation of the cholinesterase inhibitor donepezil. The authors suggest that cholinergic dysfunction may have played a role in the etiology of the patient's delirium. Delirium is a common complication of dementia that may produce agitation, which may be refractory to conventional medications such as antipsychotics and benzodiazepines. Delirium may also produce considerable morbidity. Delirium is not always reversible and there is no specific treatment for persistent delirium; the main treatment approach is to treat the underlying medical problem. The authors state that future research needs to be directed at the issue of cholinergic activity in delirium through monitoring serum anticholinergic activity and its response to procholinergic therapy. 17 references. (AA-M). •
Depression, Anxiety, and Sleep Disturbances Source: International Psychogeriatrics. 8(Supplement 3): 415-418. 1996. Summary: This journal article discusses issues in the treatment of depression, anxiety, and sleep disturbances in patients with dementia. The author reviews evidence suggesting that both pharmacologic and nonpharmacologic therapies are effective for the treatment of depression, and that treatment for depression in dementia should focus not only on symptomatic relief but also on functional improvement. He notes that little attention has been given to the treatment of anxiety in patients with dementia, and advises that benzodiazepines should be used with caution in such patients because of the risk of worsening their cognitive function. He also discusses considerations in the effective management of sleep disturbance in patients with dementia, including the use of nonpharmacologic approaches such as activity programs, environmental interventions, and educational interventions.
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Pharmacologic Management of Alzheimer's Disease Source: Clinics in Geriatric Medicine. 14(1): 129-146. February 1998. Summary: This journal article discusses pharmacologic approaches to the management of Alzheimer's disease (AD) and some of its symptoms. The first section discusses treatment strategies using various types of cholinergic drugs, including acetylcholine (ACh) precursors, cholinesterase inhibitors, a combination of ACh precursors and cholinesterase inhibitors, cholinergic agonists, and indirect enhancement of cholinergic activity in the brain. The next three sections address the use of antiinflammatory agents, antiamyloidogenic and antioxidant therapy, and estrogen replacement therapy to prevent or delay the onset of AD. The fifth section examines the management of psychosis and agitation in AD with such medications as antipsychotics, benzodiazepines, trazodone, buspirone, anticonvulsants, beta-adrenergic blockers, lithium, and selective serotonin reuptake inhibitors. Finally, the article discusses the use of selected antidepressant medications for the management of depressive symptoms in dementia. 67 references.
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Cognitive Side Effects of Medications Source: Neurologic Clinics of North America. 16(1): 141-155. February 1998. Summary: This journal article discusses the cognitive side effects of medicines that are commonly used in clinical settings. Researchers provide an overview of the direct effects on the central nervous system from several major clinical drug groups. Their study covers neuropsychiatric drugs (e.g., psychotropic agents, antidepressants, neuroleptics, antiparkinsonian agents) and medicinal drugs (e.g., antihypertensives, cardiac drugs,
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anticholinergics, anti-inflammatory agents, antibiotics). Researchers found that cognitive side effects may be produced by a variety of medications from multiple drug classes. The most commonly implicated drugs are the anticholinergics, benzodiazepines, narcotics, neuroleptics, and sedative-hypnotics. The authors discuss the specific cognitive problems that these drugs may produce. 131 references. •
Clinical Presentation and Pharmacological Therapy in Corticobasal Degeneration Source: Archives of Neurology. 55: 957-961. July 1998. Summary: This journal article evaluates the clinical presentation and treatment outcome of patients clinically diagnosed with corticobasal ganglionic degeneration. Researchers performed a chart review of 147 patients who were seen in movement disorder clinics. Clinical presentation, medications used, response to medications, and adverse effects were recorded. Data showed that parkinsonian features were present in all patients, other movement disorders in 89 percent, and higher cortical dysfunction in 93 percent. Ninety-two patients received dopaminergic drugs; 24 percent received a beneficial effect. Forty-seven of the patients received benzodiazepines; there was myoclonus improvement in 23 percent of these patients and dystonia improvement in 9 percent. Frequent adverse effects included somnolence, gastrointestinal complaints, confusion, dizziness, hallucinations, and dry mouth. The authors conclude that pharmacological intervention was largely ineffective in managing corticobasal degeneration; new treatments are needed. 2 tables, 29 references.
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Treating Sleep Disorders in Patients With Fibromyalgia Source: Journal of Musculoskeletal Medicine. 14(6):25-28,33-34; June 1997. Summary: This journal article for health professionals reviews current knowledge about sleep disorders in patients with fibromyalgia and the treatment strategies currently used. Sleep disturbance may be central to the fibromyalgia syndrome. Many patients have difficulty in falling and staying asleep and awaken unrefreshed with intensified morning aching. Alpha-delta sleep, in which internally triggered arousal results in delta sleep deprivation, appears responsible. Moreover, such triggers may also lead to depressed and anxious mood, fatigue, morning stiffness, and musculoskeletal pain, which, in turn, contribute to the nonrestorative sleep cycle. Success in improving sleep is greatest when general approaches and specific sleep interventions are combined. Psychotherapy, behavioral therapy, and exercise may lead to better sleep habits and symptomatic relief. Tricyclic agents improve sleep and overall functioning. Benzodiazepines administered with nonsteroidal anti-inflammatory drugs may improve sleep and decrease tenderness. 29 references and 2 tables. (AA-M).
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Psychiatric Symptoms and Behavioral Disturbances in Dementia: A Review of Therapy Source: International Psychogeriatrics. 8(Supplement 2): 201-207. 1996. Summary: This journal article reviews selected drug treatments for psychiatric symptoms and behavioral disturbances in dementia. Several different classes of drugs have been used in the treatment of behavioral disorders in dementia: neuroleptics, anticonvulsants, antidepressants, beta-blockers, and benzodiazepines. Neuroleptics are the drugs of first choice for treating behavioral disorders, and they generally are considered to be moderately effective. These drugs are known to improve anxiety and mood; and reduce aggression, agitation, hostility, and uncooperativeness. Anticonvulsants such as carbamazepine and sodium valproate also may be effective in
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some patients with dementia. Antidepressants have been used not only for the treatment of depression but also to reduce agitation, aggression, and shouting in patients without a definable additional affective disorder. Beta-blockers generally have been found to be effective in younger patients with evidence of brain damage, and several reports have suggested that pindolol may be effective in dementia. Patients with dementia of the Lewy body type appear to be particularly sensitive to neuroleptics, and these drugs often result in a severe Parkinsonian-like reaction. Risperidone, a new atypical neuroleptic, may be effective in treating psychotic symptoms in this type of dementia. 1 table, 25 references. •
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 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.
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Pharmacotherapy for Long-Term Care Residents With Dementia-Associated Behavioral Disturbance Source: Journal of Psychosocial Nursing. 36(2): 27-31. 1998.
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Summary: This journal article summarizes Federal guidelines for benzodiazepine and antipsychotic drug use in long-term care residents with dementia. The Nursing Home Reform Amendments of the Omnibus Budget Reconciliation Act of 1987 (OBRA 87) have resulted in close supervision of the use of unnecessary drugs for residents in Medicare and Medicaid certified nursing homes. They require documenting the behavioral indication for psychotropic drugs, monitoring their safety and efficacy, drug holidays, behavioral management instead of drugs when possible, and systematic dose reductions unless clinically contraindicated. Long-acting benzodiazepines generally are not recommended for use in older patients. Short-acting benzodiazepines may be used for anxiety, insomnia, and dementia-associated agitated states that represent a danger to the patient or others. Antipsychotics may be used for dementia with psychotic features, continuous crying or screaming that impairs functional status, and dangerous behavior. 3 tables, 14 references.
Federally Funded Research on Benzodiazepines The U.S. Government supports a variety of research studies relating to benzodiazepines. 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 benzodiazepines. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore benzodiazepines. The following is typical of the type of information found when searching the CRISP database for benzodiazepines: •
Project Title: ABUSE LIABILITY OF BENZODIAZEPINES AND CAFFEINE Principal Investigator & Institution: Griffiths, Roland R.; Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-FEB-1975; Project End 28-FEB-2004 Summary: (Applicant's Abstract) Research in baboons is proposed to characterize the intravenous reinforcing and physical dependence-producing effects of benzodiazepines and also to examine caffeine reinforcement interactions with cocaine and nicotine. Two self-injection studies will determine whether physical dependence enhances the reinforcing effects of a benzodiazepine. A series of three studies will address concerns that the abuse liability of benzodiazepines is enhanced by interactions with opioids by determining whether chronic opioid exposure increases benzodiazepine self-injection and whether the discriminative stimulus effects of benzodiazepines and opioids mutually potentiate each other. One study will determine whether the abuse liability of sedative drugs can be reduced by slowing the rate of drug onset. A final self-injection
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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study will explore the concern that flunitrazepam has a particularly high abuse liability. A second series of studies will examine benzodiazepine physical dependence. Studies will examine precipitated withdrawal effects produced by a series of novel partial/selective benzodiazepine receptor agonists in benzodiazepine-dependent baboons. Another study will use drug discrimination methods to examine the effects of these same compounds in benzodiazepine-dependent baboons that have been trained to discriminate the benzodiazepine antagonist flumazenil. A third study will explore using an antagonist to decrease the severity and/or shorten the time course of the spontaneous withdrawal syndrome. Finally, two studies will explore recent findings suggesting that caffeine potentiates the reinforcing effects of cocaine and nicotine by characterizing the effects of caffeine on the self-injection of cocaine and nicotine, and the effects of cocaine and nicotine on caffeine self-injection. Benzodiazepines are among the most widely prescribed of all psychotropic medications and caffeine is the most widely used psychotropic drug in the world. There are health risk concerns about benzodiazepine abuse and physical dependence among polydrug abusers and patients, and also about excessive caffeine use in a significant portion of the population. This research will advance our understanding of factors which contribute to the overuse, abuse and dependence on these widely self-administered drugs, provide valuable insights into possible interactions of these drugs with other widely abused drugs, and will ultimately contribute to the development of improved prevention, control and treatment procedures for various forms of drug abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACUTE DRUG WITHDRAWAL IN A GENERAL MEDICAL SETTING Principal Investigator & Institution: Weaver, Michael F.; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-JUL-1998; Project End 30-JUN-2004 Summary: This is a proposal for a Mentored Clinical Scientist Development Award to provide supervised experience in clinical research, didactic education, and some clinical activities. This will provide a foundation for a career in academic medicine with opportunities for research, teaching, and some clinical practice. This award will allow the candidate to begin research in substance abuse treatment and Health Services Research (HSR) in a supervised setting. The effects of symptom-triggered therapy versus scheduled dosing for acute withdrawal from alcohol will be studied in a general medical population. The first two years of the award period will be spent taking graduate courses in biostatistics, pharmacology, research design and methodology, attending seminars on HSR topics, and refining the final study protocol by doing a pilot study. Practical clinical experience will be gained in outpatient clinics including rotation through community programs such as a local methadone maintenance clinic, a residential center for pregnant and newly delivered women and their young children, and inpatient substance abuse services in a large urban teaching hospital. Symptomtriggered therapy with benzodiazepines is the treatment of choice for alcohol withdrawal. It has not been studied in a general medical population. Patients admitted to two general medical wards will be assigned as randomly as possible to symptomtriggered or scheduled therapy for acute alcohol withdrawal. They will be regularly assessed by a clinical assessment tool to evaluate its applicability in this population. Data will be collected on concurrent medical problems, total dose of medication for withdrawal, duration of treatment, complications, length of stay, and recidivism. The medication protocols will be evaluated in terms of acceptance by nurses and physicians, especially housestaff. The data will be evaluated from a HSR standpoint to help
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determine the most cost-effective regimen for acute drug withdrawal in a general medical population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALPHA1 PATHOPHYSIOLOGY
ADRENOCEPTOR
SUBTYPES
AND
ROLE
IN
Principal Investigator & Institution: Perez, Dianne M.; Associate Staff; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 15-JUL-1999; Project End 30-JUN-2003 Summary: Our major objective is to elucidate the molecular and biochemical mechanisms both in vitro and in vivo involved in binding and activation of alpha1adrenergic receptors (ARs) and its subsequent action on the autonomic nervous system. Alpha1-adrenergic receptors are members of the G-protein-coupled receptor family of proteins that mediate the effects of the sympathetic nervous system by binding the endogenous neurotransmitters, epinephrine and norepinephrine. Signal transduction by alpha1-ARs is involved in a variety of responses such as neurotransmission, smooth muscle contraction, cardiac and other organ system homeostasis. These receptors are a therapeutic target in the current management of hypertension, benign prostatic hypertrophy and impotence. Alterations in the signaling pathways and/or receptors themselves may contribute to the pathogenesis of neurological and cardiovascular diseases. Thus, a detailed understanding of the structure-function of these receptors and their signal transduction mechanisms will be crucial to our understanding of the pathology and treatment of these diseases. Our laboratory has made considerable strides into the structure-function of alpha1-ARs subtypes (alpha1a, alpha1b, alpha1d) by characterizing determinants in the binding pocket that contribute to agonist binding and subtype selectivity. We have also through the use of constitutively active mutations provided insights into the activation mechanism. Based on these results, we now propose to address the following specific aims on structure-function analysis in vitro by concentrating on how antagonists and benzodiazepines bind and modulate alpha1-AR function and the mechanism of the poor efficacy of the alpha1d-subtype. This will enhance our understanding of the binding pocket, the signaling differences between alpha1-subtypes and may enhance new drug design. We will also explore possible pathologies from alpha1-subtype overactivity in vivo and to more clearly define the role of the alpha1a-subtype in cardiovascular function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AMPHETAMINE, GABA TRANSMISSION, AND BEHAVIOR Principal Investigator & Institution: Gruen, Rand J.; Psychiatry; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-MAR-2004 Summary: (Adapted from the Investigator's Abstract) A large percentage of individuals who are dependent on amphetamine (amph), abuse other drugs. The most frequent pattern of polydrug abuse involves the conjoint use of amph and drugs with anxiolytic and/or sedative properties-i.e., benzodiazepines (BZs) and alcohol. Polydrug abusers are more difficult to treat due to complications which arise during detoxification involving multiple substances, and they are more likely to experience trauma, accidents, and disruptions in their family, work, and social environment. The broad, long-term objectives of this research then, are to identify biological factors which underlie this pattern of polydrug abuse. The role of GABA in amph use has not been studied
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extensively. In addition to its rewarding properties, amph intoxication is associated with a sense of anxiety and tension. Ligands that bind to the GABA-A/BZ receptor complex play a central role in anxiety. Drugs like alcohol and BZs, which exert some of their effects through the GABA-A/BZ receptor complex, appear to reduce the anxiogenic effects of amph-this may provide an incentive for their use. The specific aims of this research are to: (1) Study the effects of acute amph on behavior and GABA-A receptor binding. We will: a) examine the time-course of the effects of acute amph; and b) determine whether the effects of acute amph on behavior and GABA-A receptor binding are mediated through the GABA-A/BZ receptor complex; (2) Study the effects of repeated intermittent exposure to amph on behavior and GABA-A receptor binding. We will: a) determine whether repeated exposure leads to the development of tolerance with respect to the behavioral and receptor changes seen following acute challenge; b) determine whether reinstatement of the anxiogenic behavioral response following a dose escalation in preexposed animals is mediated through the GABA-A/BZ receptor complex; c) examine the duration of the effects of preexposure to amph; and (3) Examine the effects of amph on BZ receptor binding. We will: a) examine the time-course of the effects of acute amph; b) determine whether repeated exposure leads to the development of tolerance with respect to the receptor changes seen following acute challenge. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANESTHETIC EFFECTS ON GLYCINE AND GABA-A RECEPTORS Principal Investigator & Institution: Mihic, S John.; Associate Professor; Neurobiology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 30-JUN-2005 Summary: (provided by applicant): The overall objective of the proposed work in this developmental grant application is to further understanding of the mechanisms of ligand-gated ion channel activation, desensitization and allosteric modulator action. To this end we propose the electrophysiological characterization of newly-discovered mutants of glycine alpha1 and GABA-A alpha1 and beta2 receptor subunits. Single amino acid mutations of these subunits have been identified that result in channels that open spontaneously and desensitize in the absence of agonist. Tonic opening is revealed by a reversible strychnine- or bicuculline-induced outward current. Tonically-opening glycine and GABA-A receptors will be transiently expressed in mammalian HEK 293 cells and characterized using a fast drug application system. The use of a fast drug exchange system will allow for an accurate assessment of rates of channel opening, closing and desensitization after applying GABA-A and glycine receptor agonists or antagonists to receptors composed of wild-type or mutated subunits. Single channel outside-out patch recordings of our tonically-open channels are hypothesized to display bursts of channel opening events separated by quiescent, desensitized periods. We will then take advantage of the tonic opening and desensitization that occur spontaneously in these mutated receptors to clarify the molecular mechanisms underlying the actions of allosteric modulators. GABA and glycine receptor function is allosterically modulated by numerous classes of agents such as the barbiturates, benzodiazepines and steroidal and volatile anesthetics. Using the receptor mutants we have already created, and new mutants we propose to make, we will test the hypothesis that modulatory concentrations of these agents affect the functioning of tonically-open GABA-A and glycine receptors in the absence of agonist binding to the neurotransmitter receptor binding site, allowing us to dissociate modulator-induced stabilization of open channel states and effects on desensitization from their effects on increasing the affinity of
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neurotransmitter for its receptor. The work proposed will increase understanding not only of basic receptor/channel processes, but also shed insight into the molecular mechanisms of receptor modulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANXIOLYTIC EFFECTS AND ABUSE OF BZ RECEPTOR LIGANDS Principal Investigator & Institution: Rowlett, James K.; Assistant Professor; Psychiatry; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-JUN-1998; Project End 31-MAY-2004 Summary: (Applicant's Abstract) Benzodiazepines (BZs) are widely prescribed for the management of anxiety and sleep disorders, but their clinical usefulness is constrained by a significant potential for abuse and dependence. Considerable research is now focused on elucidating the mechanisms of action underlying the behavioral effects of BZs and related drugs, with the goal of increasing clinical utility and reducing abuse liability. Our proposed research will specifically evaluate the role of BZ receptor selectivity and intrinsic efficacy as determinants of the therapeutic vs. abuse -related effects of this important class of drugs. BZ ligands differing in receptor selectivity and/or agonist efficacy will be used as probes to characterize mechanisms of action in nonhuman primate models predictive of anxiolytic activity, subjective effects, and abuse liability. Anxiolytic activity will be evaluated in rhesus monkeys using conflict procedures in which food-maintained behavior is concurrently suppressed by response produced presentations of an aversive stimulus. Subjective effects will be evaluated in monkeys trained to discriminate the conventional BZ agonist triazolam or the BZ 1selective agonist zolpidem from vehicle. Abuse potential will be evaluated using fixedand progressive-ratio schedules of i.v. drug self-administration. Quantitative pharmacological tools including isobolographic analysis and in vivo apparent pA2 analysis will be used in conjunction with drug interaction studies to dissociate effects due to receptor selectivity and agonist efficacy. Identification of compounds that are effective anxiolytics lacking abuse potential in our studies will provide needed information for developing safer and more broadly effective anti-anxiety medications, as well as compounds that may be beneficial in the pharmacological management of BZ dependence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BABAA RECEPTORS IN AGING & ALZHEIMER'S DISEASE Principal Investigator & Institution: Gandy, Samuel E.; Director; Lankenau Institute for Medical Research Wynnewood, Pa 19096 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-JUL-2004 Summary: (Applicant's abstract) Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian CNS, hyperpolarizes neuronal membranes by opening a C1 channel intrinsic to the GABA A receptor. The proposed studies investigate the anatomical features and expression of selected GABA A receptor subunits (i.e., alpha1, alpha2, alpha3, alpha4, alpha5, beta1-3, gama2) in human hippocampus of non-pathologic mature and aged individuals (30-90 years of age) and those with Alzheimer's disease (AD) pathology. Underlying these studies are investigations of the P.I. and co-investigators demonstrating (I) subunit specific alteration (i.e., alpha1) in the CA1 field and dentate gyrus of aged rats; (ii) GABA A receptor subunit protein and mRNA alterations (i.e., alpha1, beta2, beta3) in the hippocampal formation of aged brains with AD pathology; (iii) time-dependent
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alterations of GABA A beta2/3 immunoreactivity in the dentate gyrus following perforant pathway lesions. In addition, pharmacological studies have demonstrated altered drug sensitivities, for example, to benzodiazepines, in the elderly. To date, it is not known the extent to which altered drug responses in the elderly may be attributed to emotional or physical disease, over- or undernutrition, use or abuse of other medications, or alterations in the molecular composition of the GABA A receptor. Throughout these studies we will employ immunohistochemical, in situ hybridization, in situ autoradiogaphic, and biochemical techniques in order to study the regional and laminar pattern of GABA A receptor subunit protein and mRNA expression in the hippocampal formation of aging individuals (SPECIFIC AIM 1) and those with varying extent of AD pathology (SPECIFIC AIM 2). It is our hypothesis that selected GABA A receptor subunits will display differential levels of expression and binding within the various regions of the hippocampus. Moreover, brain tissue obtained from elderly patients will not only show altered levels of expression of specific GABA A subunits, but will have a different subunit composition of the GABA A receptor complex compared to controls. In AD, we hypothesize that these receptor subunits will also display altered levels of expression and binding within selected subregions of the hippocampus. In addition, many of these changes will occur during the early phases of the disease (i.e., plastic/compensatory phase) and be unique from those observed during the end stages of the disease (i.e., neurodegenerative phase). A unique aspect of this study is the study of both aging and AD subjects. Notably, a comparison of these two populations of subjects will provide us with the opportunity of differentiating whether alterations in the anatomy of specific GABA A receptor subunits are associated with normal aging or represent a neuropathologic process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: KINETICS
BENZODIAZEPINE MODULATION
OF GABAA RECEPTOR
Principal Investigator & Institution: Czajkowski, Cynthia M.; Associate Professor; Physiology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Benzodiazepines (BDZs) exert anxiolytic and antiepileptic effects in the central nervous system (CNS) by allosteric modulation of the GABAA receptor Cl- current (IGABA). Because of the widespread clinical utility of these drugs, understanding the mechanism(s) by which BDZs alter ion channel function is an important pharmacological inquiry. To identify the structural determinants underlying BDZ modulation of kinetic transitions of channel activation, one must first determine the effects of BDZs on identified, wild-type GABAA receptors. This will be approached using rapid drug application techniques and single-channel recordings to test which of the microscopic kinetic rate constants are altered by modulatory BDZs in a1 B2g2 receptors. We will make use of mutations in the GABA binding site, the pore region, and the extracellular loop to tease apart the contributions of BDZs to binding/unbinding and gating/desensitization of IGABA. We will also make use of tethered tandem subunits to functionally separate the contributions of each of the two GABA binding sites to these processes. The studies outlined in this application will help to establish the functional mechanisms of action for clinically relevant drugs on a major CNS variant of the GABAA receptor, and aid in establishing testable hypotheses regarding structurefunction relationships in this and other ligand-gated ion channels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BENZODIAZEPINE-INDUCED GABAA RECEPTOR PLASTICITY Principal Investigator & Institution: Olsen, Richard W.; Professor; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002 Summary: The GABA inhibitory synaptic system plays a major role in the central nervous system and is implicated in human neurological and psychiatric disorders such as epilepsy, stress, anxiety and panic disorders, sleep disorders, and drug dependence, especially to benzodiazepines and ethanol. The major postsynaptic GABA receptors involved in rapid inhibitory neurotransmission are the GABA/A receptors (GABA). GABAR proteins are subject to regulation at the level of transcription, translation, assembly, cell targeting, and the functional level. Endogenous regulation includes modulation by phosphorylation, zinc ions, and neuroactive steroids. GABAR are the known target of numerous clinically relevant drugs, including anti-epileptic antianxiety, and sedative/hypnotic/aesthetic agents. These include the widely used benzodiazepines, barbiturates, and possibly alcohol. GABAR are widely accepted as the major candidate molecular target of general anesthetic action. Their predominant role in the brain makes GABA likely players in the normal plasticity mechanisms that accompany ordinary and extraordinary experiences. By subjecting rats, or in some cases, cells, to somewhat extraordinary experiences that are considered to involve GABAR, we will investigate whether plastic changes in GABAR occur and the molecular and cellular mechanisms of the long-term modifications. In particular, chronic exposure of rats to benzodiazepines, but probably an elevation of GABAR function, leads to tolerance, especially to the anti-epileptic actions of these drugs. Tolerance is accompanied by a reduced GABAR function, reduced enhancement of GABAR function by benzodiazepines, and uncoupling of GABA- benzodiazepine binding measured in vitro. Tolerance to benzodiazepines can be mimicked in cells expressing recombinant GABAR that lack normal transcriptional control, and can be reversed rapidly by exposure in rats and in cells by exposure to the benzodiazepine antagonist flumazenil. This strongly suggests that the tolerance and reversal result from a physicochemical modification of the GABAR protein itself. This project will attempt to unearth this molecular mechanisms of plasticity. Ultimately therapeutic strategies could be based on our studies, aimed rationally at preventing the unwanted or pathological alterations in GABA/A receptors characteristic of several neurological and psychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOACTIVE CYCLOADDUCTS
COMPOUNDS
FROM
ACYLNITROSO
Principal Investigator & Institution: Miller, Marvin J.; George & Winifred Clark Chair Professor; Chemistry and Biochemistry; University of Notre Dame 511 Main Bldg Notre Dame, in 46556 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 30-APR-2007 Summary: (provided by applicant): The general hypothesis of this proposal is that cycloadducts from Diels-Alder reactions of dienes with transient acyl nitroso moieties, generated by oxidation of hydroxamic acids, can serve as versatile building blocks for syntheses of a number of important and often novel bioactive molecules. The specific aims include (1) methodology development and enhancement, and (2) applications to the syntheses and study of focused targets. Methodology enhancement will include hydroxamate, 1, and diene, 3, variation, alternative asymmetric methods, and determination of the scope and limitations of a new pi-allyl polarity reversal process
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that will significantly increase synthetic versatility. Applications will include both nucleophilic and electrophilic C-O bond cleavage of 4 with N-O bond retention, in both intermolecular and intramolecular processes; N-O bond cleavage to give substituted carbocycles 5; and C=C bond reactions to give 6 and other intermediates. Products from these reactions will be used to prepare focused sets of targets, including: novel 5lipoxygenase inhibitors, neuraminidase inhibitors, benzodiazepines, diazepines, carbocyclic nucleosides and analogs (aristeromycin, carbavir, abacavir, stavudine, carbocyclic oxanosine, and their nor analogs, carbocyclic forms of polyoxins, sinefungin, nucleoside Q, puromycin and analogs), novel phosphodiesterase inhibitors, streptazolin, novel oxazolidinone antibiotics, diketopiperazines (tryprostatin analogs), novel amino acids and peptides related to bacterial diaminopimelic acids (DAP) as well as new amino acids and peptides that represent the first of a novel class of antibiotics. That this tremendous variety of targets can be accessed from the same set of precursors attests to the tremendous potential of readily available acylnitroso cycloaddition products for the design, synthesis and study of bioactive compounds, many of which will be novel. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHRONIC NEUROCHEMISTRY
BENZODIAZEPINES:
BEHAVIOR
AND
Principal Investigator & Institution: Greenblatt, David J.; Professor and Chair; Pharmacol & Exper Therapeutics; Tufts University Boston Boston, Ma 02111 Timing: Fiscal Year 2002; Project Start 30-SEP-1987; Project End 31-JAN-2006 Summary: Benzodiazepine agonists continue to be the principal pharmacologic option available for the treatment of anxiety, panic disorders, and insomnia. Despite an overall record of efficacy and safety that is generally favorable, concerns regarding tolerance, dependence, withdrawal syndromes, and abuse of benzodiazepines remain issues of medical and public health importance. Also of concern is the usage of these agents by the elderly, who may have increased susceptibility to adverse CNS depressant effects. There is continuing need for basic mechanistic data on the causes and consequences of tolerance and withdrawal; such data can form the basis for strategies to identify patients at highest risk, or to develop other pharmacologic interventions to minimize the risk of tolerance and dependence. We propose to continue and broaden our ongoing research program having this overall objective. The core of the model involves male CD-1 mice that receive continuous infusions of benzodiazepine agonists, or vehicle control, for up to 14 days via implanted osmotic pumps. During the period of infusion, and in the 7-day post-infusion withdrawal period, the following outcomes are determined: computerized ambulatory activity; pentylenetetrazole seizure threshold; in vivo benzodiazepine receptor occupancy; in vitro receptor binding; GABA(A) receptor function; receptor autoradiography; receptor subunit mRNA expression; and plasma and brain concentrations of infused substances. The principal research questions to be addressed include the following: a. Do benzodiazepine agonists with relative selectivity for the BZ1 receptor subtype have reduced liability to produce tolerance, dependence and withdrawal? b. Does the protein kinase C second messenger pathway have a modulatory role in benzodiazepine-associated tolerance? c. Does the excitatory amino acid (EAA) receptor system co-modulate the development of tolerance and withdrawal associated with benzodiazepine agonists, and does pharmacologic antagonism of specific EAA receptor systems modify these phenomena? d. Do aging organisms have differential patterns of benzodiazepine tolerance and withdrawal? Are such differences explained by protein kinase C or EAA regulatory systems? These studies should continue to provide mechanistic data relevant to the clinical management and
22
Benzodiazepines
prevention of tolerance and dependence problems associated with therapeutic use of benzodiazepine agonists. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SENSITIVITY
CLINICAL-GENETIC
VARIATION
IN
GABA
/ALCOHOL
Principal Investigator & Institution: Roache, John D.; Associate Professor of Psychiatry and Ph; Psychiatry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): NIAAA is dedicated to understanding the genetic factors that increase vulnerabilIty to alcoholism. Previous research has suggested that children of alcoholic fathers are at increased risk, perhaps because of a reduced or altered sensitivity to the effects of alcohol. A functional polymorphism of the GABA-A receptor a6 gene has been identified as a plausible cause for reduced sensitivity to motor impairment by alcohol or benzodiazepines. The polymorphism is a Proline to Serine amino acid substitution at position #385 (i.e., Pro385Ser). This is a revised R21 application that, in response to previous review critiques, has narrowed the focus of this exploratory study to more certainly address the role of the Pro385Ser a6 polvmorphism in conferring an altered drug response to positive modulators of the GABA-A complex in the children of alcoholic fathers who have not yet exhibited alcohol abuse or dependence. The proposal applies a human pharmacogenetic approach to experimentally test the hypothesis that within the population of male and female social drinkers aged 21-25 years who are presumed at risk for alcoholism because of a Family History of paternal alcoholism, there remain differences in sensitivity to motor impairment from alcohol and benzodiazepines that can be accounted for by the presence of the Pro385Ser polymorphism. Furthermore, we will explore whether this reduced impairment also may be associated with reduced self-reports of intoxication or enhanced euphoric or reinforcing effects. Participants who are social drinkers without a DSM- IV, Axis-I diagnosis, will be selected into two groups based upon whether they are homozygous (Pro/Pro) or heterozygous (Pro/Ser) for the serine-substituted allele (Pro385Ser) of the a6 subunit. In a 2x5 factorial mixed-model ANOVA design, participants from each of these groups will be tested in a crossover study administering challenge doses of placebo, ethanol, and triazolam in a laboratory environment where subjective, motor, and behavioral responses can be repeatedly assessed using standard techniques with which the investigators have a great deal of experience. This study will substantially extend our knowledge of functional differences in the pharmacodynamic effects of GABA-A positive modulators that may be attributable to the a6 polymorphism or other associated genes co-occurring within the same chromosomal cluster. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIRECT INTERACTION BETWEEN GABA-A AND GABA-B RECEPTORS Principal Investigator & Institution: Hall, Randy A.; Pharmacology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain. GABA exerts its physiological actions in the brain via the activation of two distinct types of receptor: GABA-A
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receptors, which are ligand-gated ion channels, and GABA-B receptors, which are G proteincoupled receptors. GABA-A and GABA-B receptors are known to exhibit forms of cross-talk and mutual regulation for which no mechanism has been defined. This project aims to study the importance of a novel and direct interaction found between the GABA-BR1 receptor and the gamma2 subunit of the GABA-A receptor. This physical association may provide a mechanism to allow for direct cross-talk between GABA-A and GABA-B receptors. The structural determinants and physiological significance of this interaction, however, are completely unknown at the present time. The specific regions of GABA-BR1 and the gamma2 subunit of the GABA-A receptor involved in mediating their interaction will be elucidated using a mutagenesis approach in combination with both co-immunoprecipitation and fusion protein pull-down studies. The effects of GABA-A receptor association on GABA-B receptor pharmacology will be studied in ligand binding assays, and GABA-A receptor modulation of GABA-B receptor signaling and internalization will also be analyzed. Furthermore, GABA-B receptor regulation of GABA-A receptor pharmacology, channel activity and phosphorylation will be examined, with an emphasis on determining the functional importance of the direct interaction between GABA-BR1 and the GABA-A receptor gamma2 subunit. These studies will shed new light on the regulation of cellular responses to GABA and the molecular basis for cross-talk between GABA-A and GABAB receptors. Such information is critical for a comprehensive understanding of pharmaceuticals acting on GABA receptors. GABA-A receptors are the targets for such commonly prescribed therapeutic drugs as benzodiazepines and barbiturates, while the more recently-identified GABA-B receptors represent excellent potential targets for novel therapeutic drugs aimed at treating disorders such as schizophrenia, epilepsy, anxiety, chronic pain and depression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DISCRIMINATIVE EFFECTS OF BENZODIAZEPINE WITHDRAWAL Principal Investigator & Institution: France, Charles P.; Professor; Pharmacology; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 15-MAR-1995; Project End 31-JAN-2007 Summary: Benzodiazepines and related gamma-amino butyric acid (GABA)A modulators are used widely for their anxiolytic, hypnotic and anti- convulsant effects. These same compounds are also abused, both alone and in combination with other classes of drugs (e.g., opioids), and long- term use of benzodiazepines can lead to clinically significant physical dependence. The GABAA receptor complex is the site of action of other drugs of abuse (e.g., ethanol) and GABAergic systems, in general, are thought to indirectly modulate the effects of still other drugs of abuse (e.g., cocaine). Much has been learned over the past 10 years from molecular studies on GABA receptors, yet little of this knowledge has been applied to studies in behaving organisms, particularly with regard to GABA neurobiology and substance abuse. Procedures have been developed under this grant for studying discriminative stimulus effects of GABAA modulators in rhesus monkeys and studies proposed in this application will use those procedures to investigate the neurobiology of drugs that vary in their actions on GABAergic systems. Studies under Aim 1ill will compare GABAergic and other drugs for their ability to prevent and reverse benzodiazepine withdrawal and also to mimic the subjective (discriminative) effects of benzodiazepine in normal subjects. A parallel study (Aim II) will establish a discrimination with flumazenil in monkeys treated daily with the a1-s3lective positive modulator zolpidem to test whether this widely-prescribed sedative/hypnotic produces dependence that can be
24
Benzodiazepines
differentiated from that produced by diazepam.Neuroactive steroids will be studied under Aim III to see whether th eye modify the behavioral effects of other compounds that act at the GABAA receptor complex. This study is founded on positive preliminary data with pregnanolone and a literature showing that neuroactive steroids uncouple benzodiazepine receptors from the GABAA receptor complex in vitro. Blind evaluation of compounds will continue the auspices of the Drug Evaluation Committee of the College on Drug Dependence under Aim IV. Collectively, these studies will provide important quantitative information on the nature of drug/receptor and drug/drug interactions for GABAA modulators and related drugs. These data will promote an understanding of GABAergic neurotransmission and abuse liability for a variety of clinically relevant compounds. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DRUGS OF ABUSE: NEURONAL SURVIVAL AND SIGNALING Principal Investigator & Institution: Moulder, Krista L.; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-FEB-2003; Project End 31-JAN-2005 Summary: (provided by applicant): The broadest objective of the proposed research is to characterize the changes in synaptic signaling that accompany increases and decrease in electrical activity. Chronic exposure to drugs of abuse such as ethanol, barbiturates, and benzodiazepines causes a downregulation in electrical activity, which ultimately leads to neuronal death. The goal of Aim 1 is to determine whether this decrease in neuronal activity results in reduced neurotransmitter release because of drug effects on Ca2+ currents, or in enhanced neurotransmitter release through initiation of homeostatic mechanisms. Such changes in synaptic signaling could either lessen or intensify the effects of drugs of abuse on neuronal survival. The goal of Aim 2 is to determine the effects on synaptic signaling caused by mimicking increased electrical activity with K+ depolarization. Preliminary data indicate that depolarization curtails development of glutamatergic synapses, while leaving inhibitory currents intact. Experiments will be conducted to distinguish whether a presynaptic and a postsynaptic mechanism accounts for this effect of K+ on excitatory currents. Both Aim 1 and Aim 2 will utilize whole-cell, patch-clamp techniques in a hippocampal microculture paradigm, which will facilitate examination of synaptic electrophysiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: EMOTIONAL CONTROL OF SEDATIVE SELF-MEDICATION IN PTSD Principal Investigator & Institution: Casada, John H.; Psychiatry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 01-MAR-2001; Project End 29-FEB-2004 Summary: (Applicant's Abstract) Candidate: John Casada, M.D., Ph.D. is an Assistant Professor engaged in research and clinical care focusing on posttraumatic stress disorder (PTSD). His primary career goal is to become an independent investigator conducting clinical research on the interaction of PTSD and sedative drug abuse. Though he has completed training in basic neuroscience and has conducted psychophysiology research in PTSD, he has no training in substance abuse research. Therefore, he plans to pursue training in grant preparation, human laboratory research methods, data interpretation, manuscript preparation, and operant behavioral theories essential to substance abuse research. Environment: Dr. Casada has received departmental support for his PTSD
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studies and the support of his chairman, Charles Bowden, M.D., in establishing the Emotional Trauma Program, which serves to coordinate PTSD research activities at the University Hospital System and Veterans Administration Hospital. This Mentored Career Development Award will allow Dr. Casada to formalize a mentoring relationship with John Roache, Ph.D. and provide protected time to develop research expertise and career development opportunities in collaboration with the NIDA-funded researchers in the Division of Alcohol and Drug Addiction Research. The proposed research will use human laboratory techniques to assess the role of highly arousing, negative valence emotional states, such as anxiety and anger, to promote self-medication with benzodiazepines and alcohol in PTSD patients. To accomplish this, four tasks (Guided Muscle Relaxation, Stroop Color-Word Task, Script-Driven Imagery, and the Point Subtraction Aggression Paradigm) will be used to experimentally vary levels of arousal and negative valence in 18 PTSD patients and 18 subjects who have experienced trauma but never developed PTSD. Motivation and preference for alprazolam and alcohol will be assessed by the Multiple Choice Questionnaire (MCQ) under double blind, double dummy conditions. Emotional responses will be assessed using skin conductance and heart rate as measures of arousal, corrugator electromyogram as an indicator of negative valence, and anxiety and anger ratings as self-report measures of subjective mood. This experiment will be the first to assess sedative drug self-administration in PTSD patients under controlled conditions in the human laboratory. These data will determine the role of anxiety and anger types of emotional reactions as a motive for self-medication in PTSD patients. More importantly, the data also will provide practical information for the clinical treatment of PTSD patients and others with anxiety who may be at risk for abusing prescription anxiolytics or alcohol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GABA A RECEPTOR MODULATORS IN THE DEVELOPING RAT FOREBRA Principal Investigator & Institution: Henderson, Leslie P.; Professor; Physiology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 28-SEP-2000; Project End 30-JUN-2004 Summary: (Adapted from the applicant's Description) Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone that in recent years have become significant drugs of abuse among preteen and teenage children. AAS are known to elicit detrimental effects on neuroendocrine function, as well as increase psychiatric symptoms, including anxiety, paranoia, hostility, and aggression in adults. However, little is known as to the mechanism of action of these compounds in the central nervous system, and even less is known about how these compounds may act in the developing brain. Neural transmission mediated by GABAA receptor is the primary molecular target for a wide range of both therapeutic and abused drugs, including neurosteroids, benzodiazepines, and ethanol. The investigators have shown recently that AAS induce rapid, reversible, and region-specific modulation of GABAergic currents in the forebrain of prepubertal rats, and thus can be added to the list of substances that act as allosteric modulators of this channel. Both the ontogeny of GABAA receptor subunit gene expression and developmental changes in receptor pharmacology have been well described in the hippocampus and cerebellum during the first two weeks of postnatal development. In contrast, there is a dearth of information delineating developmental changes in receptor pharmacology for other forebrain regions or in the hypothalamus, and few studies have assessed changes in GABAA receptor expression associated with puberty. In particular, no experiments have been performed to determine if sensitivity
26
Benzodiazepines
to AAS is significantly different during the progression from puberty to adulthood. In this application, the investigators will use molecular biological and electrophysiological approaches to determine if, concomitant with puberty, there are significant changes in GABAA receptor subunit expression, as well as the ability of AAS to modulate GABAergic synaptic currents. In addition, the investigators will use electrophysiological and behavioral approaches to determine if chronic AAS exposure in peripubertal versus adult rats induces significant changes in the ability of benzodiazepines or neurosteroids, as well as the AAS, to modulate GABAA receptor currents and to elicit anxiolytic or sedative effects. Together, these studies will demonstrate if puberty is associated with significant changes in the acute or chronic actions of AAS at the GABAA receptor, and thus provide important new information to indicate if adolescents are at increased risk for abuse of AAS or other psychoactive drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GABAA RECEPTOR CHANNEL ALTERATION BY PROLONGED SEIZURES Principal Investigator & Institution: Macdonald, Robert L.; Professor; Neurology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 20-JAN-2000; Project End 30-NOV-2003 Summary: (Verbatim from the Applicant's Abstract) While most partial and generalized seizures are relatively brief in duration, during some seizures, early termination fails and a prolonged epileptic state occurs that has been termed status epilepticus. Status epilepticus is relatively common, has a high morbidity and mortality and is a medical emergency requiring immediate treatment. Spontaneous seizure termination may involve activation of gamma-aminobutyric acid (GABA) receptor (GABAR)-mediated inhibition. If the GABAergic inhibition fails to terminate the seizure, a progressive reduction of GABAR-mediated inhibition develops that, when severe enough, results in a prolonged seizure. Status epilepticus in humans is treated acutely with benzodiazepines as well as barbiturates, which enhance GABAR-mediated inhibition. However, benzodiazepines are often efficacious early but not late in status epilepticus. We have shown that properties of dentate granule cell GABAR are altered during prolonged seizures in rats, with a reduction in benzodiazepine and zinc sensitivity without a change in GABA or pentobarbital sensitivity. These observations suggest that GABAR function changes during prolonged seizures, extending seizure duration and producing refractoriness to benzodiazepine treatment. Development of an understanding of this seizure-induced receptor plasticity would enhance understanding of spontaneous seizure termination and permit development of new treatment strategies for status epilepticus. The hypothesis to be tested is that during prolonged seizures, hippocampal dentate granule cell GABAR pharmacological and biophysical properties change due either to a change in receptor subtype composition or to receptor phosphorylation. The specific aims are to determine the : 1) dependence on seizure duration of development of insensitivity to benzodiazepines, 2) time course of development of decreased sensitivity of granule cell GABAR currents to diazepam and zinc, 3) sensitivity of granule cell GABAR currents GABAR modulators following prolonged seizures, 4) transient and steady state kinetic properties of granule cell GABAR single channel currents following prolonged seizures, 5) rate of recovery of regulation by diazepam and zinc of granule cell GABAR current following prolonged seizures, 6) rate of recovery of regulation by allosteric regulators of granule cell GABAR current following prolonged seizures, 7) dependence on PKA of recovery of granule cell GABAR current following prolonged seizures, 8) dependence on other kinases of
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recovery of granule cell GABAR current following prolonged seizures and 9) regulation of benzodiazepine, zinc and other allosteric regulator sensitivity of GABARs by phosphorylation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GABAPENTIN DETOXIFICATION
AND
LORAZEPAM
IN
OUTPATIENT
Principal Investigator & Institution: Malcolm, Robert J.; Professor; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002 Summary: The alcohol withdrawal syndrome (AWS) has been treated for nearly forty years with the remarkably safe and effective benzodiazepines (BZs). In the outpatient treatment of AWS, interactions with alcohol and the abuse liability of BZs invite comparisons with agents that do not share these susceptibilities. In our original Alcohol Research Center component comparing Lorazepam (LZ) to Carbamazepine (CBZ), the latter was significantly more effective in suppressing the acoustic startle response, and anxiety and depressive symptoms during treatment. In the immediate seven-day post treatment, LZ subjects showed higher levels of multiple dimensions of AWS symptoms, including higher withdrawal scores, poor sleep, and greater subjective discomfort than CBZ. CBZ, useful in research has limited clinical applications because of its widespread interactions and uncommon but serious toxicities. In the present application, we propose a double-blind controlled trial of gabapentin (GBP, 80) vs. LZ (N=80) in treatment seeking outpatients experiencing AWS. Multiple domains of AWS will be evaluated during a five-day outpatient treatment interval and a seven-day post treatment phase. Serial measures include electrophysiologic tests of eye blink acoustic startle response, aggregate withdrawal symptoms as evaluated by the CIWA-Ar, subjective assessments of sleep, global discomfort, anxiety, depression, and need for additional medications. Side effects and safety will be compared. GMP, a unique anticonvulsant, is not a controlled substance, soon will be generic, has benign side effects, has no interactions with other drugs, and has limited interactions with alcohol. Side effects and safety will be compared. GBP, a unique anticonvulsant, is not a controlled substance, soon will be generic, has benign side effects, has no interactions with other drugs, and has limited interactions with alcohol. Should GBP be superior to LZ for the treatment of AWS, it could revise the way AWS is managed in outpatients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC AND OTHER DETERMINANTS OF IN VIVO CYP3A ACTIVITY Principal Investigator & Institution: Wilkinson, Grant R.; Professor of Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-DEC-1982; Project End 30-JUN-2007 Summary: (provided by applicant): CYP3A is the most abundant of the human cytochrome P450 enzymes in both the intestine and liver. As a result, it is involved in the metabolism of over 50 percent of drugs and is an important determinant of first-pass metabolism following oral drug administration. Despite being metabolized by CYP3A, however, different substrates appear to interact with the enzyme in different ways, so that the metabolic clearance of one does not correlate with that of another. One hypothesis to account for this lack of correlation is that it reflects, in part, the different relative contributions of intestinal and hepatic CYP3A, and, thus, the route of drug
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Benzodiazepines
administration. Drugs with different metabolic characteristics and routes of administration (midazolam, triazolam and alprazolam) will be used to test this hypothesis. A second possibility that will be investigated is that the CYP3A substrateactive site interaction is substrate-dependent, accordingly, drugs may be characterized into different "groups." Correlation within "groups" will, therefore, be present to a far greater extent than between "groups." In addition to the noted benzodiazepines, this hypothesis will be tested with other CYP3A substrates, such as cyclosporine-A, erythromycin and nifedipine, which are postulated to belong to other "groups." An important characteristic of CYP3A is marked interindividual variability in activity (10to more than 40-fold), which significantly contributes to differences in drug responsiveness between subjects. A genetic determinant(s) is considered to be important in this regard but has never been formally defined and may, in fact, be different according to the tissue localization of CYP3A. Accordingly, the inheritability of CYP3A activity will be determined in monozygotic and dizygotic twins to test the hypothesis that a genetic factor is more important in regulating basal CYP3A-mediated metabolism in the liver than that in the intestine, and also in the enzyme?s inducibility at these two sites. Studies are also proposed which will establish the in vivo functional consequences of the allelic variants CYP3A4*1B and CYP3A5*3, and other known single nucleotide polymorphisms (SNPs). Finally, investigations in European-, African-American, and Japanese populations will be undertaken in order to identify SNPs associated with the interindividual variability in CYP3A activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC VULNERABILITY TO DRUGS OF ABUSE Principal Investigator & Institution: Buck, Kari J.; Associate Professor; Behavioral Neuroscience; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2003; Project Start 01-AUG-1989; Project End 31-MAR-2005 Summary: Quantitative trait loci (QTLs) are chromosomal regions containing genes that influence a complex trait such as drug withdrawal severity. We have established that there is a great deal of common genetic influence on withdrawal from barbiturates, benzodiazepines, nitrous oxide, and alcohol. During the current period, we have mapped several QTLs that jointly have a major influence on the severity of pentobarbital (PB) withdrawal. The three largest QTLs are on mouse chrs 1, 4 and 11. QTLs in each of these regions have also been provisionally mapped for diazepam withdrawal, and definitively mapped for ethanol withdrawal: the chr 1 QTL was also provisionally mapped for nitrous oxide withdrawal. Using congenic strains to isolate each of the three QTLs against a uniform (inbred) genetic background, we propose to continue toward the eventual identification of the genes that underlie each PB withdrawal QTL. We propose to: (1) Test congenics for the strongest PB QTLs for their pleiotropic effects on withdrawal from other drugs of abuse; (2) Produce polycongenics in different combinations to determine whether gene-gene (epistatic) interactions are additive, potentiating in some combinations, or epistatic in some other way; (3) Narrow each QTL interval from our present approximately 20 cM to approximately 1 cM using interval specific congenic strains (ISCS); (4) Scan promising candidate genes for cDNA differences between B6 and D2 genotypes by SSCP; (5) Produce polycongenics from specific donor segment (SDS) congenics produced from appropriate interval specific congenic strains, and test for epistatic interactions among QTLs, as well as QTL pleiotropisms for withdrawal from other drugs, and for other drug-related responses known to be genetically correlated with PB withdrawal severity; and (6) Start with an F2
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population, screen for additional QTLs not previously ascertained and produce additional congenics to facilitate eventual cloning of the genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETICALLY ENCODED PHOTOTRIGGERS OF NEURONAL ACTIVITY Principal Investigator & Institution: Miesenbock, Gero; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 23-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Heterologous proteins capable of transducing optical stimuli into electrical signals can be used to control the function of excitable cells in intact tissues or organisms. Restricted genetically to circumscribed populations of cellular targets, these selectively addressable sources of depolarizing current can be used to supply distributed inputs to neural circuits, elucidate functional synaptic connections, probe the response characteristics of circuits and systems, and unveil behaviorally relevant information carried in distributed neural representations. To achieve genetically localized photostimulation, we express ligand-gated ion channels in neurons that normally lack them, and render the agonists that gate the conductances of these channels biologically inert by chemical modification with photoremovable blocking groups ('cages'). A key-and-lock mechanism thus ensures temporal control and cell-type specificity of photostimulation: the initiation of an action potential requires a light pulse that liberates free agonist (the 'key'), and a target neuron that has been genetically programmed to express the cognate ligand-gated ion channel (the 'lock'). The Objective of this project is to advance the development of highly selective phototriggers with fast kinetics (Specific Aims 1 and 2), create modular mammalian expression systems (Specific Aims 3 and 4), and initiate optical analyses of functional neural circuits in the mammalian brain, with an emphasis on networks of inhibitory (GABAergic) interneurons in the cortex and hippocampus (Specific Aim 5). GABAergic circuits are of basic importance to the processing, storage, and retrieval of information, as illustrated by the effects of agents such as ethanol and benzodiazepines, and by the involvement of interneurons in diseases such as schizophrenia and Alzheimer's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GHB TOLERANCE AND DEPENDENCE Principal Investigator & Institution: Kuhn, Cynthia M.; Professor; Pharmacology and Cancer Biology; Duke University Durham, Nc 27706 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-MAY-2007 Summary: (provided by applicant): The purpose of this proposal is to investigate mechanisms of Gamma hydroxy butyrate (GHB) tolerance and dependence after chronic administration of low and high doses of GHB to rats. GHB is a novel sedative-hypnotic that is an emerging drug of abuse. GHB activates GHB, GABA-B and possibly GABA-A receptors, with a unique dose response relationship for each. When recreational users escalate use, tolerance develops and a withdrawal syndrome can occur that is characterized by insomnia, anxiety, and hallucinations. Tolerance and dependence to GHB are poorly characterized in animal models. We hypothesize that tolerance is related to dose and duration of exposure. We also hypothesize that the different receptor populations adapt at varying rates. We postulate that chronic treatment with lower doses or shorter regimens will cause tolerance at GHB and perhaps GABA-B receptors, while higher doses and longer treatments will lead to marked tolerance to
30
Benzodiazepines
GHB, GABA-A and GABA-B receptors. We will assess tolerance to GHB effects on sleep time, tilt plane and plus maze performance after chronic treatment with low or high doses for 7, 14 or 21 days. We will assess spontaneous and GHB (NCS-382) and GABA-B (CGP46381) antagonist-precipitated withdrawal by measuring sleep-wake cycle, locomotion as well as blood pressure and heart rate. Cross-tolerance to GABA-B (baclofen) and GABA-A (pentobarbital, diazepam) agonists will be assessed with the same behavioral measures. We will characterize inhibitory GHB mechanisms using electrophysiologic techniques in frontal cortex. GHB effects on spontaneous, evoked and mini GABA-A IPSCs and on postsynaptic potassium conductance will be determined. The effects of low and high GHB concentrations will be contrasted, and blockade by NCS-382 and CGP46381 on all parameters will be determined. Tolerance to specific GHB and GABA-B mechanisms will be studied by evaluating the same parameters in frontal cortex slices from animals treated chronically with low or high dose GHB. Finally, we will assess GHB effects on GABA-A receptors in naive and tolerant animals by measuring effects on GABA-mediated C1 uptake into synaptoneurosomes and its modulation by benzodiazepines, barbiturates and neurosteroids. These experiments should ultimately lead to the development of more effective pharmacotherapies for GHB dependence, which is an emerging drug abuse problem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GLUTAMATE HIPPOCAMPUS
RECEPTORS
IN
FLURAZEPAM-TOLERANT
Principal Investigator & Institution: Van Sickle, Bradley J.; Pharmacology and Therapeutics; Medical College of Ohio at Toledo Research & Grants Admin. Toledo, Oh 436145804 Timing: Fiscal Year 2002; Project Start 01-JUN-2002 Summary: Benzodiazepines (BZs) are useful clinically, however tolerance to many of their actions occurs with prolonged administration. Investigations of GABA-A receptors (GABARs) in rats chronically treated with flurazepam have shown significant decreases of inhibitory function in hippocampus and have uncovered changes in excitatory amino acid receptor (EAAR)-mediated activity. Preliminary studies of NMDA and AMPA receptors detected changes in subunit mRNA and protein, consistent with the hypothesis that impaired GABAR-mediated inhibition leads to compensatory changes in EAARs. Electrophysiological studies suggest that functional EAAR-mediated transmission may be altered affecting synaptic plasticity as well. From these findings, three hypotheses were developed and will be tested by 3 Specific Aims: 1) is to characterize changes in NMDA and AMPA receptor protein and receptor number using i) quantitative immunohistochemistry, ii) Western analysis and iii) autoradiographic binding studies; 2) is to examine changes in functional EAAR-mediated transmission using whole cell recordings from CA1 pyramidal cells to measure i) characteristics of mEPSCs, ii) properties of stimulus- and agonist-evoked EPSCs and iii) shifts in doseresponse curves of evoked events by the NR2B-selective antagonist ifenprodil; 3) is to assess changes in synaptic plasticity by examining i) expression of Thr286phosphorylated CaMKII by Western analysis, ii) kinase activity of CaMKII and iii) the frequency-response function of LTP in BZ tolerant hippocampus. Tolerance occurs with many drugs of abuse, so a better understanding of EAAR regulation after chronic BZ may have broader implications in the area of drug abuse research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HIPPOCAMPAL BENZODIAZEPINE TOLERANCE Principal Investigator & Institution: Tietz, Elizabeth I.; Professor; Pharmacology and Therapeutics; Medical College of Ohio at Toledo Research & Grants Admin. Toledo, Oh 436145804 Timing: Fiscal Year 2002; Project Start 01-JUL-1986; Project End 31-MAR-2005 Summary: Benzodiazepines (BZs) which act through the GABA/A receptor (GABAR), are potent anti-convulsant for a variety of epilepsies. Their clinical usefulness is limited by the appearance of functional tolerance, commonly-held to be mediated by changes at the post-synaptic on CA1 pyramidal cells in the in vitro hippocampus. In addition to changes in post-synaptic GABAR structure (alpha1 and beta3 subunit mRNA and protein down-regulation), measured in situ, and function (decreased mIPSC amplitude and C1-channel conductance), changes in GABAergic interneuron activity are proposed to contribute to BZ tolerance. Rapid BZ antagonist-induced restoration of GABAR subunit protein levels and mIPSC amplitude suggested that both translational and posttranslational mechanisms may interdependently contribute to BZ tolerance. Preliminary studies of PKA-mediated modulation of GABAR currents and the ability of a cAMP analogue to partially restore mIPSC amplitude in BZ-treated rats suggests that a modulation of PKA-mediated events, in part, contribute to GABAR system dysfunction. Additional studies have identified changes in excitatory amino acid part, contribute to GABAR system dysfunction. Additional studies have identified changes in excitatory amino acid receptor (EAAR) subunit mRNAs and protein suggesting that excitatory systems are also regulated by chronic BZ treatment in response to reduced GABA inhibition. Three central hypotheses were generated from these findings in in vitro and in situ hippocampus which will be addressed by 3 SPECIFIC AIMS: SPECIFIC AIM 1: to examine the role of intrinsic and extrinsic interneuron function in reducing GABA tone by sampling subpopulations of visualized CA1 interneurons using intracellular and whole-cell patch techniques. Specific Aim 2: is to explore the role of both 2A) translational, i.e., GABAR alpha1 subunit protein redistribution following chronic agonist and acute antagonist administration, using fluorescent co-localization and quantitative EM immunogold techniques and 2B) post-translational mechanisms, i.e., the effect of exogenous and endogenous stimulators of PKA-mediated protein phosphorylation to modulate mIPSC amplitude in CA1 pyramidal cells. SPECIFIC AIM 3: is to examine the compensatory changes which occur in excitatory amino acid receptor (EAAR) structure and function in CA1 pyramidal cells: 3A) Structural measures include: quantitative immunohistochemical techniques and Western blot analysis of microdissected hippocampus and changes in EAAR receptor binding using autoradiographic techniques. 3B) Whole-cell slice patch techniques will e used to measure EAAR receptor-mediated, evoked and miniature EPSC amplitude and decay kinetics. EAAR function will also be assessed using microfluorometric measurements of Ca2+ uptake into acutely dissociated CA1 pyramidal cells. Understanding the nature of the changes at inhibitory and excitatory synapses may allow the design of drugs and approaches to circumvent tolerance and allow us to gain a better understanding of basic mechanisms involved in the dysfunction of these receptor systems during anticonvulsant drug treatment of epileptic patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SYNDROME
HYPOCRETIN,
HISTAMINE
AND
THE
RESTLESS
LEGS
Principal Investigator & Institution: Allen, Richard P.; Assistant Professor; Neurology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218
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Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by applicant): Restless Legs Syndrome (RLS) is a common sensorymotor disorders whose symptoms predominant at night and often lead to significant sleep loss and changes in one's quality of life. Rest and transiting between sleep and wake exacerbates RLS symptoms. Accordingly, alerting activities reduce while soporific ones exacerbate the symptoms. Sedating medications such as benzodiazepines, however, do not appear to exacerbate the disorder. RLS when even moderately severe profoundly disturbs sleep, reducing sleep times to 5-6 hours or less. Patients report some daytime problems with alertness and cognitive clarity but despite this reduction in sleep times untreated patients do not describe profound episodes of sleepiness that occur for normal subjects maintained on such restricted sleep schedules. There is apparently some alerting mechanism partially compensating for the sleep loss. Our recent work has found that nocturnal CSF values of hypocretin/orexin (Hcrt) are elevated in RLS patients not currently on treatment. Hcrt is almost absent in narcoleptics and serves to maintain wakefulness operating at least in part through the stimulating aspects of the histamine system. Several RLS patients on treatment with dopamine agents report some problems with sleepiness they had not previously experienced and several also report marked exacerbation of RLS symptoms by sedating anti-histamines. We have proposed that the Hcrt and histamine system activation reduces RLS symptoms for some RLS patients. DA treatment may reduce the activating benefit from this system leaving the patient vulnerable to sleepiness but also to further exacerbation of the symptoms by further reduction in this system by an anti-histamine medication. Thus, in this model, nocturnal Hcrt levels will be less for DA treated patients and antihistamine challenge provides a test discriminating those patients who have this aspect of RLS, identified in our prior work as those with the familial early-onset form of RLS. The anti-histamine challenge may therefore provide a new technique for discriminating types of RLS, possibly aiding in the diagnosis of RLS and opening up a new area of RLS research. The approach may also be extended to other DA related conditions involving sleepiness with DA treatment. This project seeks to determine if the nocturnal CSF hypocretin of RLS patients is lower when on DA treatment and to explore the development and evaluation of anti-histamine challenge for testing RLS patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MAPPING THE NEURAL SUBSTRATE OF ANXIETY Principal Investigator & Institution: Luscher, Bernhard; Biology; Pennsylvania State University-Univ Park 201 Old Main University Park, Pa 16802 Timing: Fiscal Year 2002; Project Start 01-MAY-2001; Project End 30-APR-2004 Summary: (provided by applicant) The objective of this proposal is to identify the neural substrates underlying trait anxiety. We have found that heterozygosity of the GABAA receptor y2 subunit gene leads to a subtle impairment of postsynaptic GABAA receptor function and trait anxiety in mice. The selective behavioral and cognitive deficits of y20/~ mice, together with established knowledge on the neural circuitry of conditioned fear and the regional distribution of the GABAA receptor deficit in =y2 0/+ mice, allow predictions as to which brain regions mediate trait anxiety. We hypothesize that GABAA receptor deficits in the cerebral cortex and/or hippocampus of y2 0/ mice lead to trait anxiety and that a GABAA receptor deficit that is confmed to these brain regions will result in trait anxiety-like behavior similar to the phenotype of =y2 0/+ mice. In order to map the brain regions that mediate trait anxiety, we have generated a mouse line that allows spatiotemporally restricted inactivation of the y2 subunit gene by means of the Cre/loxP system. Upon Cre induced inactivation of the y2 subunit gene, GABAA
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receptor function will be impaired in selective brain regions defined by the Cre expression pattern of tissue-specific Cre-transgenes or by stereotaxically applied Creencoding virus. Subsequently, stereotaxic injection of Cre-recombinant virus will be used to further characterize trait anxiety. These experiments will include determination of the critical stage during development during which GABAergic deficits lead to trait anxiety. In addition, we will determine whether the cognitive deficits associated with trait anxiety reflect alteration of the acquisition or expression of conditioned fear. The neural circuits that are implicated in the anxiolytic action of the benzodiazepines have considerable anatomical overlap with the proposed neural circuits of trait anxiety and are of therapeutic interest. To test this hypothesis, Cre-induced inactivation of the y2 subunit gene, which is essential for benzodizepine action, will be used to map the brain regions mediating the anxiolytic effect of benzodiazepines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM OF ACTION OF BENZODIAZEPINES ON GABA RECEPTORS Principal Investigator & Institution: Weiss, David S.; Professor; Neurobiology; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2003; Project Start 01-APR-1997; Project End 28-FEB-2007 Summary: (provided by applicant): Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. The binding of GABA to postsynaptic GABA receptors opens a chloride-selective ion pore that is an integral component of the multimeric receptor complex. The resulting chloride flux across the cell membrane inhibits the postsynaptic neuron. Dysfunctions in GABA-mediated inhibition have been implicated in the etiology of a variety of neurological and psychological disorders. Furthermore, GABA receptors are a primary target for several neuroactive drugs including barbiturates, steroids, general anesthetics, and benzodiazepines (BZ); the latter of which is the subject of this proposal. Although it has been known for quite some time that BZs modulate GABA receptors, the molecular mechanism is still unresolved. This proposal will use a combination of molecular biology, electrophysiology, single oocyte radioactive ligand binding, and site directed fluorescent labeling to gain structural and functional insights into the actions of BZs on GABA receptors. Some of these techniques are new to the BZ field and it is hoped they will bring some fresh perspectives to the problem. The design of more efficacious BZs that can target the many different GABA receptor subtypes that have been identified in the brain will ultimately depend on understanding the structural requirements and precise mechanism of action of this important class of neuroactive compounds. The results from these proposed studies are expected to contribute to that effort. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS IN RISK TAKING: DISINHIBITORY DRUGS OF ABUSE Principal Investigator & Institution: Lane, Scott D.; Psychiatry and Behavioral Scis; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): This application seeks to achieve two broad objectives: (i) to study the effects of disinhibitory drugs of abuse on (maladaptive) human risk-taking using laboratory behavior-based procedures; (ii) to identify basic behavioral mechanisms operating in individuals (specifically young adults) who show
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Benzodiazepines
heightened susceptibility to risk taking following use of disinhibitory drugs. Disinhibitory drugs can engender increases in the (otherwise low) frequency of certain behaviors. Use of disinhibitory drugs is associated with a number of risk-taking behaviors leading to harmful outcomes -- including automobile accidents, vandalism, violent crimes, sexual assault, and risky sexual behavior. Importantly, use of disinhibitory drugs and the risky behavior that often follows is prevalent among younger adults. The social and behavioral consequences of drug-mediated risk taking in young adults are thus a considerable public health concern and a vital scientific endeavor. Studying the relationship between disinhibitory drugs and risk-taking behavior under controlled laboratory conditions will provide important scientific information. The experiments in this application propose to investigate changes in risktaking following acute administration of four drugs abused by young adults: alcohol, marijuana, and the benzodiazepines alprazolam (Xanax) and flunitrazepam (Rohypnol). While many young adults use these drugs, not all abuse them, and not all engage in excessive risk-taking while under the influence. Thus, identification of basic behavioral processes and characteristics involved in risk-taking may help predict those whose behavior is most likely to be unduly influenced by drug use. Each of the four proposed experiments will employ a laboratory-based task to measure risk-taking. This task has been systematically developed over several years, and has been shown to be sensitive to (i) individual differences in risk-taking (in both adolescent and adult populations), and (ii) acute drug effects. Each participant will work on the risk-taking task following acute administration of one of the above-mentioned disinhibitory drugs. Using a within-subject design, a range of doses will administered in order to determine dose-effect relationships. Quantitative analyses of behavior patterns will be used to identify factors that may mediate this relationship. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISTIC STUDIES OF PRO-APOPTOTIC BENZODIAZEPINES Principal Investigator & Institution: Glick, Gary D.; Professor; Chemistry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-MAY-2000; Project End 30-APR-2004 Summary: (Principal Investigator's Abstract) Systemic lupus erythematosus (SLE) is a multisystemic autoimmunune disorder of unknown etiology. Many patients afflicted with SLE develop a severe nephritis mediated by the localization of immune complexes within glomeruli. Current treatments of this nephritis and other symptoms of the disease center on the use of steroids or cytotoxic immunosuppressive agents. While effective in some patients, these agents are non-specific and can cause serious side effects that often force discontinuation of treatment. We have identified a benzodiazepine (1) that does not bind to the central benzodiazepine receptor, which shows significant efficacy in treating the glomerulonephritis and other symptoms of disease in both (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice, the two most clinically relevant animal modes of human SLE. Both in vitro and in vivo experiments demonstrate that this benzodiazepine selectively induces apoptosis in lymphocytes directly responsible for autoimmune (B and T cell) mediated inflammation. At therapeutic doses, treatment suppresses the autoimmune response without altering normal immune function or evidence of side effects. Further development of 1 into a clinically useful agent requires a better understanding of both how this molecule induces cell death, and by what means apoptosis of lymphocytes results in disease improvement. To address this need, we propose to characterize the effects 1 has on cellular immune function by determining the phenotype of lymphoid cells killed by 1 in
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vivo and in vitro. Phenotypic analysis will be based on plasma membrane determinants and cytokine expression. Next, to uncover the mechanism by which 1 functions, we will identify the sub-cellular systems (e.g. caspases, mitochondria and other components of death response) triggered to execute 1-mediated cell death. Lastly, we will isolate the receptor of 1 based on yeast three-hybrid screening. If 1 is lethal to yeast, we will pursue an alternative strategy of mutagenesis followed by classical yeast genetics and functional cloning to generate resistant strains and identify molecules necessary for 1induced death. The resistant strains developed will then serve as host strains for the three-hybrid system. These experiments will complement on-going efforts to identify the receptors(s) for 1 using more traditional affinity chromatography methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEOPAIN MULTICENTER TRIAL: DATA COORDINATING CENTER Principal Investigator & Institution: Barton, Bruce A.; Senior Statistician and Vice President; Maryland Medical Research Institute, Inc 600 Wyndhurst Ave Baltimore, Md 21210 Timing: Fiscal Year 2001; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: Frequent invasive procedures occur during neonatal intensive care causing pain and stress in preterm neonates during a critical period of increased brain plasticity. Repetitive painful experiences or prolonged exposure to analgesic drugs in preterm neonates may significantly alter their clinical and neurobehavioral outcomes. Analgesic practices recorded prospectively in 109 Neonatal Intensive Care Units (NICUs) showed that opioids and benzodiazepines were most commonly used, with large variations in clinical practice. No analgesia/sedation was given to 73.5 percent of neonates during NICU care or invasive procedures. A pilot randomized trial of morphine, midazolam, or placebo therapy in 69 preterm neonates showed reduced behavioral responses to pain and evidence of decreased incidence of death or neurologic injury in the morphine group. Trends for increased weight gain, earlier discharge, and other clinical outcomes support the need for and the feasibility of a definitive randomized trial. The NEOPAIN Multicenter Trial will randomize 940 ventilated neonates (24-32 weeks gestation) from 11 NICUs to receive continuous infusions of morphine or placebo. This design will provide 80 percent power for the detection of a 30 percent reduction in the composite outcome of neonatal death, Grade III or IV intraventricular hemorrhage, or periventricular leukomalacia. Data collection will include (maternal/infant) demographic, clinical and behavioral data. Other clinical outcomes include weight gain, severity of neonatal illness, and durations of NICU and hospital stay. Behavioral outcomes include neurobehavioral and psychometric testing at the time of hospital discharge. Trial coordination, data management and statistical analyses for the NOPAIN Trial are described in this application. The use of opioids (morphine and fentanyl) in preterm neonates is increasing without scientific evaluation and with scarce data on their clinical or adverse effects. The need for and clinical impact of prolonged analgesia in the NICU must be defined now before widespread use occurs. To provide data about the safety of opioid use, the effects of early pain/stress on the long-term neurobehavioral outcomes of prematurity in neonates without analgesia must be compared to the effects of analgesia use in neonates. This trial can provide those data. Thus, the results of this trial have the potential to significantly alter clinical practice in the NICU and reduce a major cause of severe morbidity and mortality in neonates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Benzodiazepines
Project Title: NEURAL ACTIONS OF TOLUENE Principal Investigator & Institution: Woodward, John J.; Professor; Physiology and Neuroscience; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 28-FEB-2007 Summary: (provided by applicant): Volatile solvents such as toluene, benzene and trichloroethane are widely distributed in a variety of products encountered in both industrial and home settings. These include glues, thinners, rubber cements, aerosol sprays, nail polish removers, correction fluid and dry cleaning solvents. Although the occupational hazards of exposure to these solvents have been previously examined in a variety of toxicological studies, the cellular and molecular sites of action that account for their intoxicating effects are virtually unknown. Surveys of drug use show that a significant percentage of the population has used volatile solvents for their intoxicating properties and such use is especially prevalent among adolescents and teens who may have easy access to these products. Previous behavioral studies show that toluene and other abused volatile solvents display actions similar to that observed for CNS depressants such as ethanol, barbiturates, benzodiazepines, and anesthetics. Thus, we hypothesize that abused solvents, like other CNS depressants, may exert some of its neurobehavioral effects by altering the function of specific ion channels that are involved in mediating and modulating neuronal transmission. We have generated data to support this hypothesis and have demonstrated that toluene and other volatile solvents inhibit the function of recombinant and native NMDA and acetylcholine receptors expressed in oocytes and cultured neurons. This inhibition was dosedependent and was influenced by the subunit composition expressed. In contrast to ethanol, toluene had negligible effects on currents mediated by non-NMDA receptors or on G-protein coupled potassium channels. These results suggest that abused solvents may show greater selectivity than alcohol with respect to their ability to modulate the activity of neuronal ion channels. Studies outlined in this proposal will test this hypothesis by determining the sensitivity of recombinant and native ion channels to toluene and other volatile solvents that are subject to abuse. Two-electrode voltageclamp and patch-clamp electrophysiology will be used to analyze the solvent sensitivity of recombinant ionotropic receptors expressed in oocytes and HEK cells. The molecular sites of action for toluene will be explored by testing whether sites known to regulate the alcohol/anesthetic sensitivity of these channels also regulate solvent sensitivity. Finally, the relevance of the findings obtained in recombinant receptor systems will be assessed by measuring the effects of toluene and other abused solvents on ion channels expressed in cultured brain neurons using whole-cell patch clamp and calcium imaging. Results obtained from these studies outlined are expected to greatly expand our knowledge of the cellular and molecular targets of these important drugs of abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEUROIMAGING OF BENZODIAZEPINE-INDUCED AMNESIA Principal Investigator & Institution: Mintzer, Miriam Z.; Assistant Professor; Psychiatry and Behavioral Scis; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2004 Summary: (provided by applicant) There is concern about the abuse and long term use of benzodiazepine anxiolytic/hypnotic drugs by polydrug abusers and patients. One of the most insidious adverse effects of benzodiazepines is a profound impairment in the ability to form memories of personally experienced events (episodic memory encoding).
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This project will characterize the changes in brain activity reliably associated with benzodiazepine-induced impairment of episodic memory encoding by parametrically manipulating the level of impairment, and will examine the pharmacological and neurochemical mechanisms underlying these changes. Three double blind, placebocontrolled, within-subject outpatient studies in healthy volunteers are proposed, employing well-established methods in cognitive neuroscience. Following acute drug administration, brain activity associated with performance of a verbal episodic memory encoding task will be measured by regional cerebral blood flow (rCBF) using positron emission tomography (PET) with 15O-H20. Experiment 1 will manipulate the level of encoding impairment via administration of three dose levels of the benzodiazepine hypnotic triazolam. Experiment 2 will manipulate the level of encoding impairment via conjoint administration of triazolam and the benzodiazepine receptor specific antagonist flumazenil, which has been shown to reverse benzodiazepine-induced amnesia; this experiment will also provide information about the pharmacological mechanisms underlying benzodiazepine-induced changes in rCBF during encoding. Experiment 3 will provide information about the neurochemical specificity of benzodiazepine-induced changes in rCBF during encoding by comparing the pattern of rCBF changes produced by triazolam to that produced by scopolamine, a compound which induces comparable decrements in episodic memory encoding but which acts via different receptor site/neurochemical mechanisms. Results of this project will enhance the understanding of the brain mechanisms underlying a serious adverse effect of a widely prescribed and abused class of drugs. Ultimately, data from this research may contribute to the development of new classes of anxiolytic/hypnotic compounds with reduced memory impairing potential, as well as compounds which act to reverse the memory-impairing effects of benzodiazepines. Results of the proposed research also will enhance the understanding of the functional neuroanatomy of basic human memory processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW RADIOTRACERS FOR NEUROLOGICAL PET Principal Investigator & Institution: Kilbourn, Michael R.; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: The goals of this project are the design, synthesis and preliminary in vitro and in vivo evaluation of new radiolabeled ligands for the picrotoxin binding site of the GABAA receptor. In particular, we seek the identification and characterization of ligands that display sensitivity to the functional state of the GABAA receptor in vivo. The GABAA receptor is present at a very high proportion of synapses in the brain, and dysfunction of this receptor has been implicated in a wide variety of neurological, psychiatric and drug abuse conditions. The new radioligands to be prepared will be based on the recently reported dithiane and dithiane oxide structural class of high affinity picotoxin site ligands. Preliminary in vivo studies with 11C- and 18F- labeled dithiane oxides have demonstrated blood-brain-barrier permeability, metabolic stability in the blood, and some-dependent alterations of in vivo uptake in brain after administration of a GABA agonist. New compounds will be examined for in vitro binding affinities (inhibition of binding of [35S]TBPS to rodent cortical membranes. High affinity compounds (Ki<20 nM) will then be prepared in carbon-11 or fluorine-18 form, and the regional brain pharmacokinetics in rodents determined. These distributions will also be examined in the presence of drugs known to alter the functioning of the GABAA receptor, such as GABA agonists, benzodiazepines, and
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beta-carbolines. The optimal compounds will then be examined for reproducibility and sensitivity to GABAergic perturbations using PET imaging and quantification of radiotracer pharmacokinetics in the monkey brain. The goal will be the development of radioligands with appropriate pharmacokinetics and pharmacological specificity to be suitable for in vivo studies of the picrotoxin site as a functional marker of the human brain GABAA receptor using Positron Emission Tomography (PET). In combination with existing radioligands for measurement of the numbers of benzodiazepine sites, these new functional radioligands will allow more complete characterization of GABAergic neurotransmission in the normal and diseased human brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NICOTINIC RECEPTOR & HIPPOCAMPAL SYNAPTIC FUNCTION Principal Investigator & Institution: Albuquerque, Edson X.; Professor and Chair; Pharmacol & Exper Therapeutics; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-JUL-1987; Project End 31-JUL-2007 Summary: (provided by applicant): In the hippocampus, the center for integration of cognitive functions, nicotinic receptors (nAChRs) modulate synaptic transmission mediated by the major excitatory and inhibitory transmitters - glutamate and GABA, respectively. However, hippocampal function relies also on tonically activated glutamatergic and GABAergic receptors. In fact7 some benzodiazepines that are clinically used for treatment of epileptic seizures affect more selectively tonic (steady state) than phasic (synaptic) GABAergic activity. Yet, the effects of nicotinic ligands on tonic activities in the hippocampus are unknown. In a recent study, we have demonstrated that the tryptophan metabolite kynurenic acid (KYNA), which is largely produced and released by astrocytes in the brain, modulates nicotinic cholinergic activity in the rat hippocampus. At physiologically relevant concentrations, KYNA inhibits more potently a7 nAChRs than NMDA receptors (once believed to be the major targets for KYNA in the brain) and regulates a4B2 nAChR expression. Other lines of evidence also indicate that there might be functional cross-talk between KYNA and the nicotinic cholinergic system: (i) nicotine regulates endogenous levels of KYNA in the brain and (ii) changes in KYNA levels often parallel alterations in the nicotinic cholinergic system in such neurological disorders as schizophrenia, Alzheimer's and Parkinson's diseases (AD, PD). This proposal is designed to use convergent, multidisciplinary approaches, including electrophysiological, biochemical and molecular biological assays, to address the central hypothesis that in the hippocampus the magnitude of nAChR activity modulates the degree o tonic and phasic glutamatergic or GABAergic activities and is regulated by endogenous KYNA. The specific aims are: (i) to investigate the effects of nAChR ligands on tonic and phasic forms of excitation or inhibition in the hippocampus; (ii) to examine how interactions between KYNA and the nicotinic cholinergic system modulate the tonic or phasic forms of GABAergic and glutamatergic activities in the hippocampus, and (iii) to determine the site of action of KYNA on o7 nAChRs, analyzing the possibility that the site for KYNA and for the allosteric potentiating ligand galantamine (that has been recent/y introduced for treatment of AD patients) on the nAChRs is one and the same. Knockout mice with null mutations in the gene that encodes the a7 nAChR subunit or the enzyme critical for ICYNA synthesis in the brain, kynurenine aminotransferase 11 (KATII), recombinant a7 nAChRs (mutants and chimeras) and different preparations (acute slices and heterologous systems) will be used to address these fundamental issues. The results of these studies win be far reaching; they will lead to a more comprehensive
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understanding of the means by which neuronal activity is regulated by nicotinic ligands, and provide the mechanistic basis for future development of therapeutic strategies designed to compensate, via the kynurenine pathway, for deficits in nicotinic function in disorders such as AD, PD and schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL GABAA/BZR LIGANDS THAT MODULATE MEMORY Principal Investigator & Institution: Helmstetter, Fred J.; Associate Professor; Psychology; University of Wisconsin Milwaukee Box 413, 2200 Kenwood Blvd Milwaukee, Wi 53201 Timing: Fiscal Year 2002; Project Start 05-DEC-2000; Project End 30-NOV-2003 Summary: (Adapted from the Investigator's Abstract) Benzodiazepines and related compounds bind to unique receptor sites in the brain and modify the postsynaptic effects of GABA. A large amount of evidence suggests that these ligands can exert profound effects on anxiety and on the formation of memory in humans and laboratory animals. There are several forms of the GABA-A/benzodiazepine receptor based on differential assembly of a series of subunits. Recent studies have suggested that receptors containing the alpha5 subunit are primarily localized in the hippocampus and may be specifically involved in the regulation of synaptic events underlying learning and memory. Our preliminary results indicate that inverse agonists with a high degree of selectivity for alpha5-containing receptor isoforms can enhance certain forms of memory in rats. The present study involves the design and synthesis of a series of novel alpha5-selective ligands that we will evaluate for their ability to modulate hippocampaldependent and hippocampal-independent forms of memory using a Pavlovian fear conditioning paradigm with mice and rats. A subset of these compounds will be applied directly to the dorsal hippocampus to evaluate possible mechanism of action within this structure. The development of subsite selective agonists and antagonists at GABAA/BzR receptors will provide important new tools in the investigation of the basic neural mechanisms of memory and anxiety and improve our understanding of benzodiazepine pharmacology. Drugs that enhance memory in the absence of unwanted side effects may prove to be important therapeutic agents in treating disorders of memory due to illness or aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHARMACOLOGY--ALLOSTERIC MODULATORS OF GABAA RECEPTORS Principal Investigator & Institution: Guidotti, Alessandro; Professor; Psychiatry; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-SEP-1992; Project End 30-NOV-2003 Summary: (from applicant's abstract): The overall goal of our research project is to utilize the diversity of GABAalpha receptor structure and function to develop via new strategies safer and more effective neuroactive drugs acting as modulators of GABAalpha receptor function capable of anticonvulsant, anxiolytic, and antipanic action without eliciting tolerance or physical dependence. The present proposal is the continuation of an ongoing project aimed at understanding and further defining the role of "neurosteroids" in drug- induced positive and negative allosteric modulation of GABA action at GABAalpha receptors. The hypothesis of the proposed studies is that an increase of the GABAalpha receptor-active neurosteroid allopregnanolone (ALLO) elicited by fluoxetine or other SSRIs may be associated with the antidysphoric,
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anxiolytic, and anticonvulsant actions of this class of drugs. Because ALLO and related steroids acting at GABAalpha receptors play a putative role in modulating anxiety, mood, and cognitive behavior, to validate our hypothesis we need to establish whether the effect of SSRIs on neurosteroids is class-specific or whether other major classes of psychotherapeutic agents that act on mood and cognition (i.e., antidepressants, typical and atypical antipsychotics, benzodiazepines, cognition enhancers) alter neurosteroid biosynthesis and release. The focus on fluoxetine (Prozac), other serotonin reuptake inhibitors (SSRIs), and neurosteroids stems from our original observation that fluoxetine and other SSRIs increase the brain content of allopregnanolone (ALLO), which in nanomolar concentrations with nongenomic action positively modulates GABAalpha receptor function, and also decreases the brain content of 5alpha-dihydroprogesterone (5alpha- DHP), which also in nanomolar concentrations with genomic action (via progesterone receptors) may control GABAalpha receptor subunit gene expression. We propose a systematic investigation of the action of fluoxetine, other SSRIs, and other antidepressant and psychotherapeutic agents on brain neurosteroid biosynthesis and release with the following Specific Aims: (1) establish the onset and the duration of changes in ALLO and 5alpha- DHP content in various rat brain regions and microdialysates following administration of fluoxetine or other SSRIs; (2) determine if the increase of ALLO elicited by SSRIs is specific for this class of drugs; (3) establish if there is a correlation between the increase in brain and microdialysate ALLO content and the behavioral effects that reveal the strength of the underlying GABAergic transmission; (4) determine if the 33alpha-hydroxysteroid oxidoreductase enzymes are the target for fluoxetinee's action on neurosteroid treatment; and (5) study if neurosteroids alter GABAalpha receptor subunit expression following long-term fluoxetine treatment. Additional evidence that neurosteroid alterations are causally associated with SSRI drug treatment would enable a completely new insight into the development of safer and more efficacious antidepressants by focusing on their neurosteroidal actions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PREVENTING HARM FROM ALCOHOL USE IN OLDER ADULTS Principal Investigator & Institution: Moore, Alison A.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Up to 40 percent of older persons who drink may be at-risk for harm. This risk is due to age-related physiological changes that increase the effects of a given dose of alcohol and age-associated increases in comorbidity and medication use that may cause adverse effects when even small amounts of alcohol are consumed. Most trials of brief advice to reduce drinking among primarily younger populations have reduced subjects' alcohol use by 10-20 percent. These trials have focused on drinkers who are at risk because of the amount they drink, or because they have symptoms of alcohol abuse or dependence. No trials have yet focused on older drinkers who are at risk because of the interaction of alcohol use and co-morbidity (e.g., diabetes, hypertension) and medication use (e.g., anticoagulants, nonprescription antihistamines). To test whether a screening and brief advice preventive intervention targeted to older persons may reduce such at-risk drinking and prevent subsequent harm, we propose a 12-month, randomized, controlled trial involving 880 subjects attending primary care clinics at two non-academic sites. Our intervention will consist of advice given to both at-risk drinkers and their physicians personalized to address the particular reasons a subject is identified as an at-risk drinker. We will identify at-risk
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drinkers using a new screening measure, the Short Alcohol-Related Problems Survey (shARPS). Respondents may be identified as at-risk drinkers because they have a single risk (e.g., drinking and using benzodiazepines) or multiple risks (e.g., drinking and using narcotics, drinking and having depression). At-risk drinkers will be randomized to either receive brief advice about at-risk drinking (intervention) or a booklet on healthy behaviors (control). To assess the efficacy of the intervention, subjects will undergo assessments of their alcohol-associated risks at recruitment, and 3 and 12 months later. Our analyses will assess the effect of the intervention on the prevalence of at-risk drinking, the amount of drinking, and the numbers of risks identifying those subjects still considered at-risk drinkers. This study will be the first to assess a preventive intervention to reduce risks of alcohol use, alone or in conjunction with comorbidity and medication use among older adults in primary care. If such an intervention is successful, potentially hundreds of thousands of older persons may benefit from a reduction in their risks associated with alcohol use and prevention of harm. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REDUCING BENZODIAZEPINES AND HIP FRACTURE IN THE ELDERLY Principal Investigator & Institution: Soumerai, Stephen B.; Ambulatory Care & Prevention; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-SEP-2004 Summary: (provided by applicant): Benzodiazepines (BZDs) are important, effective and widely used medications for treating anxiety, panic, sleep, seizure, and bipolar disorders. Epidemiological studies to date have produced conflicting data about hip fracture risk associated with BZD use by the elderly. This study provides a unique opportunity to compare an epidemiological assessment of the BZD-hip fracture relationship with results based on the effects of a statewide natural experiment that resulted in a sudden, sustained reduction in BZD use. The overall aim of this study is to determine whether BZDs are associated with increased hip fracture incidence in the elderly and, if so, which characteristics of BZD use are most likely to increase the risk. The proposed investigation will use a classical epidemiological design (Phase I) and a unique longitudinal, controlled, intervention-based (quasi-experimental) design (Phase II). The study populations will consist of elderly New York (NY) and New Jersey (NJ) Medicaid enrollees between October 1987 and December 1990. Phase I, an open cohort study of more than 50,000 elderly NJ Medicaid recipients, will estimate the magnitude and significance of the BZD-hip fracture association overall and in specific risk groups. Most importantly, Phase II will test whether a NY policy that dramatically reduced BZD use also decreased hip fracture incidence (overall and in specific risk groups). On January 1, 1989, New York implemented a triplicate prescription program, a potent barrier to BZD prescribing, that resulted in a sudden, sustained decrease of over 50 percent in BZD use in most patient groups, including the elderly. The Phase II survival analyses of this natural experiment will compare changes in hip fracture incidence associated with the dramatic decline in BZD use in NY (intervention state) with changes in NJ (control state) where BZD use remained constant during the study period (total N=14,000). Medicaid and Medicare data provide reliable, valid, person-specific measures of demographics, medication and health services use over time, including hip fracture occurrence. The proposed study will provide important data on the association between BZDs, used by more than 20 percent of the elderly, and hip fractures, a major
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cause of morbidity and mortality. Phase II analyses will also contribute a novel method for evaluating health outcomes of changes in medication use in large populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF NEURONAL RECEPTORS Principal Investigator & Institution: Barnes, Eugene M.; Professor of Biochemistry; Biochem and Molecular Biology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-AUG-1991; Project End 30-APR-2003 Summary: GABAA receptors (GABAARs) are the major sites for fast synaptic inhibition in the brain. The long-term goal of this project is to understand the neuronal regulation of GABAAR density and subcellular distribution. The investigators have previously demonstrated that acute exposure of cortical neurons to GABA or benzodiazepine agonists induces the transfer of surface GABAARs into a labile intracellular pool. In order to examine the underlying mechanisms and to evaluate their role in agonistevoked GABAAR downregulation, three specific objectives are developed in this proposal. (1) To test the hypothesis that acute exposure of cortical neurons to benzodiazepines induces the sequestration of GABAAR subunits. Exoplasmic regions of GABAAR polypeptides on living neurons will be labeled with impermeant cleavable reagents. Following acute exposure to agonists, sequestered receptors will be recovered by stripping the surface label and doubly immunoprecipitating cell extracts with antibodies against GABAAR alpha1, beta2, and beta4 subunits. (2) To test the hypothesis that interactions of GABAARs with coated-pit proteins are evoked by agonists. The agonist-induced interactions of GABAAR subunits with inositol polyphosphate binding proteins as well as proteins identified by yeast two-hybrid screening will be examined by co-precipitation. (3) To test the hypothesis that GABAARs are degraded by distinct agonist-dependent and agonist-independent pathways. GABAAR subunits will be labeled internally by incorporation of 35S-Met/Cys and externally by impermeant noncleavable reagents. The effect of agonists and protease inhibitors on the turnover rates will be determined. It is suggested that this project will provide new insights into pathways which modulate synaptic function. By means of these regulatory mechanisms, cell-cell communication and drug-cell interaction can produce persistent changes in neuronal excitability. Furthermore, these are likely to represent molecular mechanisms which establish tolerance and habituation to benzodiazepines, barbiturates, and alcohol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SELECTIVE ANXIOLYTICS VIA BZR SUBTYPE SPECIFIC LIGANDS Principal Investigator & Institution: Cook, James M.; Professor; Chemistry; University of Wisconsin Milwaukee Box 413, 2200 Kenwood Blvd Milwaukee, Wi 53201 Timing: Fiscal Year 2002; Project Start 01-SEP-1991; Project End 30-NOV-2005 Summary: Adapted from applicant's abstract): The understanding and treatment of pathological anxiety have long been a prime concern in regard to mental health. Alterations in GABAA function from controls are known to occur in anxiety disorders,6 including panic disorder, epilepsy,7 hypersensitive behavior,7b phobias,6 schizophrenia,8 alcoholism,9 Anglemans syndrome,7b and Rhetts syndrome,10 as well as effects which lead to/or complicate drug abuse.11 The 1,4-benzodiazepines, employed to treat anxiety disorders as well as sleep disorders exhibit anxiolytic, anticonvulsant, muscle relaxant/ataxic and sedative-hypnotic effects.5-12 Despite the
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clinical effectiveness of these drugs there is a need for selective anxiolytics and anticonvulsants which are devoid of myorelaxant/ataxic and sedative-hypnotic effects.5 Since BzR (benzodiazepine receptor) ligands allosterically modulate this system,1-5 the design of BzR subtype selective ligands5,25 is one means to generate better therapeutic agents.5 The combination of ligand affinities, molecular modeling and CoMFA analysis has been employed to determine the similarities and differences between BzR subtypes.25,26 This approach has permitted the synthesis of the most alpha5beta2gamma2 subtype selective agonist 5a reported to date,29 as well as several potent alpha5 selective inverse agonists 1a and 2a (50-75 fold more selective).25,28 Moreover, BCCt 6a (a neutral antagonist)31,32 and 3PBC 7a have been shown to be selective for alpha1beta2gamma2 subtypes, the former t-butylester is the most alpha1 selective agent in vitro reported to date.31,32 The alpha4/alpha6 "diazepaminsensitive" ligands 3a,b and 4a,b are again the most potent selective DI ligands reported to date. These ligands serve as lead compounds in the search for BzR subtype specific agents. Based on modeling, variation of the ligand substituents (chiral or achiral; polar or nonpolar) which occupy lipophilic pockets L1, L2, L3, or Ldi of the pharmacophore/receptor model will provide the desired subtype selectivity. The lead compounds are illustrated in Schemes I and II, while the target compounds are depicted in Schemes III-XI. The goal is to develop ligands that are > 150 times more selective for either alpha1,alpha5,alpha4, or alpha6 (later alpha2,alpha3) subtypes in order to determine which biological function is mediated by which subtype(s). Characterization of the pharmacology of BzR at the subtype level is crucial for understanding the physiological processes which underlie anxiety, including panic disorder,6 convulsions,7 sleep disorders and cognition,16 as well as the design of selective agents to treat these disease states with reduced abuse potential. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SELF-ADMINISTRATION OF ABUSED INHALANTS IN MICE Principal Investigator & Institution: Bowen, Scott E.; Psychology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): Although the abuse of inhalants continues to be a significant public health problem throughout the U.S. and the world, there has been very little systematic examination of the reinforcing properties of these compounds. Therefore, the aim of this research proposal is to investigate and develop a method of inhalant self-administration that can be used long-term in mice to simulate the full array of human behaviors associated with solvent abuse including acquisition, maintenance, extinction and reinstatement of both inhalant-seeking and inhalant-taking behavior. This research will focus on the current hypothesis that a majority of the abused inhalants produce a profile of neurobehavioral effects that are analogous to those produced by abused depressant drugs (e.g. barbiturates, alcohol, benzodiazepines) [Evans and Balster, 1991]. A key objective of this research proposal is the design and implementation of a preclinical model of inhalant self-administration with a primary focus on the abused inhalants toluene and 1,1,1-trichloroethane. We are proposing two series of studies for this grant. In the first series, we propose to characterize the subjective and psychomotor effects of toluene and 1,1,1-trichloroethane and to compare them to other abused inhalants. The information collected from the first series of tests will then be used as a guide for our next series of studies. In the second series of studies, we propose to design and build an apparatus (i.e., a dynamic solvent delivery system interfaced with an operant monitoring system), which will reliably deliver a "dose" of
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inhalant on an intermittent basis. Once completed, we will use the system to develop and validate this method of solvent inhalation by training mice to press a lever for inhalant delivery and by varying both the "dose" of inhalant and the response requirements necessary for obtaining it. Finally, the research described in the present application will extend the knowledge base of psychomotor and subjective effects of abused inhalants. In addition, this research will have important implications for understanding basic mechanisms underlying and controlling inhalant abuse, for the development of treatment medications and behavioral techniques for modifying the abuse of inhalants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ST. JOHN'S WORT VS PLACEBO IN SOCIAL PHOBIA Principal Investigator & Institution: Kobak, Kenneth A.; Senior Research Scientist; Dean Fdn for Health, Research & Educatn Research and Education Middleton, Wi 53562 Timing: Fiscal Year 2002; Project Start 17-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): Social Phobia is a prevalent and debilitating condition, with a lifetime prevalence rate to be 13.3 percent. Socially phobic patients have been found to be functionally impaired in the areas of education, employment and social relationships, to have poorer quality of life, and increased suicidal ideation and psychiatric comorbidity. Double-blind studies have found benzodiazepines, selective and non-selective MAOI inhibitors, several SSRIs, and the anticonvulsants pregabalin and gabapentin to be effective. However, side effects with these compounds suggests the need for better tolerated compounds, e.g., in the paroxetine multi-center trial (the only drug with an FDA approved indication), 27 percent reported somnolence, 26 percent nausea, and 37 percent of males reported delayed ejaculation; 34 percent of patients discontinued the trial early. There has been considerable worldwide interest in St. John's Wort (SJW) (Hypericum perforatum) as a treatment of mild to moderate depression. There have been 23 randomized trials suggesting SJW is more effective than placebo for the treatment of outpatients with mild to moderate depression. SJW is very well tolerated with mild side effects observed in only 2.5 percent of cases in a large (3250 patients) drug monitoring study. Pharmacokinetic studies have found Hypericum to have affinity for serotonin, dopamine and GABA alpha and GABA beta receptors, each of which have been implicated in social phobia, thus there is a suggestion that SJW may be effective for this disorder. This will be a 12-week, double blind, placebo-controlled trial, designed to generate effect size data that will be used to determine sample size needed to power a definitive study. Forty patients will be randomized to either SJW (LI 160) or matching placebo. This will be a flexible-dose design, starting at 300 mg tid to a maximum of 1800 mg total per day. An intent-to-treat analysis will be employed. Subjects will be evaluated weekly for two weeks, then bi-weekly thereafter. The primary outcome measure will be the change from baseline to endpoint on the Liebowitz Social Anxiety Scale. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STEROIDS AND GABA:PHYSIOLOGY OF RECEPTOR SUBUNIT CHANGES Principal Investigator & Institution: Smith, Sheryl S.; Associate Professor; Physiology and Pharmacology; Suny Downstate Medical Center 450 Clarkson Ave New York, Ny 11203 Timing: Fiscal Year 2002; Project Start 15-MAR-1995; Project End 31-JAN-2005
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Summary: (Applicant's Abstract) The goal of the present study is to determine the functional significance of GABAA receptor (GABA-R) subunit changes produced by fluctuations in endogenous hormonal levels. Towards this end, we will assess mRNA and protein levels of alpha4 and delta subunits concomitant with evaluation of synaptic current as well as characterization of GABA-gated current in acutely dissociated CA1 hippocampal neurons upon withdrawal from the GABA-modulatory 3alpha,5alphaTHP (3alpha-OH-5alpha-pregnan-20-one). This hormone paradigm mimics hormonal conditions underling periods of endogenous hormone withdrawal, such as premenstrual syndrome. Findings supported by the previous funding period established that 3alpha,5alpha-THP withdrawal results in anxiogenic, pro-convulsant effects similar to those seen after withdrawal from other GABA-modulatory compounds, such as the benzodiazepines (BDZs). These behavioral effects were well-correlated with a marked decrease in the decay time for GABA-gated current, which resulted in a decrease in total integrated GABA current, an effect due specifically to upregulation of the alpha4 subunit of the GABA-R. This increase in the alpha4 subunit also resulted in a near total BDZ insensitivity. The goal of the present studies is to determine the effect of alpha4 subunit upregulation on synaptic currents recorded from the hippocampal slice preparation; mIPSCs as well as evoked IPSCs will be determined across hormone state and correlated with alpha4 subunit levels using Western blot procedures. We will also evaluate the kinetics of GABA-gated current using excised outside-out patches under non-equilibrium conditions of receptor saturation and ultra-fast GABA exposure (<1 msec). These conditions more closely mimic those of actual synaptic events. Decay time constants for GABA-gated current, as well as rate of desensitization, will be determined in cells with alpha4-containing GABA-R (hormone-induced or transfected HEK-293 cells) and compared with control alpha2-containing receptors. In addition, we will test the hypothesis that the 3alpha,5alpha-THP insensitivity we observe is due to upregulation of the delta subunit of the GABA-R, assessed using whole cell patch clamp techniques. In both cases, antisense-induced suppression of subunit expression will be employed to further verify the role of these subunits in modifying changes in synaptic current and 3alpha,5alpha-THP tolerance. These studies will test the hypothesis that alterations in intrinsic properties of GABA-R occur as a result of altered subunit composition after hormone exposure and withdrawal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNAPTIC ORGANIZATION OF THE BASOLATERAL AMYGDALA Principal Investigator & Institution: Mcdonald, Alexander Joseph.; Professor; Developmental Biology and Anatomy; University of South Carolina at Columbia Byrnes Bldg., Room 501 Columbia, Sc 29208 Timing: Fiscal Year 2002; Project Start 01-JUL-1999; Project End 30-JUN-2003 Summary: (Adapted From The Applicant's Abstract): The proposed study is the beginning of a long-term investigation of the synaptic organization of the basolateral amygdala that will focus on the basal amygdalar nucleus (BAN). The amygdala is one of the chief forebrain regions concerned with emotion. Clinical interest in the basolateral amygdala stems from its involvement in temporal lobe epilepsy, Alzheimer's disease, and psychiatric disorders (including anxiety, depression, and schizophrenia). It is also one of the main regions targeted by benzodiazepines and other psychiatric medications. Despite the importance of this brain region, very little is known about the synaptic organization of its constituent psychiatric disorders involving the amygdala. The proposed studies will focus on the inhibitory interneurons of the BAN. These investigations will use immunocytochemical methods at the light and electron
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microscopic levels to identify the main subpopulations of inhibitory interneurons and to analyze their connections: 1) with the principal neurons of the BAN, 2) with the serotonergic, dopaminergic, and noradrenergic afferents to the BAN, and 3) with each other. The synaptic connections of electrophysiological characterized principal neurons and interneurons will also be examined; this represents the first time that electrophysiological and ultrastructural techniques will be combined to elucidate the synaptic organization of the basolateral amygdala. In addition, it will be determined if particular interneuronal subpopulations in the BAN exhibit specific subtypes of GABAergic, glutamatergic, and monoaminergic receptors, and whether there are extensive non-synaptic interactions of monoaminergic transmitters with BAN neurons.III. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TEMPLATE POLYMERIZATION Principal Investigator & Institution: Shea, Kenneth J.; Professor; Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 01-APR-1994; Project End 31-DEC-2003 Summary: Molecular imprinting is a general method for creating binding and receptor sites for organic molecules in crosslinked network polymers. The objectives of this proposal are to expand the boundaries of molecular imprinting to create artificial receptors and binding sites for drugs and drug intermediates, oligonucleotides, and other complex organic targets. Specifically we propose to broaden the range of molecules that can be targeted by molecular imprinting. We will develop new formulations for imprinting acidic compounds and molecules that contain perfluoroalkyl groups. We also propose to synthesize receptors for benzodiazepines, oligonucleotides, carbohydrate derivatives, small peptides, and intermediates in drug synthesis. The integration of imprinted polymers into useful technology requires an ability to fabricate these materials in a variety of morphologies. Along these lines we have developed methods for molecularly imprinted thin films and membranes (MIM's). We propose to evaluate these materials for a number of applications, including their use as the polymer phase in solid phase extraction devices, and as semipermeable membranes for the separation of complex organic molecules and enantiomers. Imprinted films will also be evaluated as the recognition element for sensor devices. This latter application will utilize a fluorescent signal to report the binding event. Finally we have proposed a study designed to get at how binding sites are created during the polymerization process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TREATING ADDICTION TO SLEEP MEDICATION Principal Investigator & Institution: Lichstein, Kenneth L.; Professor; Psychology; University of Memphis Memphis, Tn 38152 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-MAR-2008 Summary: (provided by applicant): Hypnotic-dependent insomnia (HDI) refers to insomnia maintained by the chronic use of sleep medications (hypnotics) with associated tolerance and dependence. Benzodiazepines, one class of commonly used sleep medications, are particularly prone to producing addiction and negative side effects. Similar, but often less severe negative effects, are associated with nonbenzodiazepine prescription sleep medications. The efficacy of psychological treatments for insomnia is well established, but there has been relatively little research
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on the use of these same treatments for people with insomnia who are also addicted to sleep medication. The planned study will treat 90 young and middle-aged adults, ages 21-59, diagnosed with HDI secondary to prescribed sleep medication in a randomized experiment with three conditions: scheduled gradual hypnotic withdrawal supplemented by stress management (relaxation, stimulus control, and sleep hygiene), scheduled gradual hypnotic withdrawal supplemented by placebo desensitization, and scheduled gradual hypnotic withdrawal only. Assessments at baseline, posttreatment/withdrawal, and 1-year follow-up will include monitoring of hypnotic consumption, self-report and laboratory sleep evaluations, drug screens, and measures of daytime functioning. Side effects during the drug withdrawal period will also be monitored by self-report. The study will attempt to determine if adding psychological treatments to gradual drug withdrawal will improve success of drug withdrawal, diminish withdrawal side-effects, improve sleep, or improve daytime functioning compared to gradual drug withdrawal alone in the management of HDI. This project fits within the guidelines of a Stage II clinical trial according to the Behavioral Therapies Development Program of the National Institute on Drug Abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: USE OF BENZODIAZEPINES BY OLDER PRIMARY CARE PATIENTS Principal Investigator & Institution: Cook, Joan M.; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-MAY-2005 Summary: (provided by applicant): This R21 application is for an Exploratory/Developmental Project addressing the high prevalence of use of benzodiazepines by older primary care (PC) patients and their continued prescription by primary care providers (PCPs). This pattern of prescription and use persists despite clear evidence that these medications pose potentially significant health risks and despite the availability of medications and psychotherapies that are safer and more appropriate. There are already numerous randomized clinical trials evaluating strategies for facilitating discontinuation of benzodiazepines. However, there has been little dissemination of these strategies, and both the external and internal validity of these trials can be questioned because of low uptake, biased sampling, and selective retention of patients. Inappropriate use of benzodiazepines by the elderly is seen as a public health problem and prescriptions by PCP's is seen as a quality of care issue, yet we lack effective clinical tools to facilitate reduction in use. We propose a mixed method triangulation design to explicate older patients' and PCPs' perspectives on use of benzodiazepines. The first specific aim is to elicit PCPs' general implicit model of benzodiazepine prescription, including reactions to recommendations about their use. The second specific aim is to elicit patients' explanatory model, including their relevant experiences contributing to their use as well as their understanding of the locus of decision-making concerning their use. The third specific aim is to understand agreements and discrepancies between PCP and patient perspectives. The project involves a three phase sequential assessment: 1) qualitative interviews of 30 PCPs concerning general beliefs and attitudes about benzodiazepine prescription to older patients; 2) qualitative interviews and quantitative assessment of 5 patients drawn from each PCP concerning their symptomatic status and continued use of benzodiapezines; 3) follow-up assessment of PCP's concerning these specific patients and the PCPs response to our preliminary findings (member-checking). The key goal of this project is to understand the acceptability of both benzodiazepines usage by older patients and of
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strategies to reduce this use in order to design intervention studies yielding robustly acceptable and effective strategies for discontinuation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “benzodiazepines” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for benzodiazepines in the PubMed Central database: •
[gamma]-Aminobutyric Acid Type A Receptor Point Mutation Increases the Affinity of Compounds for the Benzodiazepine Site. by Pritchett DB, Seeburg PH.; 1991 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=51030
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A point mutation in the [gamma]2 subunit of [gamma]-aminobutyric acid type A receptors results in altered benzodiazepine binding site specificity. by Buhr A, Sigel E.; 1997 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23149
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A quantitative assay to measure the relative DNA-binding affinity of pyrrolo[2,1-c] [1,4]benzodiazepine (PBD) antitumour antibiotics based on the inhibition of restriction endonuclease BamHI. by Puvvada MS, Hartley JA, Jenkins TC, Thurston DE.; 1993 Aug 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=309864
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Altered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit mutation [[gamma]2(R43Q)] found in human epilepsy. by Bowser DN, Wagner DA, Czajkowski C, Cromer BA, Parker MW, Wallace RH, Harkin LA, Mulley JC, Marini C, Berkovic SF, Williams DA, Jones MV, Petrou S.; 2002 Nov 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=137562
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Benzodiazepine Receptors Mediate Regional Blood Flow Changes in the Living Human Brain. by Matthew E, Andreason P, Pettigrew K, Carson RE, Herscovitch P, Cohen R, King C, Johanson C, Greenblatt DJ, Paul SM.; 1995 Mar 28; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=42301
3 4
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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Benzodiazepine use in pregnancy and major malformations or oral cleft: metaanalysis of cohort and case-control studies. by Dolovich LR, Addis A, Vaillancourt JM, Power JD, Koren G, Einarson TR.; 1998 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31092
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Benzodiazepine-induced superoxide signalsB cell apoptosis: mechanistic insight and potential therapeutic utility. by Blatt NB, Bednarski JJ, Warner RE, Leonetti F, Johnson KM, Boitano A, Yung R, Richardson BC, Johnson KJ, Ellman JA, Opipari AW Jr, Glick GD.; 2002 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150800
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Benzodiazepine-Insensitive Mice Generated by Targeted Disruption of the [gamma]2 Subunit Gene of [gamma]-Aminobutyric Acid Type A Receptors. by Gunther U, Benson J, Benke D, Fritschy J, Reyes G, Knoflach F, Crestani F, Aguzzi A, Arigoni M, Lang Y, Bluethmann H, Mohler H, Luscher B.; 1995 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41223
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Benzodiazepines and hip fractures in elderly people: case-control study. by Pierfitte C, Macouillard G, Thicoipe M, Chaslerie A, Pehourcq F, Aissou M, Martinez B, Lagnaoui R, Fourrier A, Begaud B, Dangoumau J, Moore N.; 2001 Mar 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30096
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Brain Concentrations of Benzodiazepines are Elevated in an Animal Model of Hepatic Encephalopathy. by Basile AS, Pannell L, Jaouni T, Gammal SH, Fales HM, Jones EA, Skolnick P.; 1990 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=54303
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Discontinuation of benzodiazepines among older insomniac adults treated with cognitive-behavioural therapy combined with gradual tapering: a randomized trial. by Baillargeon L, Landreville P, Verreault R, Beauchemin JP, Gregoire JP, Morin CM.; 2003 Nov 11; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=236226
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Educating physicians to reduce benzodiazepine use by elderly patients: a randomized controlled trial. by Pimlott NJ, Hux JE, Wilson LM, Kahan M, Li C, Rosser WW.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151988
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Effect of peripheral benzodiazepine receptor ligands on lipopolysaccharide-induced tumor necrosis factor activity in thioglycolate-treated mice. by Matsumoto T, Ogata M, Koga K, Shigematsu A.; 1994 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=284547
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Eubacterial signal transduction by ligands of the mammalian peripheral benzodiazepine receptor complex. by Donohue TJ.; 1997 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33664
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Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines. by Izzo E, Auta J, Impagnatiello F, Pesold C, Guidotti A, Costa E.; 2001 Mar 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=30679
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High daily doses of benzodiazepines among Quebec seniors: prevalence and correlates. by Egan MY, Wolfson C, Moride Y, Monette J.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=61036
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Identification of des-(Gly-Ile)-endozepine as an effector of corticotropin-dependent adrenal steroidogenesis: stimulation of cholesterol delivery is mediated by the peripheral benzodiazepine receptor. by Besman MJ, Yanagibashi K, Lee TD, Kawamura M, Hall PF, Shively JE.; 1989 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=297522
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Imaging of a glioma using peripheral benzodiazepine receptor ligands. by StarostaRubinstein S, Ciliax BJ, Penney JB, McKeever P, Young AB.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304322
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Inhibition of human immunodeficiency virus type 1 Tat-dependent activation of translation in Xenopus oocytes by the benzodiazepine Ro24-7429 requires transactivation response element loop sequences. by Braddock M, Cannon P, Muckenthaler M, Kingsman AJ, Kingsman SM.; 1994 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=236260
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Isolation of the Mitochondrial Benzodiazepine Receptor: Association with the Voltage-Dependent Anion Channel and the Adenine Nucleotide Carrier. by McEnery MW, Snowman AM, Trifiletti RR, Snyder SH.; 1992 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48827
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Lateral geniculate lesions block circadian phase-shift responses to a benzodiazepine. by Johnson RF, Smale L, Moore RY, Morin LP.; 1988 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=281738
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Ligands of the Peripheral Benzodiazepine Receptor Are Potent Inhibitors of Plasmodium falciparum and Toxoplasma gondii In Vitro. by Dzierszinski F, Coppin A, Mortuaire M, Dewailly E, Slomianny C, Ameisen JC, DeBels F, Tomavo S.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128807
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Linkage disequilibrium between the beta frequency of the human EEG and a GABAA receptor gene locus. by Porjesz B, Almasy L, Edenberg HJ, Wang K, Chorlian DB, Foroud T, Goate A, Rice JP, O'Connor SJ, Rohrbaugh J, Kuperman S, Bauer LO, Crowe RR, Schuckit MA, Hesselbrock V, Conneally PM, Tischfield JA, Li TK, Reich T, Begleiter H.; 2002 Mar 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122592
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Long term benzodiazepine use for insomnia in patients over the age of 60: discordance of patient and physician perceptions. by Mah L, Upshur RE.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113266
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Low neurotoxicity of LJC 10,627, a novel 1 beta-methyl carbapenem antibiotic: inhibition of gamma-aminobutyric acidA, benzodiazepine, and glycine receptor binding in relation to lack of central nervous system toxicity in rats. by Hikida M, Masukawa Y, Nishiki K, Inomata N.; 1993 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=187638
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Mitochondrial Benzodiazepine Receptor Linked to Inner Membrane Ion Channels by Nanomolar Actions of Ligands. by Kinnally KW, Zorov DB, Antoneko YN, Snyder SH, McEnery MW, Tedeschi H.; 1993 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=45875
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Mitochondrial benzodiazepine receptors regulate steroid biosynthesis. by Mukhin AG, Papadopoulos V, Costa E, Krueger KE.; 1989 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=298592
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Porphyrins are endogenous ligands for the mitochondrial (peripheral-type) benzodiazepine receptor. by Verma A, Nye JS, Snyder SH.; 1987 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304628
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Protracted treatment with diazepam increases the turnover of putative endogenous ligands for the benzodiazepine/beta-carboline recognition site. by Miyata M, Mocchetti I, Ferrarese C, Guidotti A, Costa E.; 1987 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304447
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Stable Expression of Mammalian type A [gamma]-Aminobutyric Acid Receptors in Mouse Cells: Demonstration of Functional Assembly of Benzodiazepine- Responsive Sites. by Hadingham KL, Harkness PC, McKernan RM, Quirk K, Bourdelles BL, Horne AL, Kemp JA, Barnard EA, Ragan CI, Whiting PJ.; 1992 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49504
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The Combinatorial Synthesis and Chemical and Biological Evaluation of a 1,4Benzodiazepine Library. by Bunin BA, Plunkett MJ, Ellman JA.; 1994 May 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=43857
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Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects. by Ancoli-Israel S, Walsh JK, Mangano RM, Fujimori M.; 1999 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=181075
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.
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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To generate your own bibliography of studies dealing with benzodiazepines, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “benzodiazepines” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for benzodiazepines (hyperlinks lead to article summaries): •
A prospective, randomized, controlled trial of benzodiazepines and nitroglycerine or nitroglycerine alone in the treatment of cocaine-associated acute coronary syndromes. Author(s): Honderick T, Williams D, Seaberg D, Wears R. Source: The American Journal of Emergency Medicine. 2003 January; 21(1): 39-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12563578&dopt=Abstract
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Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Author(s): Hajak G, Muller WE, Wittchen HU, Pittrow D, Kirch W. Source: Addiction (Abingdon, England). 2003 October; 98(10): 1371-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519173&dopt=Abstract
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Alcohol and benzodiazepines in fatal poisonings. Author(s): Koski A, Ojanpera I, Vuori E. Source: Alcoholism, Clinical and Experimental Research. 2002 July; 26(7): 956-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12170103&dopt=Abstract
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Alcohol and/or benzodiazepine use in injured road users. Author(s): Kurzthaler I, Wambacher M, Golser K, Sperner G, Sperner-Unterweger B, Haidekker A, Pavlic M, Kemmler G, Fleischhacker WW. Source: Human Psychopharmacology. 2003 July; 18(5): 361-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858322&dopt=Abstract
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Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Author(s): Atack JR. Source: Current Drug Targets. Cns and Neurological Disorders. 2003 August; 2(4): 21332. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12871032&dopt=Abstract
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Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Author(s): Bruce SE, Vasile RG, Goisman RM, Salzman C, Spencer M, Machan JT, Keller MB. Source: The American Journal of Psychiatry. 2003 August; 160(8): 1432-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12900305&dopt=Abstract
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Association of benzodiazepine injection with the prescription of temazepam capsules. Author(s): Dobbin M, Martyres RF, Clode D, Champion De Crespigny FE. Source: Drug and Alcohol Review. 2003 June; 22(2): 153-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12850901&dopt=Abstract
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Benzodiazepine exposure and history of trauma. Author(s): Sansone RA, Hruschka J, Vasudevan A, Miller SN. Source: Psychosomatics. 2003 November-December; 44(6): 523-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14597692&dopt=Abstract
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Benzodiazepine receptor deficiency and tinnitus. Author(s): Shulman A, Strashun AM, Seibyl JP, Daftary A, Goldstein B. Source: Int Tinnitus J. 2000; 6(2): 98-111. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14689626&dopt=Abstract
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Benzodiazepine use and physical performance in community-dwelling older women. Author(s): Gray SL, Penninx BW, Blough DK, Artz MB, Guralnik JM, Wallace RB, Buchner DM, LaCroix AZ. Source: Journal of the American Geriatrics Society. 2003 November; 51(11): 1563-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14687385&dopt=Abstract
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Benzodiazepine use and risk of mortality in individuals aged 85 years or older. Author(s): Vinkers DJ, Gussekloo J, van der Mast RC, Zitman FG, Westendorp RG. Source: Jama : the Journal of the American Medical Association. 2003 December 10; 290(22): 2942-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14665654&dopt=Abstract
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Benzodiazepine utilization patterns in Alzheimer's disease patients. Author(s): Lagnaoui R, Moore N, Moride Y, Miremont-Salame G, Begaud B. Source: Pharmacoepidemiology and Drug Safety. 2003 September; 12(6): 511-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14513664&dopt=Abstract
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Benzodiazepines and anterior pituitary function. Author(s): Arvat E, Giordano R, Grottoli S, Ghigo E. Source: J Endocrinol Invest. 2002 September; 25(8): 735-47. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12240908&dopt=Abstract
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Benzodiazepines and related drugs for insomnia in palliative care. Author(s): Hirst A, Sloan R. Source: Cochrane Database Syst Rev. 2002; (4): Cd003346. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12519593&dopt=Abstract
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Benzodiazepines and risk of hip fractures in older people: a review of the evidence. Author(s): Cumming RG, Le Couteur DG. Source: Cns Drugs. 2003; 17(11): 825-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12921493&dopt=Abstract
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Benzodiazepines and the risk of falling. Author(s): Roggla H, Moser B, Roggla G. Source: Therapie. 2002 March-April; 57(2): 209-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12185978&dopt=Abstract
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Benzodiazepines and the risk of urinary incontinence in frail older persons living in the community. Author(s): Landi F, Cesari M, Russo A, Onder G, Sgadari A, Bernabei R; Silvernet-HC Study Group. Source: Clinical Pharmacology and Therapeutics. 2002 December; 72(6): 729-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12496754&dopt=Abstract
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Benzodiazepines as potent and selective bradykinin B1 antagonists. Author(s): Wood MR, Kim JJ, Han W, Dorsey BD, Homnick CF, DiPardo RM, Kuduk SD, MacNeil T, Murphy KL, Lis EV, Ransom RW, Stump GL, Lynch JJ, O'Malley SS, Miller PJ, Chen TB, Harrell CM, Chang RS, Sandhu P, Ellis JD, Bondiskey PJ, Pettibone DJ, Freidinger RM, Bock MG. Source: Journal of Medicinal Chemistry. 2003 May 8; 46(10): 1803-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723943&dopt=Abstract
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Benzodiazepines for neuroleptic-induced tardive dyskinesia. Author(s): Umbrich P, Soares KV. Source: Cochrane Database Syst Rev. 2003; (2): Cd000205. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12804389&dopt=Abstract
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Benzodiazepines in schizophrenia: prefrontal cortex atrophy predicts clinical response to alprazolam augmentation. Author(s): Seeley WW, Turetsky N, Reus VI, Wolkowitz OM. Source: World J Biol Psychiatry. 2002 October; 3(4): 221-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12516314&dopt=Abstract
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Benzodiazepines: more “behavioural” addiction than dependence. Author(s): de las Cuevas C, Sanz E, de la Fuente J. Source: Psychopharmacology. 2003 May; 167(3): 297-303. Epub 2003 April 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12669174&dopt=Abstract
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Binding characteristics of SSR180575, a potent and selective peripheral benzodiazepine ligand. Author(s): Vin V, Leducq N, Bono F, Herbert JM. Source: Biochemical and Biophysical Research Communications. 2003 October 24; 310(3): 785-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14550272&dopt=Abstract
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Biomarkers for the effects of benzodiazepines in healthy volunteers. Author(s): de Visser SJ, van der Post JP, de Waal PP, Cornet F, Cohen AF, van Gerven JM. Source: British Journal of Clinical Pharmacology. 2003 January; 55(1): 39-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12534639&dopt=Abstract
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Can continuing benzodiazepine use be predicted? Author(s): Neutel CI, Walop W, Patten SB. Source: Can J Clin Pharmacol. 2003 Winter; 10(4): 202-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14712326&dopt=Abstract
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Cardiac risk at the onset of treatment in patients treated with benzodiazepines and clozapine. Author(s): Borentain S, Millet B, Olie JP. Source: European Psychiatry : the Journal of the Association of European Psychiatrists. 2002 November; 17(7): 419-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12547310&dopt=Abstract
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Clinical impairment of benzodiazepines--relation between benzodiazepine concentrations and impairment in apprehended drivers. Author(s): Bramness JG, Skurtveit S, Morland J. Source: Drug and Alcohol Dependence. 2002 October 1; 68(2): 131-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12234642&dopt=Abstract
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Comparing patterns of long-term benzodiazepine use between a Dutch and a Swedish community. Author(s): van Hulten R, Isacson D, Bakker A, Leufkens HG. Source: Pharmacoepidemiology and Drug Safety. 2003 January-February; 12(1): 49-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12616847&dopt=Abstract
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Comparison of the fatal toxicity index of zopiclone with benzodiazepines. Author(s): Reith DM, Fountain J, McDowell R, Tilyard M. Source: Journal of Toxicology. Clinical Toxicology. 2003; 41(7): 975-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14705844&dopt=Abstract
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Concomitant prescribing of benzodiazepines during antidepressant therapy in the elderly. Author(s): van Dijk KN, de Vries CS, ter Huurne K, van den Berg PB, Brouwers JR, de Jong-van den Berg LT. Source: Journal of Clinical Epidemiology. 2002 October; 55(10): 1049-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12464383&dopt=Abstract
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Correlates of benzodiazepine use among a sample of arrestees surveyed through the Arrestee Drug Abuse Monitoring (ADAM) Program. Author(s): Yacoubian GS Jr. Source: Substance Use & Misuse. 2003 January; 38(1): 127-39. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12602810&dopt=Abstract
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Dependence potential of antidepressants compared to benzodiazepines. Author(s): van Broekhoven F, Kan CC, Zitman FG. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2002 June; 26(5): 939-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12369270&dopt=Abstract
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Development and psychometric evaluation of the Benzodiazepine Craving Questionnaire. Author(s): Mol AJ, Voshaar RC, Gorgels WJ, Breteler MH, van Balkom AJ, van de Lisdonk EH, van der Ven AH, Zitman FG. Source: Addiction (Abingdon, England). 2003 August; 98(8): 1143-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873249&dopt=Abstract
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Direct injection micellar liquid chromatographic determination of benzodiazepines in serum. Author(s): Capella-Peiro ME, Bose D, Martinavarro-Dominguez A, Gil-Agusti M, Esteve-Romero J. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2002 November 25; 780(2): 241-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12401349&dopt=Abstract
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Discontinuation of benzodiazepines among older insomniac adults treated with cognitive-behavioural therapy combined with gradual tapering: a randomized trial. Author(s): Baillargeon L, Landreville P, Verreault R, Beauchemin JP, Gregoire JP, Morin CM. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2003 November 11; 169(10): 1015-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14609970&dopt=Abstract
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Don't ask, don't tell, but benzodiazepines are still the leading treatments for anxiety disorder. Author(s): Stahl SM. Source: The Journal of Clinical Psychiatry. 2002 September; 63(9): 756-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12363113&dopt=Abstract
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Educating physicians to reduce benzodiazepine use by elderly patients: a randomized controlled trial. Author(s): Pimlott NJ, Hux JE, Wilson LM, Kahan M, Li C, Rosser WW. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2003 April 1; 168(7): 835-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12668540&dopt=Abstract
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Effect of benzodiazepines on structural and conceptual/lexical priming. Author(s): Boucart M, Biederman I, Cuervo C, Danion JM, Wagemans J. Source: Psychopharmacology. 2002 December; 165(1): 43-50. Epub 2002 October 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12474117&dopt=Abstract
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Effects of benzodiazepines on explicit memory in a paediatric surgery setting. Author(s): Buffett-Jerrott SE, Stewart SH, Finley GA, Loughlan HL. Source: Psychopharmacology. 2003 August; 168(4): 377-86. Epub 2003 July 04. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12845417&dopt=Abstract
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Effects of peripheral benzodiazepine receptor ligands on proliferation and differentiation of human mesenchymal stem cells. Author(s): Lee DH, Kang SK, Lee RH, Ryu JM, Park HY, Choi HS, Bae YC, Suh KT, Kim YK, Jung JS. Source: Journal of Cellular Physiology. 2004 January; 198(1): 91-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14584048&dopt=Abstract
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Effects of state surveillance on new post-hospitalization benzodiazepine use. Author(s): Wagner AK, Soumerai SB, Zhang F, Mah C, Simoni-Wastila L, Cosler L, Fanning T, Gallagher P, Ross-Degnan D. Source: International Journal for Quality in Health Care : Journal of the International Society for Quality in Health Care / Isqua. 2003 October; 15(5): 423-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14527986&dopt=Abstract
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Enzymatic hydrolysis improves the sensitivity of Emit screening for urinary benzodiazepines. Author(s): Borrey D, Meyer E, Duchateau L, Lambert W, Van Peteghem C, De Leenheer A. Source: Clinical Chemistry. 2002 November; 48(11): 2047-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12406993&dopt=Abstract
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Factors associated with high prescribing of benzodiazepines and minor opiates. A survey among general practitioners in Norway. Author(s): Bjorner T, Laerum E. Source: Scandinavian Journal of Primary Health Care. 2003 June; 21(2): 115-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12877376&dopt=Abstract
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Fatal methadone toxicity: signs and circumstances, and the role of benzodiazepines. Author(s): Caplehorn JR, Drummer OH. Source: Aust N Z J Public Health. 2002 August; 26(4): 358-62; Discussion 362-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12233958&dopt=Abstract
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Fatal overdoses of tramadol: is benzodiazepine a risk factor of lethality? Author(s): Clarot F, Goulle JP, Vaz E, Proust B. Source: Forensic Science International. 2003 June 24; 134(1): 57-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842359&dopt=Abstract
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GABA systems, benzodiazepines, and substance dependence. Author(s): Malcolm RJ. Source: The Journal of Clinical Psychiatry. 2003; 64 Suppl 3: 36-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12662132&dopt=Abstract
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GABAA receptors and benzodiazepines: a role for dendritic resident subunit mRNAs. Author(s): Costa E, Auta J, Grayson DR, Matsumoto K, Pappas GD, Zhang X, Guidotti A. Source: Neuropharmacology. 2002 November; 43(6): 925-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12423662&dopt=Abstract
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GABAA-benzodiazepine-chloride receptor-targeted therapy for tinnitus control: preliminary report. Author(s): Shulman A, Strashun AM, Goldstein BA. Source: Int Tinnitus J. 2002; 8(1): 30-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14763233&dopt=Abstract
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GABAergic mechanisms involved in the vagally mediated heart rate response to muscle contraction as revealed by studies with benzodiazepines. Author(s): Farmer MR, Ross HF, Chowdhary S, Osman F, Townend JN, Coote JH. Source: Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society. 2003 February; 13(1): 45-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12664247&dopt=Abstract
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Gaboxadol: in vitro interaction studies with benzodiazepines and ethanol suggest functional selectivity. Author(s): Storustovu S, Ebert B. Source: European Journal of Pharmacology. 2003 April 25; 467(1-3): 49-56. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12706454&dopt=Abstract
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Health service utilization and benzodiazepine use among heroin users: findings from the Australian Treatment Outcome Study (ATOS). Author(s): Darke S, Ross J, Teesson M, Lynskey M. Source: Addiction (Abingdon, England). 2003 August; 98(8): 1129-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873247&dopt=Abstract
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Hemoglobin metabolites mimic benzodiazepines and are possible mediators of hepatic encephalopathy. Author(s): Ruscito BJ, Harrison NL. Source: Blood. 2003 August 15; 102(4): 1525-8. Epub 2003 April 24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12714506&dopt=Abstract
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Imipramine and buspirone in patients with panic disorder who are discontinuing long-term benzodiazepine therapy. Author(s): Rynn M, Garcia-Espana F, Greenblatt DJ, Mandos LA, Schweizer E, Rickels K. Source: Journal of Clinical Psychopharmacology. 2003 October; 23(5): 505-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14520129&dopt=Abstract
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Influence of benzodiazepines on auditory perception. Author(s): Morand-Villeneuve N, Micheyl C, Gagnieu MC, Lemoine P, Sebert P, Collet L, Veuillet E. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2003 April; 28(4): 778-86. Epub 2002 September 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12655325&dopt=Abstract
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Initial 3-month usage characteristics predict long-term use of benzodiazepines: an 8year follow-up. Author(s): van Hulten R, Teeuw KB, Bakker A, Leufkens HG. Source: European Journal of Clinical Pharmacology. 2003 February; 58(10): 689-94. Epub 2003 February 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12610746&dopt=Abstract
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In-patient benzodiazepine withdrawal: comparison of fixed and symptom-triggered taper methods. Author(s): McGregor C, Machin A, White JM. Source: Drug and Alcohol Review. 2003 June; 22(2): 175-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12850904&dopt=Abstract
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Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study. Author(s): Gerra G, Zaimovic A, Giusti F, Moi G, Brewer C. Source: Addiction Biology. 2002 October; 7(4): 385-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14578014&dopt=Abstract
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Is the use of benzodiazepines associated with incident disability? Author(s): Gray SL, LaCroix AZ, Blough D, Wagner EH, Koepsell TD, Buchner D. Source: Journal of the American Geriatrics Society. 2002 June; 50(6): 1012-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12110059&dopt=Abstract
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Is there a rationale for prescription of benzodiazepines in the elderly? Review of the literature. Author(s): Petrovic M, Mariman A, Warie H, Afschrift M, Pevernagie D. Source: Acta Clin Belg. 2003 January-February; 58(1): 27-36. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723259&dopt=Abstract
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Lack of relationship between long-term use of benzodiazepines and escalation to high dosages. Author(s): Soumerai SB, Simoni-Wastila L, Singer C, Mah C, Gao X, Salzman C, RossDegnan D. Source: Psychiatric Services (Washington, D.C.). 2003 July; 54(7): 1006-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12851438&dopt=Abstract
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Linear non-competitive inhibition of solubilized human gamma-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines. Author(s): Tian G, Sobotka-Briner CD, Zysk J, Liu X, Birr C, Sylvester MA, Edwards PD, Scott CD, Greenberg BD. Source: The Journal of Biological Chemistry. 2002 August 30; 277(35): 31499-505. Epub 2002 June 18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12072428&dopt=Abstract
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Longitudinal study on the prevalence of benzodiazepine (mis)use in a prison: importance of the analytical strategy. Author(s): Borrey D, Meyer E, Duchateau L, Lambert W, Van Peteghem C, De Leenheer AP. Source: Addiction (Abingdon, England). 2003 October; 98(10): 1427-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14519180&dopt=Abstract
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Lorazepam should no longer be used as a prototypical benzodiazepine. Author(s): Pompeia S, Bueno OF, Tufik S. Source: Psychopharmacology. 2003 September; 169(2): 211-2. Epub 2003 May 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12774189&dopt=Abstract
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Molecular determinants of KCNQ1 channel block by a benzodiazepine. Author(s): Seebohm G, Chen J, Strutz N, Culberson C, Lerche C, Sanguinetti MC. Source: Molecular Pharmacology. 2003 July; 64(1): 70-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12815162&dopt=Abstract
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Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. Author(s): Allison C, Pratt JA. Source: Pharmacology & Therapeutics. 2003 May; 98(2): 171-95. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12725868&dopt=Abstract
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Nonconvulsive status epilepticus resulting from benzodiazepine withdrawal. Author(s): Olnes MJ, Golding A, Kaplan PW. Source: Annals of Internal Medicine. 2003 December 2; 139(11): 956-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14644903&dopt=Abstract
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Normal coupling of brain benzodiazepine and neurosteroid modulatory sites on the GABA-A receptor complex in human hepatic encephalopathy. Author(s): Ahboucha S, Desjardins P, Chatauret N, Pomier-Layrargues G, Butterworth RF. Source: Neurochemistry International. 2003 November; 43(6): 551-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12820983&dopt=Abstract
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Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Author(s): Curran HV, Collins R, Fletcher S, Kee SC, Woods B, Iliffe S. Source: Psychological Medicine. 2003 October; 33(7): 1223-37. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14580077&dopt=Abstract
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Out-of-hospital management of benzodiazepine-resistant status epilepticus in a child with Wolf-Hirschhorn syndrome. Author(s): Toomes M, Maleck WH, Koetter KP, Petroianu GA. Source: Epileptic Disorders : International Epilepsy Journal with Videotape. 2003 June; 5(2): 115-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875955&dopt=Abstract
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Paradoxical reactions to benzodiazepines in intravenous sedation: a report of 2 cases and review of the literature. Author(s): Robin C, Trieger N. Source: Anesthesia Progress. 2002 Winter; 49(4): 128-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12779114&dopt=Abstract
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Peripheral benzodiazepine binding sites in platelets of patients affected by mitochondrial diseases and large scale mitochondrial DNA rearrangements. Author(s): Martini C, Chelli B, Betti L, Montali M, Mancuso M, Giannaccini G, Rocchi A, Murri L, Siciliano G. Source: Molecular Medicine (Cambridge, Mass.). 2002 December; 8(12): 841-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12606819&dopt=Abstract
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Pharmacoeconomic evaluation of a patient education letter aimed at reducing longterm prescribing of benzodiazepines. Author(s): Morgan JD, Wright DJ, Chrystyn H. Source: Pharmacy World & Science : Pws. 2002 December; 24(6): 231-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12512155&dopt=Abstract
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Predictors of relapse after discontinuation of long-term benzodiazepine use by minimal intervention: a 2-year follow-up study. Author(s): Voshaar RO, Gorgels W, Mol A, van Balkom A, Breteler M, van de Lisdonk E, Mulder J, Zitman F. Source: Family Practice. 2003 August; 20(4): 370-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12876104&dopt=Abstract
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Prevalence and potential consequences of benzodiazepine use in senior citizens: results from the Canadian Study of Health and Aging. Author(s): Hogan DB, Maxwell CJ, Fung TS, Ebly EM; Canadian Study of Health and Aging. Source: Can J Clin Pharmacol. 2003 Summer; 10(2): 72-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12879145&dopt=Abstract
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Psychomotor development in children exposed in utero to benzodiazepines, antidepressants, neuroleptics, and anti-epileptics. Author(s): Mortensen JT, Olsen J, Larsen H, Bendsen J, Obel C, Sorensen HT. Source: European Journal of Epidemiology. 2003; 18(8): 769-71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12974552&dopt=Abstract
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Rapid increase of morphine and benzodiazepine usage in the last three days of life in children with cancer is related to neuropathic pain. Author(s): Dougherty M, DeBaun MR. Source: The Journal of Pediatrics. 2003 April; 142(4): 373-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12712053&dopt=Abstract
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Safety of benzodiazepines in newborns. Author(s): Ng E, Klinger G, Shah V, Taddio A. Source: The Annals of Pharmacotherapy. 2002 July-August; 36(7-8): 1150-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12086545&dopt=Abstract
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Segmental ion spray LC-MS-MS analysis of benzodiazepines in hair of psychiatric patients. Author(s): Kronstrand R, Nystrom I, Josefsson M, Hodgins S. Source: Journal of Analytical Toxicology. 2002 October; 26(7): 479-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12423003&dopt=Abstract
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Selections from current literature: benzodiazepines revisited. Author(s): Bobrow RS. Source: Family Practice. 2003 June; 20(3): 347-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738706&dopt=Abstract
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Sleep EEG power spectra, insomnia, and chronic use of benzodiazepines. Author(s): Bastien CH, LeBlanc M, Carrier J, Morin CM. Source: Sleep. 2003 May 1; 26(3): 313-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12749551&dopt=Abstract
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Stereoselective pharmacokinetics of pazinaclone, a new non-benzodiazepine anxiolytic, and its active metabolite in healthy subjects. Author(s): Hussein Z, Mulford DJ, Bopp BA, Granneman GR. Source: British Journal of Clinical Pharmacology. 1993 October; 36(4): 357-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12959315&dopt=Abstract
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Synthesis and antitumour activity of a series of cyclic amidines of 2,3-dihydro-1H-1,5benzodiazepines. Author(s): Janciene R, Kosychova L, Bukelskiene V, Domkus V, Stumbreviciute Z, Ragaleviciene V, Puodziunaite BD. Source: Arzneimittel-Forschung. 2002; 52(6): 475-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12109049&dopt=Abstract
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Synthesis and structure-activity relationships of 2,3-benzodiazepines as AMPA receptor antagonists. Author(s): Zappala M, Grasso S, Micale N, Polimeni S, De Micheli C. Source: Mini Reviews in Medicinal Chemistry. 2001 September; 1(3): 243-53. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12369971&dopt=Abstract
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Synthesis of C-8 methanesulphonate substituted pyrrolobenzodiazepines as potential antitumour agents. Author(s): Kamal A, Ramulu P, Srinivas O, Ramesh G. Source: Bioorganic & Medicinal Chemistry Letters. 2003 October 20; 13(20): 3517-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14505661&dopt=Abstract
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Synthesis of novel C2-aryl pyrrolobenzodiazepines (PBDs) as potential antitumour agents. Author(s): Cooper N, Hagan DR, Tiberghien A, Ademefun T, Matthews CS, Howard PW, Thurston DE. Source: Chemical Communications (Cambridge, England). 2002 August 21; (16): 1764-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196988&dopt=Abstract
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Tapering off long-term benzodiazepine use with or without group cognitivebehavioural therapy: three-condition, randomised controlled trial. Author(s): Voshaar RC, Gorgels WJ, Mol AJ, van Balkom AJ, van de Lisdonk EH, Breteler MH, van den Hoogen HJ, Zitman FG. Source: The British Journal of Psychiatry; the Journal of Mental Science. 2003 June; 182: 498-504. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12777340&dopt=Abstract
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Testing for benzodiazepine inebriation--relationship between benzodiazepine concentration and simple clinical tests for impairment in a sample of drugged drivers. Author(s): Bramness JG, Skurtveit S, Morland J. Source: European Journal of Clinical Pharmacology. 2003 November; 59(8-9): 593-601. Epub 2003 September 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14504853&dopt=Abstract
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The behavioral and cognitive effects of two benzodiazepines associated with drugfacilitated sexual assault. Author(s): Dowd SM, Strong MJ, Janicak PG, Negrusz A. Source: J Forensic Sci. 2002 September; 47(5): 1101-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12353555&dopt=Abstract
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The costs of benzodiazepine-associated hospital-treated fall Injuries in the EU: a Pharmo study. Author(s): Panneman MJ, Goettsch WG, Kramarz P, Herings RM. Source: Drugs & Aging. 2003; 20(11): 833-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12964889&dopt=Abstract
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The effects of benzodiazepines on event-related potential indices of automatic and controlled processing in schizophrenia: a preliminary report. Author(s): Murakami T, Nakagome K, Kamio S, Kasai K, Iwanami A, Hiramatsu K, Fukuda M, Hata A, Honda M, Watanabe A, Kato N. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2002 May; 26(4): 651-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12188096&dopt=Abstract
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The impact of attitudes and beliefs on length of benzodiazepine use: a study among inexperienced and experienced benzodiazepine users. Author(s): van Hulten R, Bakker AB, Lodder AC, Teeuw KB, Bakker A, Leufkens HG. Source: Social Science & Medicine (1982). 2003 March; 56(6): 1345-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12600370&dopt=Abstract
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The injection of methadone and benzodiazepines among Sydney injecting drug users 1996-2000: 5-year monitoring of trends from the Illicit Drug Reporting System. Author(s): Darke S, Topp L, Ross J. Source: Drug and Alcohol Review. 2002 March; 21(1): 27-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12189001&dopt=Abstract
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The proapoptotic benzodiazepine Bz-423 affects the growth and survival of malignant B cells. Author(s): Boitano A, Ellman JA, Glick GD, Opipari AW Jr. Source: Cancer Research. 2003 October 15; 63(20): 6870-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14583485&dopt=Abstract
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The relative amount of cRNA coding for gamma2 subunits affects stimulation by benzodiazepines in GABA(A) receptors expressed in Xenopus oocytes. Author(s): Boileau AJ, Baur R, Sharkey LM, Sigel E, Czajkowski C. Source: Neuropharmacology. 2002 September; 43(4): 695-700. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12367615&dopt=Abstract
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The role of benzodiazepines in elderly suicides. Author(s): Carlsten A, Waern M, Holmgren P, Allebeck P. Source: Scandinavian Journal of Public Health. 2003; 31(3): 224-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12850977&dopt=Abstract
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The role of extended-release benzodiazepines in the treatment of anxiety: a riskbenefit evaluation with a focus on extended-release alprazolam. Author(s): Klein E. Source: The Journal of Clinical Psychiatry. 2002; 63 Suppl 14: 27-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562116&dopt=Abstract
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Therapeutic response of benzodiazepine, orphenadrine citrate and occlusal splint association in TMD pain. Author(s): Rizzatti-Barbosa CM, Martinelli DA, Ambrosano GM, de Albergaria-Barbosa JR. Source: Cranio. 2003 April; 21(2): 116-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12723857&dopt=Abstract
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Therapeutic response to benzodiazepine in panic disorder subtypes. Author(s): Valenca AM, Nardi AE, Mezzasalma MA, Nascimento I, Zin WA, Lopes FL, Versiani M. Source: Sao Paulo Medical Journal = Revista Paulista De Medicina. 2003 March 5; 121(2): 77-80. Epub 2003 July 14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12870055&dopt=Abstract
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Topiramate in benzodiazepine withdrawal. Author(s): Cheseaux M, Monnat M, Zullino DF. Source: Human Psychopharmacology. 2003 July; 18(5): 375-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12858324&dopt=Abstract
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Validation of a microtiter plate ELISA for screening of postmortem blood for opiates and benzodiazepines. Author(s): Kemp P, Sneed G, Kupiec T, Spiehler V. Source: Journal of Analytical Toxicology. 2002 October; 26(7): 504-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12423008&dopt=Abstract
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Zopiclone and zaleplon vs benzodiazepines in the treatment of insomnia: Canadian consensus statement. Author(s): Montplaisir J, Hawa R, Moller H, Morin C, Fortin M, Matte J, Reinish L, Shapiro CM. Source: Human Psychopharmacology. 2003 January; 18(1): 29-38. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12532313&dopt=Abstract
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CHAPTER 2. NUTRITION AND BENZODIAZEPINES Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and benzodiazepines.
Finding Nutrition Studies on Benzodiazepines 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 “benzodiazepines” (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 “benzodiazepines” (or a synonym): •
Production of antibodies against benzodiazepines for competitive enzyme immunoassay detection in plant extracts [Solanum tuberosum L.]. Author(s): Istituto Sperimentale per le Colture Industriali, Bologna (Italy) Turin Univ. (Italy). Dipartimento di Chimica Analitica Source: Grassi, G. Moschella, A. Giraudi, G. Giovannoli, C. Baggiani, C. Italian-Journalof-Food-Science (Italy). (1998). volume 10(1) page 5-15.
Additional physician-oriented references include: •
A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly. Author(s): Department of Physiology, Faculty of Medicine, University of Buenos Aires, Argentina.
[email protected] Source: Cardinali, Daniel P Gvozdenovich, Elisa Kaplan, Marcos R Fainstein, Isidoro Shifis, Hugo A Perez Lloret, Santiago Albornoz, Liliana Negri, Armando Neuroendocrinol-Lett. 2002 February; 23(1): 55-60 0172-780X
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Allosteric regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors by thiocyanate and cyclothiazide at a common modulatory site distinct from that of 2,3-benzodiazepines. Author(s): Neuronal Excitability Section, Epilepsy Research Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1408, USA. Source: Donevan, S D Rogawski, M A Neuroscience. 1998 December; 87(3): 615-29 03064522
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Alprazolam, a benzodiazepine, does not modify the ACTH and cortisol response to hCRH and AVP, but blunts the cortisol response to ACTH in humans. Author(s): Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Italy. Source: Grottoli, S Maccagno, B Ramunni, J Di Vito, L Giordano, R Gianotti, L DeStefanis, S Camanni, F Ghigo, E Arvat, E J-Endocrinol-Invest. 2002 May; 25(5): 420-5 0391-4097
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Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms. Author(s): Department of Pharmacology and Therapeutics, Physiology and Biophysics, and Institute for Biomolecular Science, University of South Florida, Tampa, Florida 33612, USA. Source: Walters, R J Hadley, S H Morris, K D Amin, J Nat-Neurosci. 2000 December; 3(12): 1274-81 1097-6256
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Benzodiazepines facilitate the stimulatory action of gamma-aminobutyric acid (GABA) on basal and veratridine-evoked catecholamine release from cultured bovine adrenal chromaffin cells. Author(s): Department of Pharmacology, Hiroshima University School of Dentistry, Japan. Source: Kitayama, S Morita, K Dohi, T Tsujimoto, A Arch-Int-Pharmacodyn-Ther. 1989 Jul-August; 300254-64 0003-9780
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Benzodiazepines in the brain. Their origin and possible biological roles. Author(s): Instituto de Biologia Celular, Fac. Medicina, Buenos Aires, Argentina.
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Source: Medina, J H Pena, C Piva, M Wolfman, C de Stein, M L Wasowski, C Da Cunha, C Izquierdo, I Paladini, A C Mol-Neurobiol. 1992 Winter; 6(4): 377-86 0893-7648 •
Binding of girisopam (a 2,3-benzodiazepine derivative) to the substantia nigra is prevented by lesioning of the striatonigral pathway. Author(s): Department of Anatomy, Semmelweis University Medical School, Budapest, Hungary. Source: Palkovits, M Lovas, G Horvath, E Neuroscience. 1998 April; 83(3): 799-806 03064522
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Daytime sleepiness, performance, mood, nocturnal sleep: the effect of benzodiazepine and caffeine on their relationship. Author(s): Naval Health Research Center, San Diego, CA 92138-9174. Source: Johnson, L C Spinweber, C L Gomez, S A Matteson, L T Sleepage 1990 April; 13(2): 121-35 0161-8105
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Diazepam alters brain 5-HT function in man: implications for the acute and chronic effects of benzodiazepines. Source: Nutt, D J Cowen, P J Psychol-Med. 1987 August; 17(3): 601-7 0033-2917
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Direct automated EMIT d.a.u. analysis of N,N-dimethylformamide-modified serum, plasma, and postmortem blood for benzodiazepines, benzoylecgonine, cannabinoids, and opiates. Author(s): National Medical Services, Inc., Willow Grove, Pennsylvania 19090. Source: Blum, L M Klinger, R A Rieders, F J-Anal-Toxicol. 1989 Sep-October; 13(5): 285-8 0146-4760
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Effect of benzodiazepines on the proliferation of mouse spleen lymphocytes in vitro. Author(s): Department of Experimental Endocrinology, Medical Academy of Lodz, Poland. Source: Pawlikowski, M Lyson, K Kunert Radek, J Stepien, H J-Neural-Transm. 1988; 73(2): 161-6 0300-9564
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Effects of hippocampal injections of a novel ligand selective for the alpha 5 beta 2 gamma 2 subunits of the GABA/benzodiazepine receptor on Pavlovian conditioning. Author(s): Department of Psychology, University of Wisconsin.Milwaukee, Milwaukee, Wisconsin 53201, USA. Source: Bailey, D J Tetzlaff, J E Cook, J M He, X Helmstetter, F J Neurobiol-Learn-Mem. 2002 July; 78(1): 1-10 1074-7427
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Endogenous benzodiazepines. Author(s): Department of Pharmaceutical Sciences, University of Modena, Italy. Source: Baraldi, M Avallone, R Corsi, L Venturini, I Baraldi, C Zeneroli, M L Therapie. 2000 Jan-February; 55(1): 143-6 0040-5957
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Enzymatic solid-phase assay for biotin and a biotin-benzodiazepine conjugate. Author(s): Department of Chemistry, University of Hawaii at Manoa, Honolulu 96822. Source: Takeuchi, T Rechnitz, G A Bioconjug-Chem. 1990 Jul-August; 1(4): 227-30 10431802
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Extraction and purification from Ceratonia siliqua of compounds acting on central and peripheral benzodiazepine receptors. Author(s): Department of Pharmaceutical Sciences, Via Campi 183, Modena and Reggio Emilia University, 41100, Modena, Italy.
[email protected] Source: Avallone, R Cosenza, F Farina, F Baraldi, C Baraldi, M Fitoterapia. 2002 August; 73(5): 390-6 0367-326X
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GABAA receptor subunit interactions important for benzodiazepine and zinc modulation: a patch-clamp and single cell RT-PCR study. Author(s): Laboratory of Neuropathology, University of Copenhagen, 11, Frederik V vej, DK-2100, Copenhagen, Denmark. Source: Alsbo, C W Kristiansen, U Moller, F Hansen, S L Johansen, F F Eur-J-Neurosci. 2001 May; 13(9): 1673-82 0953-816X
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Influence of benzodiazepines on antiparkinsonian drug treatment in levodopa users. Author(s): Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands.
[email protected] Source: van de Vijver, D A M C Roos, R A C Jansen, P A F Porsius, A J de Boer, A ActaNeurol-Scand. 2002 Jan; 105(1): 8-12 0001-6314
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Modification of the EMIT tox benzodiazepine assay for screening of alprazolam in serum. Author(s): Victoria General Hospital, Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada. Source: Fraser, A D Bryan, W Isner, A F J-Anal-Toxicol. 1988 Jul-August; 12(4): 197-9 0146-4760
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Molecular modeling and QSAR analysis of the interaction of flavone derivatives with the benzodiazepine binding site of the GABA(A) receptor complex. Author(s): Instituto de Quimica y Fisicoquimica Biologicas, Faultad de Farmacia y Bioquimica, Buenos Aires, Argentina. Source: Marder, M Estiu, G Blanch, L B Viola, H Wasowski, C Medina, J H Paladini, A C Bioorg-Med-Chem. 2001 February; 9(2): 323-35 0968-0896
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Naloxone-sensitive and GABAA receptor mediated analgesic response of benzodiazepines in mice. Source: Kunchandy, J Kulkarni, S K Methods-Find-Exp-Clin-Pharmacol. 1987 February; 9(2): 95-9 0379-0355
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No interactive effects of naltrexone and benzodiazepines on pain during phobic fear. Author(s): Department of Medical Psychology, Maastricht University, The Netherlands.
[email protected] Source: Janssen, S A Arntz, A Behav-Res-Ther. 1999 Jan; 37(1): 77-86 0005-7967
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Oxaprozin cross-reactivity in three commercial immunoassays for benzodiazepines in urine. Author(s): Division of Clinical Chemistry, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
[email protected] Source: Fraser, A D Howell, P J-Anal-Toxicol. 1998 Jan-February; 22(1): 50-4 0146-4760
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Oxaprozin interference with urinary benzodiazepine immunoassays and noninterference with receptor assay. Author(s): Department of Clinical Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
[email protected] Source: Nishikawa, T Kamijo, Y Ohtani, H Fraser, A D J-Anal-Toxicol. 1999 Mar-April; 23(2): 125-6 0146-4760
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PAF-acether-induced mortality in mice: protection by benzodiazepines. Author(s): Laboratory of Pharmacodynamics, Faculty of Pharmacy, Dijon, France. Source: Tanniere Zeller, M Rochette, L Bralet, J Drugs-Exp-Clin-Res. 1989; 15(11-12): 5538 0378-6501
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Peripheral-type benzodiazepine receptors are involved in the regulation of cholesterol side chain cleavage in adrenocortical mitochondria. Author(s): Department of Pharmacology I, Jikei University School of Medicine, Tokyo. Source: Yanagibashi, K Ohno, Y Nakamichi, N Matsui, T Hayashida, K Takamura, M Yamada, K Tou, S Kawamura, M J-Biochem-(Tokyo). 1989 December; 106(6): 1026-9 0021-924X
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Potential effects of benzodiazepines on cocaine reinforcement in rats. Author(s): Department of Pharmacology, Louisiana State University Medical Center, Shreveport 71130. Source: Goeders, N E NIDA-Res-Monogr. 1992; 119190-4 1046-9516
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Simultaneous HPLC analysis of the hypnotic benzodiazepines nitrazepam, estazolam, flunitrazepam, and triazolam in plasma. Author(s): Laboratoire de Toxicologie Fondamentale, Clinique et du Medicament, Faculte de Pharmacie, Strasbourg, France. Source: Boukhabza, A Lugnier, A A Kintz, P Mangin, P J-Anal-Toxicol. 1991 NovDecember; 15(6): 319-22 0146-4760
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Stereoselective effect of phenprocoumon enantiomers on the binding of benzodiazepines to human serum albumin. Author(s): Central Research Institute for Chemistry, Hungarian Academy of Sciences, Budapest. Source: Fitos, I Simonyi, M Chirality. 1992; 4(1): 21-3 0899-0042
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The efficacy of 22,23-dihydroavermectin B1 (Ivermectin) acting singly or in combination with a benzodiazepine on microfilariae of Onchocerca species and Brugia pahangi (an in vitro study). Author(s): Department of Medical Microbiology, College of Health Sciences, University of Nairobi, Kenya. Source: Estambale, B B Howells, R E Zentralbl-Bakteriol. 1989 July; 271(2): 249-55 09348840
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/
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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
The following is a specific Web list relating to benzodiazepines; 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: •
Minerals Clorazepate Dipotassium Source: Healthnotes, Inc.; www.healthnotes.com
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CHAPTER 3. ALTERNATIVE BENZODIAZEPINES
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Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to benzodiazepines. 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 benzodiazepines 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 “benzodiazepines” (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 benzodiazepines: •
3,5-Dihydro-4H-2,3-benzodiazepine-4-thiones: a new class of AMPA receptor antagonists. Author(s): Chimirri A, De Sarro G, De Sarro A, Gitto R, Quartarone S, Zappala M, Constanti A, Libri V. Source: Journal of Medicinal Chemistry. 1998 August 27; 41(18): 3409-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9719593&dopt=Abstract
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5,7-Dihydroxy-6-methoxyflavone, a benzodiazepine site ligand isolated from Scutellaria baicalensis Georgi, with selective antagonistic properties. Author(s): Huen MS, Leung JW, Ng W, Lui WS, Chan MN, Wong JT, Xue H. Source: Biochemical Pharmacology. 2003 July 1; 66(1): 125-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12818372&dopt=Abstract
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6-Chloro-3'-nitroflavone is a potent ligand for the benzodiazepine binding site of the GABA(A) receptor devoid of intrinsic activity. Author(s): Viola H, Wolfman C, Marder M, Goutman JD, Bianchin M, Wasowski C, Calvo DJ, Izquierdo I, Paladini AC, Medina JH. Source: Pharmacology, Biochemistry, and Behavior. 2000 February; 65(2): 313-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10672984&dopt=Abstract
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Adenosine A1 and benzodiazepine receptors and glucose metabolism in the visual structures of rats monocularly deprived by enucleation or eyelid suture at a sensitive period. Author(s): Wang WF, Ishiwata K, Kiyosawa M, Shimada J, Senda M, Mochizuki M. Source: Japanese Journal of Ophthalmology. 2003 March-April; 47(2): 182-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738553&dopt=Abstract
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Anxiolytic effect of wogonin, a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi. Author(s): Hui KM, Huen MS, Wang HY, Zheng H, Sigel E, Baur R, Ren H, Li ZW, Wong JT, Xue H. Source: Biochemical Pharmacology. 2002 November 1; 64(9): 1415-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12392823&dopt=Abstract
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Anxiolytic natural and synthetic flavonoid ligands of the central benzodiazepine receptor have no effect on memory tasks in rats. Author(s): Salgueiro JB, Ardenghi P, Dias M, Ferreira MB, Izquierdo I, Medina JH. Source: Pharmacology, Biochemistry, and Behavior. 1997 December; 58(4): 887-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9408191&dopt=Abstract
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Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects. Author(s): Viola H, Wasowski C, Levi de Stein M, Wolfman C, Silveira R, Dajas F, Medina JH, Paladini AC. Source: Planta Medica. 1995 June; 61(3): 213-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7617761&dopt=Abstract
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Attenuation of benzodiazepine dependence in mice by a tri-substituted benzoflavone moiety of Passiflora incarnata Linneaus: a non-habit forming anxiolytic. Author(s): Dhawan K, Dhawan S, Chhabra S. Source: Journal of Pharmacy & Pharmaceutical Sciences [electronic Resource] : a Publication of the Canadian Society for Pharmaceutical Sciences, Societe Canadienne Des Sciences Pharmaceutiques. 2003 May-August; 6(2): 215-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12935433&dopt=Abstract
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Azirino[1, 2-d][1, 4]benzodiazepine derivatives and related 1,4-benzodiazepines as anticonvulsant agents in DBA/2 mice. Author(s): De Sarro G, Chimirri A, Zappala M, Guisti P, Lipartiti M, De Sarro A. Source: General Pharmacology. 1996 October; 27(7): 1155-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8981061&dopt=Abstract
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Benzodiazepine binding site-interactive flavones from Scutellaria baicalensis root. Author(s): Liao JF, Wang HH, Chen MC, Chen CC, Chen CF. Source: Planta Medica. 1998 August; 64(6): 571-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9776664&dopt=Abstract
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Benzodiazepine receptor agonists modulate thymocyte apoptosis through reduction of the mitochondrial transmembrane potential. Author(s): Tanimoto Y, Onishi Y, Sato Y, Kizaki H. Source: Japanese Journal of Pharmacology. 1999 February; 79(2): 177-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10202853&dopt=Abstract
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Benzodiazepines in the intensive care unit. Author(s): Young CC, Prielipp RC. Source: Critical Care Clinics. 2001 October; 17(4): 843-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11762264&dopt=Abstract
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Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia. Author(s): Wagner J, Wagner ML, Hening WA. Source: The Annals of Pharmacotherapy. 1998 June; 32(6): 680-91. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9640488&dopt=Abstract
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Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal? Author(s): Poyares DR, Guilleminault C, Ohayon MM, Tufik S. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2002 April; 26(3): 539-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11999905&dopt=Abstract
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Comparative anticonvulsant activity of some 2,3-benzodiazepine derivatives in rodents. Author(s): De Sarro G, Ferreri G, Gareri P, Russo E, De Sarro A, Gitto R, Chimirri A. Source: Pharmacology, Biochemistry, and Behavior. 2003 February; 74(3): 595-602. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12543224&dopt=Abstract
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Comparison of anticonvulsive and acute neuroprotective activity of three 2,3benzodiazepine compounds, GYKI 52466, GYKI 53405, and GYKI 53655. Author(s): Szabados T, Gigler G, Gacsalyi I, Gyertyan I, Levay G.
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Source: Brain Research Bulletin. 2001 June; 55(3): 387-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11489346&dopt=Abstract •
Correlates of benzodiazepine abuse in methadone maintenance treatment. A 1 year prospective study in an Israeli clinic. Author(s): Bleich A, Gelkopf M, Schmidt V, Hayward R, Bodner G, Adelson M. Source: Addiction (Abingdon, England). 1999 October; 94(10): 1533-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10790905&dopt=Abstract
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Differential effects of in vitro peroxidation on peripheral- and central-type benzodiazepine receptors. Protection by diverse antioxidants. Author(s): Courtiere A, Molard F, Reybaud J. Source: Biochemical Pharmacology. 1995 November 27; 50(11): 1815-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8615860&dopt=Abstract
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Drug discrimination analysis of partial agonists at the benzodiazepine site. I. Differential effects of U-78875 across training conditions in baboons and rats. Author(s): Ator NA, Griffiths RR. Source: The Journal of Pharmacology and Experimental Therapeutics. 1999 June; 289(3): 1434-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10336537&dopt=Abstract
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Efficacy of kava-kava in the treatment of non-psychotic anxiety, following pretreatment with benzodiazepines. Author(s): Malsch U, Kieser M. Source: Psychopharmacology. 2001 September; 157(3): 277-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11605083&dopt=Abstract
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Endogenous benzodiazepines. Author(s): Baraldi M, Avallone R, Corsi L, Venturini I, Baraldi C, Zeneroli ML. Source: Therapie. 2000 January-February; 55(1): 143-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10860017&dopt=Abstract
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Evaluation of inhibitory effect of diphenhydramine on benzodiazepine dependence in rats. Author(s): Nath C, Patnaik GK, Saxena RC, Gupta MB. Source: Indian J Physiol Pharmacol. 1997 January; 41(1): 42-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10225031&dopt=Abstract
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Extraction and purification from Ceratonia siliqua of compounds acting on central and peripheral benzodiazepine receptors. Author(s): Avallone R, Cosenza F, Farina F, Baraldi C, Baraldi M.
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Source: Fitoterapia. 2002 August; 73(5): 390-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12165334&dopt=Abstract •
Flavonoids from Leptospermum scoparium with affinity to the benzodiazepine receptor characterized by structure activity relationships and in vivo studies of a plant extract. Author(s): Haberlein H, Tschiersch KP, Schafer HL. Source: Pharmazie. 1994 December; 49(12): 912-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7838881&dopt=Abstract
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Furanocoumarins with affinity to brain benzodiazepine receptors in vitro. Author(s): Bergendorff O, Dekermendjian K, Nielsen M, Shan R, Witt R, Ai J, Sterner O. Source: Phytochemistry. 1997 March; 44(6): 1121-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9055449&dopt=Abstract
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High prevalence of benzodiazepine dependence in out-patient users, based on the DSM-III-R and ICD-10 criteria. Author(s): Kan CC, Breteler MH, Zitman FG. Source: Acta Psychiatrica Scandinavica. 1997 August; 96(2): 85-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9272191&dopt=Abstract
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Identification of benzodiazepines in Artemisia dracunculus and Solanum tuberosum rationalizing their endogenous formation in plant tissue. Author(s): Kavvadias D, Abou-Mandour AA, Czygan FC, Beckmann H, Sand P, Riederer P, Schreier P. Source: Biochemical and Biophysical Research Communications. 2000 March 5; 269(1): 290-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10694515&dopt=Abstract
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Influence of benzodiazepines on auditory perception. Author(s): Morand-Villeneuve N, Micheyl C, Gagnieu MC, Lemoine P, Sebert P, Collet L, Veuillet E. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2003 April; 28(4): 778-86. Epub 2002 September 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12655325&dopt=Abstract
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Inhibition of bacteriophage T7 RNA polymerase in vitro transcription by DNAbinding pyrrolo[2,1-c][1,4]benzodiazepines. Author(s): Puvvada MS, Forrow SA, Hartley JA, Stephenson P, Gibson I, Jenkins TC, Thurston DE. Source: Biochemistry. 1997 March 4; 36(9): 2478-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9054552&dopt=Abstract
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Inhibition of benzodiazepine binding in vitro by amentoflavone, a constituent of various species of Hypericum. Author(s): Baureithel KH, Buter KB, Engesser A, Burkard W, Schaffner W. Source: Pharmaceutica Acta Helvetiae. 1997 June; 72(3): 153-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9204773&dopt=Abstract
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Interaction of flavones from the roots of Scutellaria baicalensis with the benzodiazepine site. Author(s): Hui KM, Wang XH, Xue H. Source: Planta Medica. 2000 February; 66(1): 91-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10705749&dopt=Abstract
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Naturally occurring 2'-hydroxyl-substituted flavonoids as high-affinity benzodiazepine site ligands. Author(s): Huen MS, Hui KM, Leung JW, Sigel E, Baur R, Wong JT, Xue H. Source: Biochemical Pharmacology. 2003 December 15; 66(12): 2397-407. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14637197&dopt=Abstract
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Overview--flavonoids: a new family of benzodiazepine receptor ligands. Author(s): Medina JH, Viola H, Wolfman C, Marder M, Wasowski C, Calvo D, Paladini AC. Source: Neurochemical Research. 1997 April; 22(4): 419-25. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9130252&dopt=Abstract
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Protoporphyrin IX, an endogenous ligand of the peripheral benzodiazepine receptor, potentiates induction of the mitochondrial permeability transition and the killing of cultured hepatocytes by rotenone. Author(s): Pastorino JG, Simbula G, Gilfor E, Hoek JB, Farber JL. Source: The Journal of Biological Chemistry. 1994 December 9; 269(49): 31041-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7983042&dopt=Abstract
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Recent benzodiazepine use in depressed patients: a confound of psychoimmunologic studies? Author(s): Bartlett JA, Andreoli A, Pascual T, Keller SE. Source: Brain, Behavior, and Immunity. 1996 December; 10(4): 380-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9045752&dopt=Abstract
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Role of benzodiazepine-GABAA receptor complex in attenuation of U-50,488Hinduced analgesia and inhibition of tolerance to its analgesia by ginseng total saponin in mice. Author(s): Nemmani KV, Ramarao P.
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Source: Life Sciences. 2002 March 1; 70(15): 1727-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12002518&dopt=Abstract •
Stress, neuropsychiatric disorders and immunological effects exerted by benzodiazepines. Author(s): Covelli V, Maffione AB, Nacci C, Tato E, Jirillo E. Source: Immunopharmacology and Immunotoxicology. 1998 May; 20(2): 199-209. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9653667&dopt=Abstract
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Structure-activity relationships of flavonoids, isolated from Scutellaria baicalensis, binding to benzodiazepine site of GABA(A) receptor complex. Author(s): Wang H, Hui KM, Chen Y, Xu S, Wong JT, Xue H. Source: Planta Medica. 2002 December; 68(12): 1059-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12494329&dopt=Abstract
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The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat. Author(s): Caldji C, Francis D, Sharma S, Plotsky PM, Meaney MJ. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2000 March; 22(3): 219-29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10693149&dopt=Abstract
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Tolerance to anticonvulsant effects of some benzodiazepines in genetically epilepsy prone rats. Author(s): De Sarro G, Di Paola ED, Aguglia U, de Sarro A. Source: Pharmacology, Biochemistry, and Behavior. 1996 September; 55(1): 39-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8870036&dopt=Abstract
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Ventral tegmental area dopamine neurons mediate the shock sensitization of acoustic startle: a potential site of action for benzodiazepine anxiolytics. Author(s): Gifkins A, Greba Q, Kokkinidis L. Source: Behavioral Neuroscience. 2002 October; 116(5): 785-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12369800&dopt=Abstract
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Vigilance impairment after a single dose of benzodiazepines. Author(s): Kozena L, Frantik E, Horvath M. Source: Psychopharmacology. 1995 May; 119(1): 39-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7675948&dopt=Abstract
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
•
AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
•
Chinese Medicine: http://www.newcenturynutrition.com/
•
drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html
•
Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
•
Google: http://directory.google.com/Top/Health/Alternative/
•
Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
•
Open Directory Project: http://dmoz.org/Health/Alternative/
•
HealthGate: http://www.tnp.com/
•
WebMD®Health: http://my.webmd.com/drugs_and_herbs
•
WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
•
Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to benzodiazepines; 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 Alcohol Withdrawal Source: Healthnotes, Inc.; www.healthnotes.com Alcoholism Source: Integrative Medicine Communications; www.drkoop.com Anxiety Source: Healthnotes, Inc.; www.healthnotes.com Anxiety Source: Integrative Medicine Communications; www.drkoop.com Anxiety and Panic Attacks Source: Prima Communications, Inc.www.personalhealthzone.com Chronic Fatigue Syndrome Source: Integrative Medicine Communications; www.drkoop.com
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Dementia Source: Integrative Medicine Communications; www.drkoop.com Epilepsy Source: Healthnotes, Inc.; www.healthnotes.com Fibromyalgia Source: Integrative Medicine Communications; www.drkoop.com Insomnia Source: Healthnotes, Inc.; www.healthnotes.com Insomnia Source: Integrative Medicine Communications; www.drkoop.com Insomnia Source: Prima Communications, Inc.www.personalhealthzone.com Photodermatitis Source: Integrative Medicine Communications; www.drkoop.com Restless Legs Syndrome Source: Healthnotes, Inc.; www.healthnotes.com Senile Dementia Source: Integrative Medicine Communications; www.drkoop.com Sleeplessness Source: Integrative Medicine Communications; www.drkoop.com Stress Source: Integrative Medicine Communications; www.drkoop.com Sunburn Source: Integrative Medicine Communications; www.drkoop.com Vertigo Source: Healthnotes, Inc.; www.healthnotes.com •
Alternative Therapy Herbal Medicine Source: Integrative Medicine Communications; www.drkoop.com
•
Herbs and Supplements Alprazolam Source: Healthnotes, Inc.; www.healthnotes.com Anticonvulsants Source: Healthnotes, Inc.; www.healthnotes.com
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Ava Source: Integrative Medicine Communications; www.drkoop.com Benzodiazepines Source: Healthnotes, Inc.; www.healthnotes.com Benzodiazepines Source: Prima Communications, Inc.www.personalhealthzone.com GABA Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10027,00.html General Anesthetics Source: Healthnotes, Inc.; www.healthnotes.com German Chamomile Alternative names: Matricaria recutita Source: Integrative Medicine Communications; www.drkoop.com Ginkgo Alternative names: Ginkgo biloba Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Humulus Alternative names: Hops; Humulus lupulus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Hydrastis Alternative names: Goldenseal; Hydrastis canadensis L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Kava Alternative names: Piper methysticum Source: Healthnotes, Inc.; www.healthnotes.com Kava Source: Prima Communications, Inc.www.personalhealthzone.com Kava Kava Alternative names: Ava Source: Integrative Medicine Communications; www.drkoop.com Lemon Balm Alternative names: Melissa officinalis Source: Healthnotes, Inc.; www.healthnotes.com
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Linden Alternative names: Tilia spp. Source: Healthnotes, Inc.; www.healthnotes.com Mad-Dog Skullcap Source: Integrative Medicine Communications; www.drkoop.com Matricaria Alternative names: Chamomile; Matricaria chamomilla Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Matricaria Recutita Source: Integrative Medicine Communications; www.drkoop.com Melatonin Source: Integrative Medicine Communications; www.drkoop.com Melatonin Source: Prima Communications, Inc.www.personalhealthzone.com Melissa Source: Prima Communications, Inc.www.personalhealthzone.com Mistletoe Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10109,00.html Oxazepam Source: Healthnotes, Inc.; www.healthnotes.com Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Passiflora Alternative names: Passion Flower; Passiflora alata L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Piper Alternative names: Kava; Piper methysticum Forst.f Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Piper Methysticum Source: Integrative Medicine Communications; www.drkoop.com Scutellaria Lateriflora Alternative names: Skullcap Source: Integrative Medicine Communications; www.drkoop.com
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Skullcap Alternative names: Mad-dog Skullcap Source: Integrative Medicine Communications; www.drkoop.com Triazolam Source: Healthnotes, Inc.; www.healthnotes.com Uncaria Asian Alternative names: Asian species; Uncaria sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Valerian Alternative names: Valeriana officinalis Source: Healthnotes, Inc.; www.healthnotes.com Valerian Alternative names: Valeriana officinalis Source: Integrative Medicine Communications; www.drkoop.com Valerian Source: Prima Communications, Inc.www.personalhealthzone.com Valeriana Alternative names: Valerian; Valeriana officinalis Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Valeriana Officinalis Source: Integrative Medicine Communications; www.drkoop.com Viburnum Alternative names: Cramp Bark, Highbush Cranberry; Viburnum sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Withania Ashwagandha Alternative names: Ashwagandha; Withania somnifera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON BENZODIAZEPINES Overview In this chapter, we will give you a bibliography on recent dissertations relating to benzodiazepines. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “benzodiazepines” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on benzodiazepines, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Benzodiazepines ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to benzodiazepines. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
Anxiety and the Benzodiazepine/GABA-Chloride Ionophore Receptor Complex: Implications for Learned Helplessness, Coping and Behavioral Depression (Librium, Escape Deficit, B-Carboline) by Drugan, Robert Charles, PhD from University of Colorado at Boulder, 1984, 114 pages http://wwwlib.umi.com/dissertations/fullcit/8428645
•
Sex Differences in Patterns of Benzodiazepine Tranquilizer Use: Social Support As an Explanatory Factor (Aging, Sex-Roles) by Smith, Karen Stephanie, PhD from Duke University, 1985, 202 pages http://wwwlib.umi.com/dissertations/fullcit/8610311
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Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. PATENTS ON BENZODIAZEPINES 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 “benzodiazepines” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on benzodiazepines, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Benzodiazepines By performing a patent search focusing on benzodiazepines, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. 8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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The following is an example of the type of information that you can expect to obtain from a patent search on benzodiazepines: •
4-heteroaryl-1,3-benzodiazepines (heteroaryl)benzeneethanamines
and
2-substituted-.alpha.-
Inventor(s): Brucato; Salvatore M. (Carteret, NJ), Martin; Lawrence L. (Lebanon, NJ), Payack; Joseph F. (Somerset, NJ) Assignee(s): Hoechst-roussel Pharmaceuticals Inc. (somerville, Nj) Patent Number: 5,292,760 Date filed: April 22, 1992 Abstract: Novel 4,5-dihydro-4-heteroaryl-3H-1,3-benzodiazepines, intermediates, processes for the preparation thereof, and methods for treating depression, inhibiting convulsions and treating anxiety utilizing compounds and compositions thereof are disclosed. Excerpt(s): (x) Y is loweralkyl or chlorine. As used throughout the specification and appended claims, the term "loweralkyl" shall mean a straight or branched chain hydrocarbon group containing no unsaturation and having from 1 to 5 carbon atoms such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, and the like. The term "cycloalkyl" shall mean a saturated hydrocarbon group possessing at least one carbocyclic ring and having from 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term "loweralkoxy" shall mean a monovalent substituent which consists of a loweralkyl group linked through an ether oxygen and having its free valence bond from the ether oxygen, such as methoxy, ethoxy, isopropoxy, t-butoxy, pentoxy, and the like. The term "aryl" shall mean phenyl or phenyl substituted with one or more chloro, bromo, fluoro, loweralkyl, methoxy, hydroxy, or trifluoromethyl groups. The term "aralkyl" refers to a radical formed by attachment of a loweralkyl function having up to 4 carbon atoms, inclusive to an aryl moiety. The term "alkanoyl" shall mean the residue of an alkyl carboxylic acid (alkanoic acid) having from 1 to 5 carbon atoms formed by the removal of the hydroxy group of the carboxylic acid moiety. Examples of alkanoyl groups include formyl, acetyl, propionyl, butyryl, pentanoyl and the like. The term "loweralkenyl" shall mean a saturated hydrocarbon group of 1 to 5 carbon atoms having one or more carbon-carbon double bonds, and the term "alkynyl" shall mean a hydrocarbon group of 1 to 5 carbon atoms having one or more carbon-carbon triple bonds. As shown by Reaction Scheme A, Formula III compounds wherein R.sup.3 is amino, R.sup.5 is hydrogen and R.sup.1 is loweralkyl or aralkyl are produced by reacting a N-(2-methylphenyl)-2,2dimethylpropanamide 1, via the corresponding dilithium adduct 2, with a heteroaryl carboxaldehyde imine 3 to produce a heteroaryl-substituted intermediate 4, hydrolysis of which yields the corresponding diamine 5. Web site: http://www.delphion.com/details?pn=US05292760__
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•
4-phenyl-1,3-benzodiazepines and 2-amino-.alpha.-phenylphenethylamines treating convulsions and protecting neurons
for
Inventor(s): Crichlow; Charles A. (Stockton, CA), Martin; Lawrence L. (Lebanon, NJ), Worm; Manfred (Wiesbaden-Naurod, CA) Assignee(s): Hoechst-roussel Pharmaceuticals Incorporated (somerville, Nj) Patent Number: 5,260,339 Date filed: October 8, 1992 Abstract: Novel 4-phenyl-1,3-benzodiazepines and 2-amino-.alpha.phenylphenethylamines, novel intermediates thereof, and methods of preparing same are described. These benzodiazepines are useful as antidepressants, analgetics and anticonvulsants. The 2-amino-.alpha.-phenylphenethylamines are useful as anticonvulsant and neuroprotective agents. Excerpt(s): Preferred compounds of the present invention are those in which R and R.sub.1 are alkyl of from 1 to 5 carbon atoms. Particularly preferred compounds are those wherein R is methyl or ethyl and R.sub.1 is methyl. In the above intermediates, anticonvulsants and neuron protectors, i.e., the phenethylamines and the corresponding acyl derivatives thereof, preferred compounds are those in which R.sub.1 is alkyl of from 1 to 5 carbon atoms. Particularly preferred compounds are those in which R.sub.1 is methyl. The physiologically acceptable salts of the present invention are acid addition salts which may be prepared from inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as from organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic. Web site: http://www.delphion.com/details?pn=US05260339__ •
Adenosinergic agonist containing pharmaceutical composition with analgesic activity Inventor(s): Camborde; Francoise (Rueil Malmaison, FR), Cloarec; Alix (Triel Sur Siene, FR), Gungor; Timur (Brandon Farms, NJ), Teulon; Jean-Marie (La Celle Saint Cloud, FR) Assignee(s): Laboratoires Upsa (agen, Fr) Patent Number: 6,015,797 Date filed: December 7, 1998 Abstract: The object of the present invention is a pharmaceutical composition, which comprises, as active principle, a combination of an adenosinergic agonist and a compound selected from the opiates, benzodiazepines and NMDA antagonists. Excerpt(s): The object of the present invention is a novel pharmaceutical combination which especially finds application in the treatment of various types of pain which can be of inflammatory origin or neuropathic origin. More specifically, the invention relates to a pharmaceutical composition which comprises, as active principle, a combination of an adenosinergic agonist and a compound selected from the opiates, benzodiazepines and NMDA antagonists. It is known that adenosine is an endogenous molecule which participates in the regulation of many functions, in the central nervous system and peripherally, via the activation of specific receptors (Daly, I. W. in: T. W. Stone (Ed.) Purines Pharmacological and Physiological Roles, Macmillan, London. 1985: pp. 5-15). The inhibitory role of adenosine in the modulation of the transmission of the pain message is now well-establishcd (Sawynok, J., M. I. Sweeney. Neurosci. 1989;(32):557569).
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Web site: http://www.delphion.com/details?pn=US06015797__ •
Amino-ketone solid support templates Inventor(s): Mjalli; Adnan M. M. (7393 Wolfspring Trace, Louisville, KY 40241) Assignee(s): None Reported Patent Number: 6,117,940 Date filed: October 16, 1998 Abstract: A solid support template for solid phase synthesis of amino group containing compounds is provided that comprises amino-ketone core compounds of the general formula:A-L-NH(CR.sub.1 R.sub.2).sub.n COR.sub.3linked to appropriate insoluble substrates to create solid support templates having the general formula:Polymer-X-LNH(CR.sub.1 R.sub.2).sub.n COR.sub.3where L is a multifunctional monomer carrying a first functional group that forms a covalent bond with X and a second functional group comprising an amine and L, R.sub.1, R.sub.2 and R.sub.3 are selected from the group consisting of alkyl, alkyl-aryl, alkenyl, alkenyl-aryl groups having up to 6 carbon atoms and substituted forms thereof. The amino-ketone templates are useful for the solid phase synthesis of compounds such as the imidazoles, benzodiazepines, pyrazines, and steroid mimics. Excerpt(s): The present invention relates to amino-ketone templates linked to insoluble materials and methods for producing products generated through a plurality of chemical reactions utilizing amino-ketone templates on solid support. The use of solid phase synthesis techniques for the synthesis of polypeptides and oligonucleotides is well known in the art. More recently, the use of solid phase techniques for the synthesis of small organic molecules has become a major focus of research. Of prime importance has been the ability of solid phase techniques to be automated, with an attendant increase in compound throughput and efficiency in research. This has been exploited with great vigor in the area of pharmaceutical research where it has been estimated that 10,000 compounds must be synthesized and tested in order to find one new drug (Science, 259, 1564, 1993). The focus on combinatorial chemistry techniques to increase compound throughput has now become almost universal in the pharmaceutical and agricultural industries. An additional aspect relates to the chemical diversity of the compound stocks that are available for screening in pharmaceutical companies in the search for new lead structures. These have tended to be limited to the classes of compounds previously investigated through medicinal chemical techniques within each company. Therefore the availability of new classes of molecules for screening has become a major need. Web site: http://www.delphion.com/details?pn=US06117940__
•
Benzodiazepine treatment Inventor(s): Snorrason; Ernir (Stigahlid 80, 105 Reykjav ik, IS) Assignee(s): None Reported Patent Number: 5,589,475 Date filed: August 22, 1994
Patents 93
Abstract: The use of a pharmaceutically acceptable cholinesterase inhibitor or a prodrug therefor for counteracting the sedative, hypnotic or respiratory depressive effects of benzodiazepines, substantially without interfering with the anxiolytic, antipsychotic, anticonvulsant, and muscle relaxant activity of benzodiazepines. When benzodiazepines are used for treatment of diseases where the sedative, hypnotic or respiratory depressive effects are undesirable, such as diseases selected from the group consisting of anxiety, anxiety neurosis, anxiety reactions, panic reactions, schizophrenia, affective or schizoaffective type schizophrenia, borderline psychosis, agitating endogene depressions, hyperactivity in children, and muscle spasms, the cholinesterase inhibitor of the present invention is particularly effective. The invention also is directed to use a pharmaceutically acceptable cholinesterase inhibitor or a prodrug therefor for the treatment of schizophrenia, in particular affective or schizoaffective type schizophrenia. The acetyl cholinesterase is preferably one that acts substantially selectively at nicotinic receptor sites, and which has selectively for acetyl cholinesterase opposed to butyryl cholinesterase, e.g., galanthamine or a galanthamine derivative. Excerpt(s): The present invention relates to the use of cholinesterase inhibitors, such as galanthamine, for the preparation of a pharamceutical composition for counteracting the sedative or hypnotic or respiratory depressive effects of benzodiazepines, substantially without interfering with the anxiolytic, antipsychotic, anticonvulsant, and muscle relaxant activity of benzodiazepines. Expressed in another manner, the invention relates to a method for counteracting the sedative, hypnotic or respiratory depressive effects of benzodiazepines, substantially without interfering with the above-mentioned anxiolytic and other desired properties of benzodiazepines, comprising administering, to a patient in subjected to benzodiazepine therapy, that is, a patient who receives benzodiazepine, an effective amount of a pharmaceutically acceptable cholinesterase inhibitor. An aspect of the invention relates to the treatment of schizophrenia, in particular affective or schizoaffective type of schizophrenia, by administering, to a patient suffering from such a condition, an effective amount of a cholinesterase inhibitor, such as galanthamine. Web site: http://www.delphion.com/details?pn=US05589475__ •
CCK or gastrin modulating 5-heterocyclic-1, 5 benzodiazepines Inventor(s): Aquino; Christopher Joseph (Long Beach, WA), Sugg; Elizabeth Ellen (Durham, NC), Szewczyk; Jerzy Ryszard (Chapel Hill, NC) Assignee(s): Glaxo Wellcome Inc. (rtp, Nc) Patent Number: 5,739,129 Date filed: October 11, 1996 Abstract: Compounds of general formula (I) and physiologically salts thereof, processes for their preparation and their use as modulators of the effects of gastrin and CCK. Excerpt(s): This invention relates to 5-heterocyclo-1,5-benzodiazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particulary, it relates to compounds which exhibit agonist activity for CCK-A receptors thereby enabling them to modulate the hormones gastrin and cholecystokinin (CCK) in mammals. Cholecystokinins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system. Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxyl terminal octapeptide, CCK-8 (also a
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naturally occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14- amino acid forms, with the minimum active sequence being the Cterminal tetrapeptide, Trp-Met-Asp-Phe-NH.sub.2 (CCK-4) which is the common structural element shared by both CCK and gastrin. The CCK-A receptor, commonly referred to as the "peripheral-type" receptor, is primarily found in the pancreas, gallbladder, lieure, pyloric sphincter and on vagal afferent nerve fibers. Type-A CCK receptors are also found in the brain in discrete regions and serve to provide a number of CNS effects. Due to the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species, considerable interest has been generated toward the development of new substances which function as Type-A receptor-selective CCK agonists in order to serve as anorectic agents. Web site: http://www.delphion.com/details?pn=US05739129__ •
Compositions and methods for treating wrinkles and/or fine lines of the skin Inventor(s): Breton; Lionel (Versailles, FR), De Lacharriere; Olivier (Paris, FR) Assignee(s): L'oreal (paris, Fr) Patent Number: 5,869,068 Date filed: October 2, 1995 Abstract: Compositions which contain an agonist substance of one or a number of receptors associated with a chlorine channel are useful for slackening and/or relaxing cutaneous tissue, and in particular for the purpose of treating wrinkles and fine lines of the skin. Such compositions can be administered topically or by injection. Preferred agonists include glycine, serine, taurine,.beta.-alanine, N-(benzyloxycarbonyl)glycine (Z-glycine), gamma-aminobutyric acid (GABA), isoguvacine, isonipecotic acid, 4,5,6,7tetrahydroisoxazolo›5,4-c!pyrid-3(2H)-one, benzodiazepines, steroids, and barbiturates. The composition can additionally contain a retinoid and/or a hydroxy acid. Excerpt(s): The present invention relates to the use of substances which are agonists of a receptor associated with a chlorine channel in a cosmetic and/or dermatological composition, in particular for the purpose of treating wrinkles and fine lines of the skin, and to cosmetic and/or dermatological compositions which contain such a substance. Women, and indeed even men, are currently inclined to wish to appear young for as long as possible and consequently are looking to soften the signs of ageing of the skin, which are reflected in particular by wrinkles and fine lines. In this respect, advertising and fashion present products intended to retain a radiant and wrinkle-free skin, these being the signs of young skin, for as long as possible, all the more so since physical appearance has an effect on mental attitude and/or on morale. It is consequently important to feel physically and spiritually young. Until now, wrinkles and fine lines have been treated using cosmetic products containing active agents which act on the skin, for example by moisturizing it or by improving its cell renewal or alternatively by promoting the synthesis of collagen of which the cutaneous tissue is composed. However, to date, it is not known to act on wrinkles by involving the muscle components present in the skin. Web site: http://www.delphion.com/details?pn=US05869068__
Patents 95
•
Heterocyclic carboxamide compounds effective in the treatment of drug abuse Inventor(s): Bohme; Andrees (Paris, FR), Dubroeucq; Marie-Christine (Enghein-lesBains, FR), Fratta; Walter (Cagliari, IT), Guyon; Claude (Saint-Maur-des-Fosses, FR), Imperato; Assunta (Paris, FR), Manfre; Franco (Limeil-Brevannes, FR) Assignee(s): Rhone-poulenc Rorer S.a. (antony, Fr) Patent Number: 6,150,387 Date filed: August 7, 1998 Abstract: This invention relates to the use of heterocyclic carboxamide compounds for preventing or reducing self-administration, by a human or animal patient, of a drug or a substance capable of giving rise to pharmacomania or to overuse. The preferred types of drugs or substances are nicotine, caffeine, benzodiazepines, narcotics, and hallucinogens. Excerpt(s): This application is a 371 of PCT/FR97/00209, filed Feb. 3, 1997. Today, drug dependence, pharmacomania and, more generally, the abuse of legal or banned substances is a major problem in the world, and products enabling these behaviour patterns to be decreased or abolished have become necessary. Compounds enabling drug abuse or the abuse of substances giving rise to pharmacomania or to overuse, that is to say compounds which decrease or abolish the taking of these products, have now been found, and this forms the subject of the present application. Among these drugs and substances giving rise to pharmacomania or to overuse, there may be mentioned nicotine, benzodiazepines, caffeine, narcotics such as amphetamines, cocaine, cannabinoids, morphine and derivatives and opioids, hallucinogens such as LSD, ecstasy, mescaline and psylocibin and, in general, all compounds whose abuse poses a public health problem. Web site: http://www.delphion.com/details?pn=US06150387__
•
Method for the treatment of schizophrenia Inventor(s): Snorrason; Ernir (Stigahlid 80, 105 Reykjav ik, IS) Assignee(s): None Reported Patent Number: 5,633,238 Date filed: June 5, 1995 Abstract: The present invention relates to the use of cholinesterase inhibitors, such as galanthamine, for the preparation of a pharmaceutical composition for counteracting the sedative or hypnotic or respiratory depressive effects of benzodiazepines, substantially without interfering with the anxiolytic, antipsychotic, anticonvulsant, and muscle relaxant activity of benzodiazepines.Expressed in another manner, the invention relates to a method for counteracting the sedative, hypnotic or respiratory depressive effects of benzodiazepines, substantially without interfering with the above-mentioned anxiolytic and other desired properties of benzodiazepines, comprising administering, to a patient in subjected to benzodiazepine therapy, that is, a patient who receives benzodiazepine, an effective amount of a pharmaceutically acceptable cholinesterase inhibitor.An aspect of the invention relates to the treatment of schizophrenia, in particular affective or schizoaffective type of schizophrenia, by administering, to a patient suffering from such a condition, an effective amount of a cholinesterase inhibitor, such as galanthamine.
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Excerpt(s): Benzodiazepines have been used for several decades, but have become increasingly popular because of their effects and their low toxicity compared to other drugs of similar actions. antipsychotic. Thus, the benzodiazepines are relevant as drugs in connection with a broad spectrum of diseases. Web site: http://www.delphion.com/details?pn=US05633238__ •
Method for treatment of recurrent paroxysmal neuropsychiatric Inventor(s): Daniel; David G. (6408-P Seven Corners Pl., Falls Church, VA 22044) Assignee(s): None Reported Patent Number: 5,457,100 Date filed: June 3, 1993 Abstract: Recurrent paroxysmal neuropsychiatric disorders selected from (1) acute dystonic reactions, (2) seizure disorders and (3) panic disorders may be treated by means of aerosol inhalation of (1) anticholinergic and/or antihistaminic agents, (2) benzodiazepines and (3) antihistaminic agents, respectively. Excerpt(s): This invention relates to methods for the treatment of recurrent paroxysmal neuropsychiatric disorders of rapid onset and brief duration, such as acute dystonic reactions, seizure disorder and panic disorder. Acute Dystonic Reactions are a common, frightening, extremely uncomfortable and potentially fatal side effect of neuroleptic medications. These reactions are characterized by acute muscular rigidity and cramping (sometimes of sufficient severity to dislocate joints, obscure vision, or to obstruct the airway). Neuroleptic medications are widely used throughout the world and are the mainstay of pharmacologic treatment of schizophrenia, mood disorders with psychotic components, Tourette's syndrome, agitated, explosive behavior, intractable hiccups, and intractable vomiting. Of patients taking neuroleptic medication, 11.9% will experience acute dystonic reactions. Panic Disorder is a psychiatric syndrome characterized by extreme anxiety or terror which is accompanied by severe muscle tension and autonomic hyperactivity. It occurs in discrete episodes of abrupt onset ("panic attacks") and is a recurrent condition. Web site: http://www.delphion.com/details?pn=US05457100__
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Method of monitoring therapeutic agent consumption Inventor(s): Kell; Michael (Atlanta, GA) Assignee(s): Private Clinic Laboratories, Inc. (atlanta, Ga) Patent Number: 5,776,783 Date filed: September 17, 1996 Abstract: Quantitative compliance markers and associated methods for monitoring patient compliance with medication prescriptions associated with compliance markers have been found to eliminate the need for specific quantitative relationships for each new drug tested. Such compliance markers and methods for monitoring patient compliance utilize pharmacologically inert substances, namely the weak acids benzodiazepines, or non-metabolizable substances in association with an underlying drug at a measurable dosage, so as to correlate compliance marker concentration with
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underlying medication concentration to determine amount of actual medication ingested. Excerpt(s): The present invention relates generally to monitoring patient compliance with medication prescriptions. More particularly, the invention relates to compositions and methods for monitoring patient compliance using quantitative compliance markers in association with prescribed medications. In the fields of human and animal medicine, psychiatry and animal husbandry, insuring that the patient or animal ingests the proper amount of medicine, hormone or nutrient to produce a desired effect is a commonly encountered problem. For example, human research has demonstrated that patients typically ingest only half the amount of medications prescribed by their physicians. Thus, patients placed on prescribed medication treatment programs are often monitored. Both subjective and objective methods are used to identify bothersome symptoms and to implement necessary changes during the course of treatment. Monitoring generally continues for as long as treatment is provided. For example, the Hamilton Anxiety Scale can be used to quantify the amount of anxiety remaining as treatment proceeds for an anxiety-related condition. If the level of residual anxiety decreases significantly, say from the proper prescription of a benzodiazepine drug, like diazepam, then the physician and patient can be assured that treatment is efficacious and should be continued. Preferably both quantitative and analytical methods should be used to monitor the patient on a repetitive basis to insure that the patient is indeed ingesting the prescribed amounts of medication. Currently, the most common method of monitoring patients for medication compliance is clinical observation which involves individual counseling and close personal supervision by physicians. Physicians observe physiological signs and symptoms such as intoxication, drug withdrawal typically occurring for benzodiazepines, barbiturates and opioids, or residual signs of illness such as tremor in anxiety, sighing in depression, and nociception in pain syndromes. Physicians also listen to patient complaints regarding degree of pain relief and evaluate psychological changes over time. This method however is time consuming, expensive and highly subjective. Needless to say, it is fraught with potential errors. Web site: http://www.delphion.com/details?pn=US05776783__ •
Process for the aminocarbonylation of benzazepines and benzodiazepines Inventor(s): Etridge; Stephen K. (Maidstone, GB), Hayes; Jerome (Tunbridge Wells, GB), Walsgrove; Timothy Charles (Tunbridge Wells, GB), Wells; Andrew S. (Tunbridge Wells, GB) Assignee(s): Smithkline Beecham Plc (brentford, Gb) Patent Number: 6,225,465 Date filed: May 14, 1999 Abstract: A new process for preparing substituted 7-aminocarbonyl-3-oxo-2,3,4,5tetrahydro-1H-1,4-benzodiazepines is disclosed. Excerpt(s): This invention relates to processes and intermediates for preparing pharmaceutically active compounds. More, particularly, this invention relate to the aminocarbonylation of benzazepines and benzodiazepines. Tetraydro-1-benzazepines and tetrahydro-1,4-benzodiazepines form the core structure of a variety of pharmaceutically useful compounds. In particular, WO 93/00095 (PCT/US92/05463) and WO 94/14776 (PCT/US93/12436) disclose 7-aminocarbonyl tetrahydro-1benzazepines and tetrahydro-1,4-benzodiazepines which are reported, to be inhibitors
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of the fibrinogen and vitronectin receptors and useful as inhibitors of platelet aggregation, osteoporosis, angiogenesis and cancer metastasis. Methods to prepare such compounds typically employ a trisubstituted phenyl derivative as a starting material. The trisubstituted phenyl derivative incorporates two substituents to form the azepine ring, and a third substituent to introduce the 7-carbonyl substituent. Such starting materials may be difficult and costly to obtain, and may limit the chemistry which may be employed to form the azepine ring,. Prior processes generally introduce the aminocarbonyl group into the molecule via a 7-carboxyl group which is coupled to an amino group by conventional methods for forming amide bonds. Methods disclosed in WO 93/00095 and WO 94/14776 are exemplary. Web site: http://www.delphion.com/details?pn=US06225465__ •
Rapid opioid detoxification Inventor(s): Gooberman; Lance L. (35 Gill Rd., Haddonfield, NJ 08033) Assignee(s): None Reported Patent Number: 6,004,962 Date filed: September 11, 1995 Abstract: Rapid opioid detoxification procedures are provided which include sedating a patient with a rapid-acting, safely reversible intravenous anesthetic agent having a very short full recovery period. The patient is administered an opioid antagonist while sedated and can be revived to an ambulatory condition within eight hours of initiating therapy. The described methods for detoxification can be used with dually-addicted patients who have abused opiates, such as heroin, as well as benzodiazepines. Even with these dually-addicted patients, the process is completely reversible early on in the procedure if any adverse complications arise. Excerpt(s): This invention relates to methods of rapidly detoxifying opioid addicts so as to relieve conscious symptoms, and more particularly, to methods of detoxification employing sedation and a narcotic antagonist while permitting the patient to be ambulatory within eight hours of beginning treatment. Heroin addiction is a growing healthcare problem in the United States. The United States Department of Health and Human Services' Substance Abuse Branch issued a report in December of 1994 stating that the number of emergency department visits directly related to heroin use rose from 48,000 in 1992 to 63,000 in 1993, a 31% increase. The rate of heroin-related episodes per 100,000 people rose 81%, from 15 to 28 per 100,000, between 1990 and 1993. Upon breaking down the heroin-using population into ethnic groups and age groups, it has been demonstrated that all subsets have increased rates of use for this time period. Human opiate detoxification has been in use for some time. More than 31,000 individuals of the Empire Blue Cross and Blue Shield subscriber base in New York were hospitalized at least once for opiate dependency between 1982 and 1992. The majority of these individuals were working adults, and their principal reason for hospitalization was addiction treatment. Drug detoxification accounted for 96% of the admissions, and the length of stay ranged between five and ten days. Web site: http://www.delphion.com/details?pn=US06004962__
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Reagants and methods for immobilized polymer synthesis and display Inventor(s): Holmes; Christopher P. (Sunnyvale, CA) Assignee(s): Affymax Technologies N.v (greenford, Gb) Patent Number: 5,679,773 Date filed: January 17, 1995 Abstract: Compounds and methods for solid phase synthesis of organic molecules including peptides, oligonucleotides, benzodiazepines,.beta.-turn mimetics, and prostaglandins. The present invention provides new reagents in the form of linking groups and resins and substrates having attached linking groups which are useful in solid phase synthesis of high density arrays of organic molecules. The invention also provides methods which increase yields of various organic synthesis strategies. Excerpt(s): The present invention relates to the field of solid phase polymer synthesis. More specifically, the invention provides methods and reagents for solid phase synthesis of oligomer arrays which may be used, for example, in screening studies for determination of binding affinity. The synthesis of biological polymers such as peptides and oligonucleotides has been evolving in dramatic fashion from the earliest stages of solution synthesis to solid phase synthesis of a single polymer to the more recent preparations of libraries having large numbers of diverse oligonucleotide sequences on a single solid support or chip. The evolution of solid phase synthesis of biological polymers began with the early "Merrifield" solid phase peptide synthesis, described in Merrifield, J. Am. Chem. Soc. 85:2149-2154 (1963), incorporated herein by reference for all purposes. Solid-phase synthesis techniques have also been provided for the synthesis of several peptide sequences on, for example, a number of "pins." See e.g., Geysen et al., J. Immun. Meth. 102:259-274 (1987), incorporated herein by reference for all purposes. Other solid-phase techniques involve, for example, synthesis of various peptide sequences on different cellulose disks supported in a column. See Frank and Doting, Tetrahedron 44:6031-6040 (1988), incorporated herein by reference for all purposes. Still other solid-phase techniques are described in U.S. Pat. No. 4,728,502 issued to Hamill and WO 90/00626 (Beattie, inventor). Web site: http://www.delphion.com/details?pn=US05679773__
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Reductive alkylation of secondary amines with hydrosilane Inventor(s): Chen; Bang-Chi (Plainsboro, NJ), Guo; Peng (Lawrenceville, NJ), Sundeen; Joseph E. (Yardley, PA) Assignee(s): Bristol-myers Squibb Company (princeton, Nj) Patent Number: 6,100,395 Date filed: January 10, 2000 Abstract: A novel process for the production of tertiary amines by reductive alkylation of second amine using hydrosilane and a Lewis acid is disclosed. The novel process has applications in the preparation of imidazole-containing benzodiazepines, inhibitors of farnesyl protein transferase. Excerpt(s): The present invention concerns a new process for the reductive alkylation of secondary amines using hydrosilane with applications to the preparation of imidazolecontaining benzodiazepines, inhibitors of farnesyl protein transferase which find utility in the treatment of a variety of cancers and other diseases (Ding, C. Z.; Hunt, J. T.; Kim,
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S.-h.; Mitt, T.; Bhide, R.; Leftheris, K. WO 9730992; Chem. Abstr. 1998,127, 278213). Many methods have been previously reported for the reductive alkylation of secondary amines with carbonyl compounds in the presence of a reducing agent. The reducing agent includes: zinc (Lockemann, G. DE 503113; Chem. Abstr. 1931, 25, 522), H.sub.2 /Pd(or Pt, Ni) (Emerson, W. S. Org. React. 1948, 4,174; Schaus, J. M.; Huser, D. L.; Titus, R. D. Synth. Commun. 1990, 20, 3553), selenophenol (Fujimori, K.; Yoshimoto, H.; Oae, S. Tetrahedron Lett. 1980, 21, 3385), NaBH.sub.4 (Verardo, G.; Giumanini, A. G.; Strazzolini, P. Synth. Commun. 1994, 24, 609), and NaCNBH.sub.3 (Lee, M.; Garbiras, B. J. Synth. Commun. 1994, 24, 3129). All these reducing agents suffer one or more drawbacks. They are either toxic such as selenophenol and NaCNBH.sub.3, or are not selective such as zinc, H.sub.2)Pd(or Pt, Ni) and NaBH.sub.4 since a number of other reducible groups could be affected by these reagents. NaBH(OAc).sub.3 was subsequently introduced to address these problems (Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996,61, 3849) and this reagent was used in the preparation of the aforementioned imidazole-containing benzodiazepine compounds (Ding, C. Z.; Hunt, J. T.; Kim, S.-h.; Mitt, T.; Bhide, R.; Leftheris, K., WO 9730992; Chem. Abstr. 1998, 127, 278213). Although the desired products were obtained from 1 H-benzodiazepine starting materials, a large excess of aldehyde was required for a satisfactory conversion. In addition, expensive chromatographic separation of products was necessary which rendered this method not amenable to large scale preparation. Reduction of imines preformed from primary anilines and aldehydes to secondary anilines with Et.sub.3 SiH/TFA has been previously reported (Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633; Loim, N. M. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1968,1345). Reduction of the preformed aminal from secondary amine and formaldehyde to give tertiary amine using Et.sub.3 SiH/TFA has also been disclosed (Beulshausen, T.; Groth, U.; Schoellkopf, U. Liebigs Ann. Chem. 1992, 523). However, it remains as a question whether the direct reductive alkylation of a secondary amine with an aldehyde using Et.sub.3 SiH/TFA would work, since it was well documented that aldehydes react readily with Et.sub.3 SiH/TFA to give the corresponding alcohols and even methylenes (Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633; West, C. T.; Donnelly, S. J.; Kooistra, D. A.; Doyle, M. P. J. Org. Chem. 1973, 38, 2675). Web site: http://www.delphion.com/details?pn=US06100395__ •
Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support Inventor(s): Ellman; Jonathan A. (Berkeley, CA) Assignee(s): The Regents of the University of California (oakland, Ca) Patent Number: 5,288,514 Date filed: September 14, 1992 Abstract: Methods, compositions, and devices for synthesis of therapeutically useful compounds. The invention provides a rapid approach for combinatorial synthesis and screening of libraries of derivatives of therapeutically important classes of compounds such as benzodiazepines, prostaglandins and.beta.-turn mimetics. In order to expediently synthesize a combinatorial library of derivatives based upon these core structures, general methodology for the solid phase synthesis of these derivatives is also provided. This disclosure thus also describes an important extension of solid phase synthesis methods to nonpolymeric organic compounds.
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Excerpt(s): The present invention relates to the field of solid phase chemistry. More specifically, in one embodiment the invention provides a method, device, and compositions for solid phase and combinatorial synthesis of organic compounds and, most particularly, therapeutically important classes of compounds such as benzodiazepines, prostaglandins, and B-turn mimetics. Obtaining a better understanding of the important factors in molecular recognition in conjunction with developing potent new therapeutic agents is a major focus of scientific research. Chemical and biological methods have recently been developed for the generation of large combinatorial libraries of peptides and oligonucleotides that are then screened against a specific receptor or enzyme in order to determine the key molecular recognition elements of the biopolymer for that receptor or enzyme. Unfortunately, peptides and oligonucleotides tend to have limited oral activities and rapid clearing times. Therefore, such materials tend to have limited utility as bioavailable therapeutic agents. Virtually any bioavailable organic compound can be accessed by chemical synthesis; however, such organic compounds are still synthesized and evaluated one at a time in many cases, thus dramatically limiting the number of derivatives which can be studied. Web site: http://www.delphion.com/details?pn=US05288514__ •
Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives Inventor(s): Anderson; Benjamin A. (Zionsville, IN), Hansen; Marvin M. (Indianapolis, IN), Varie; David L. (Indianapolis, IN), Vicenzi; Jeffrey T. (Brownsburg, IN), Zmijewski; Milton J. (Carmel, IN) Assignee(s): Eli Lilly and Company (indianapolis, In) Patent Number: 5,665,878 Date filed: March 28, 1995 Abstract: A process for stereoselectively forming N-substituted dihydro-2,3 benzodiazepines which are useful as AMPA receptor antagonists. The process includes an opening reduction step which sets the stereochemistry of the intermediates and the final compounds to the desired enantiomer. The reduction step may be carried out by an enzymatic reduction. Excerpt(s): This invention relates to a novel process for synthesizing certain dihydro-2,3benzodiazepine derivatives, and has special application to a process for producing these compounds in high enantiomeric purity and yields. It also relates to intermediates useful in the process. U.S. Pat. No. 4,835,152 discloses that the compound 1-(4aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaz epine possesses central nervous system effects. R.sup.4 represents hydrogen; a C.sub.1-6 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxyl, amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen(s); as well as a benzoyl, palmitoyl, cyclopropanecarbonyl, C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl group; and the dotted lines represent valence bonds optionally being present, with the proviso that no double bond exists between the N(3) and C(4) atoms when both R.sup.3 and R.sup.4 stand for hydrogen. Web site: http://www.delphion.com/details?pn=US05665878__
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Synthesis of benzodiazepines Inventor(s): Kraus; George A. (Ames, IA) Assignee(s): Iowa State University Research Foundation, Inc. (ames, Ia) Patent Number: 5,466,799 Date filed: August 8, 1994 Abstract: A general method is provided for the synthesis of substituted 2,3-dihydro-5phenyl-1H-1,4-benzodiazepines by the reaction of bis-trifiated-2,5-dihydroxy benzophenones with 1,2-bisaminoethanes, followed by displacement of the 7-trifloxy group. Excerpt(s): Although 5-phenyl-3H-1,4-benzodiazepin-2-(1H)-one can be prepared from 2-aminobenzophenone and glycine ether ester hydrochloride in one step, the synthesis of ring-substituted benzodiazepines requires the use of bis-substituted benzophenones, such as 2-amino-5-chlorobenzophenone, that are both more difficult to obtain and to manipulate. See, for example, U.S. Pat. No. 3,313,815. Thus, a need exists for new syntheses of benzodiazepines that can be readily adapted to the synthesis of a variety of known and novel diazepam analogs. Likewise, starting dihydroxybenzophenone (II) can be readily prepared by the photochemical alpha-addition of a benzaldehyde of formula (R.sub.3)(R.sub.4)ArCHO to a 3,5-, 3,6- or 5,6-disubstituted quinone, by the general procedure of A. M. Felix et al., J. Heterocycl. Chem., 5, 731 (1968). Compounds of formula 1, comprising substituents R.sub.3 -R.sub.6, can be readily prepared by the photochemical reaction of benzaldehydes with benzoquinones, as disclosed by G. A. Kraus et al., J. Org. Chem., 57, 3256 (1992), and references cited therein. Compound 1 is fast reacted with a triflating agent such as N-phenyltrifluoromethanesulfonimide, in the presence of a base such as hydride anion, to yield bis(triflate) 2. Compound 2 is reacted with molar excess of N-methylethylenediamine in an organic solvent such as CH.sub.3 CN to yield 3. N-methylethylenediamine can be replaced with other substituted diamines of general formula R.sub.1 NHCH.sub.2 CH(R.sub.2)NH.sub.2 wherein R.sub.1 and R.sub.2 are as defined above. When R.sub.2 is OY, Y can be an acid labile protecting group such as trialkylsilyl, tetrahydrofuranyl or 1-ethoxyethoxy. Web site: http://www.delphion.com/details?pn=US05466799__
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System for benzodiazepine detection Inventor(s): Binder; Steven R. (Berkeley, CA), King; David L. (Benicia, CA) Assignee(s): Bio-rad Laboratories, Inc. (hercules, Ca) Patent Number: 5,352,585 Date filed: June 29, 1993 Abstract: Biological samples are analyzed for benzodiazepines in a single isocratic analysis using a chromatographic column system containing an immobilized enzyme reactor which cleaves glucuronic acid-conjugated benzodiazepines, an anion exchange column, a hydrophobic cation exchange column and a reverse-phase analytical column. Preferred methods of performing the analysis further involve the use of a hydrophobic cation exchange precolumn prior to the anion exchange column. The system readily lends itself to automation, automatic periodic sampling and benzodiazepine identification and quantification. The system is particularly well adapted to the determination and identification of benzodiazepines in urine samples.
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Excerpt(s): This invention lies in the field of analytical systems and methods for biological fluids such as serum and urine. In particular, the technology to which this invention relates is that of chromatographic systems for automated drug analyses in biological fluids. Benzodiazepines are normally prescribed for therapeutic use, as tranquilizers, muscle relaxants, hypnotics, sedatives, treatments for insomnia, anticonvulsants, and the like. The variety of these drugs and their level of consumption by the public is increasing at a fast rate. They frequently become drugs of abuse, however, and can easily reach toxic levels when administered for purposes other than therapeutic. For this reason, it is frequently necessary to determine the presence, type and amount of benzodiazepines in samples of urine and other biological fluids. (5) the requirement for high levels of technical expertise. Web site: http://www.delphion.com/details?pn=US05352585__ •
Transdermal administration of short or intermediate half-life benzodiazepines Inventor(s): Dunbar; Darth M. (San Mateo, CA), Sharma; Kuldeepak (Mountain View, CA) Assignee(s): Cygnus Therapeutic Systems (redwood City, Ca) Patent Number: 5,225,198 Date filed: August 27, 1991 Abstract: Method and laminated composite for administering short or intermediate halflife benzodiazepines such as alprazolamine or triazolam transdermally to treat conditions such as anxiety in the case of alprazolam and insomnia in the case of triazolam. The composite comprises an impermeable backing layer and a reservoir layer containing the benzodiazepine and a permeation enhancer combined with a solventbased acrylic polymer adhesive with the amounts of benzodiazepine and enhancer being sufficient to cause the benzodiazepine to pass through the skin at a rate in excess of about one.mu.g/cm.sup.2 /hr. Excerpt(s): This invention relates to methods and devices for administering short- and intermediate-acting benzodiazepines, particularly alprazolam and triazolam, transdermally. Alprazolam (8-chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo(4,3-a) (1,4)benzodiazepine) is a short to intermediate half-life benzodiazepine drug. It is sold commercially in the U.S. under the brand name Xanax in the form of tablets for treatment of anxiety, depression, and panic disorders. U.S. Pat. No. 3,987,052 describes the preparation and oral administration of alprazolam. It is given orally in doses of 0.25 to 0.5 mg with a maximum dose up to 4 mg for adults. Therapeutic plasma concentrations are typically in the 17 to 30 ng/ml range. (USP Drug Information for the Health Care Professional, page 595, 10th Ed., 1990.) The pharmacokinetics and pharmacodynamics of alprazolam after oral and intravenous administration are reported in J. Clin. Psychiatry (1983) 44 (8, Sec. 2) and Psychopharmacology (1984) 84:452-456. Triazolam (8-chloro-6-(2-chlorophenyl)-1-methyl-4H-1,2,4-triazolo-(4,3-a)1,4-benzod iazepine is a short half-life benzodiazepine drug. It is sold commercially in the U.S. under the brand name Halcion in the form of oral tablets for treatment of insomnia. It is given orally at does of 125-250.mu.g. Web site: http://www.delphion.com/details?pn=US05225198__
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Patent Applications on Benzodiazepines 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 benzodiazepines: •
5H-2,3-benzodiazepine antagonists of excitatory amino acid receptors Inventor(s): Li, Baoqing; (Collegeville, PA), Maccecchini, Maria-Luisa; (West Chester, PA), Pei, Xue-Feng; (Lansdale, PA) Correspondence: Holland & Knight Llp; Suite 2000; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309; US Patent Application Number: 20020025958 Date filed: June 15, 2001 Abstract: Substituted benzodiazepine compositions are provided which are active as non-NMDA ionotropic excitatory amino acid (EAA) receptor antagonists. The compounds are generally 7- or 8-mono substituted 5H-2,3-benzodiazepines. The compositions are useful for treating disorders associated with excessive activation of the non-NMDA subtype of the ionotropic EAA receptor. The compounds further are useful as testing agents to identify and characterize other compounds for the treatment of these disorders. The compounds are useful therapeutically as sedatives or for the treatment of neurosychopharmacological disorders such as stroke, ischemia and epilepsy. The compositions may be provided in combination with a suitable carrier for oral or parenteral administration. The compounds may be administered orally or parenterally for the treatment of a variety of disorders associated with non-NMDA EEA receptor function. Excerpt(s): This invention relates to mono-substituted 5H-2,3-benzodiazepine compounds useful as antagonists of excitatory amino acid receptors. During the past twenty-five years a great deal of attention has been directed toward the excitatory amino acids (EAA's), glutamate and aspartate, since they are believed to be the neurotransmitters responsible for the fast excitatory transmission in the mammalian central nervous system. The ionotropic EAA receptors are generally sub-classified into NMDA and non-NMDA receptors. These classifications are defined by those receptors which preferentially bind N-methyl-D-aspartate (NMDA) and those that are not responsive to NMDA but responsive to.alpha.-amino-3-hydroxy-5-methyl-4isoxazoleproprionic acid (AMPA) or kainic acid (KA). Tamawa et al, describe 2,3benzodiazepines (Eur. J Pharmacol., 167:193-199, 1989) which inhibit AMPA stimulated currents in neuronal cells. The 2,3-benzodiazepines such as GYKI 52466 and 53655 described by Tamawa are non-competitive AMPA antagonists which bind to a novel modulatory site on the AMPA receptor. Meldrum (Stroke, 23:861, 1992 & Brain Res., 571:115, 1992) has shown that GYKI 52466 is effective in rat models of both global and focal ischemia. GYKI 52466 was effective in a middle cerebral artery occlusion (MCAO) model of ischemia when given either continuously for 2 hours just after occlusion or delayed for one hour. The compounds reduced cortical infarct volumes by 68% and 48% respectively. In another model of neurodegenerative disease, GYKI 52466 was as effective as the glutamate site competitive antagonist NBQX in rat common carotid arteries model of global ischemia. These two animal models suggest that these
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This has been a common practice outside the United States prior to December 2000.
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compounds may be useful for the treatment of stroke and neurodegenerative ischemic conditions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Agonists and antagonists of peripheral-type benzodiazepine receptors Inventor(s): Joly, Alison; (San Mateo, CA), Schreiner, George F.; (Los Altos Hills, CA), Stanton, Lawrence W.; (Redwood City, CA), White, R. Tyler; (Fremont, CA) Correspondence: Knobbe Martens Olson & Bear Llp; 2040 Main Street; Fourteenth Floor; Irvine; CA; 92614; US Patent Application Number: 20030032637 Date filed: December 27, 2001 Abstract: The invention concerns the use of agonists and antagonists of peripheral-type benzodiazepine receptors (PTBR) in the diagnosis and treatment of cardiac hypertrophy and other circulatory conditions. The invention specifically concerns the use of PTBR antagonists in the prevention or treatment of decompensated cardiac hypertrophy and, eventually, heart failure. The invention also concerns the use of PTBR agonists in the management of conditions calling for increased blood flow or cardiac output, including injury or functional compromise of the heart, increased demand for physical exercise, or an acquired or inherited predisposition to cardiac contractile disfunction. Pharmaceutical compositions for the treatment of such conditions and screening methods to identify PTBR agonists and antagonists are also included. Excerpt(s): This is a continuation of U.S. patent application Ser. No. 09/461,780, filed Dec. 15, 1999, now U.S. Pat. No. ______, which claims priority to U.S. Provisional Patent Application No. 60/113,008, filed Dec. 18, 1998, both of which are hereby incorporated by reference. The present invention concerns the use of agonists and antagonists of the peripheral-type benzodiazepine receptors (PTBRs). More particularly, the invention concerns the use of PTBR agonists and antagonists (including PTBR ligands) in the diagnosis and treatment of cardiac hypertrophy and other circulatory conditions. In response to hormonal, physiological, hemodynamic and pathological stimuli, adult ventricular muscle cells can adapt to increased workloads through the activation of a hypertrophic process. This process is characterized by an increase in the contractile protein content of cardiac muscle cells without a proliferative response because the adult cardiomyocyte is terminally differentiated and has lost its ability to divide. Cardiac growth during the hypertrophic process therefore results primarily from an increase in protein content per individual cardiomyocyte, with little or no change in cell number. The acquisition of the cardiac hypertrophic phenotype is in part dependent upon the activation of cardiac muscle gene program. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Benzodiazepine derivatives Inventor(s): Kajigaya, Yuki; (Kawasaki-Shi, JP), Kayahara, Takashi; (Kawasaki-Shi, JP), Nakagawa, Tadakiyo; (Kawasaki-Shi, JP), Sakurai, Kuniya; (Kawasaki-Shi, JP), Takahashi, Mitsuo; (Kawasaki-Shi, JP), Takehana, Shunji; (Kawasaki-Shi, JP), Tashiro, Kazumi; (Kawasaki-Shi, JP), Tokumasu, Munetaka; (Kawasaki-Shi, JP), Yoshida, Kaoru; (Kawasaki-Shi, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030186969 Date filed: March 27, 2003 Abstract: The present invention provides benzodiazepine derivatives of the following formula, analogs thereof and pharmaceutically acceptable salts thereof. The compounds of the present invention have an excellent effect of inhibiting activated bloodcoagulation factor X. These compounds are usable as agents for treating various diseases concerned with the activated blood-coagulation factor X. 1 Excerpt(s): The present invention relates to new benzodiazepine derivatives which can be orally administrated to exhibit a strong anticoagulant effect by reversibly inhibiting activated blood-coagulation factor X; anticoagulants containing them as active ingredients; and agents for preventing or treating diseases caused by thrombi or emboli. These diseases include, for example, cerebrovascular disorders such as cerebral infarction, cerebral stroke, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA) and subarachnoidal hemorrhage (vasospasm); ischemic heart diseases such as acute and chronic myocardial infarction, unstable angina and coronary thrombolysis; pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism; peripheral arterial occlusive disease; deep vein thrombosis; disseminated intravascular coagulation; thrombus formation after an artificial blood vessel-forming operation or an artificial valve substitution; reocclusion and restenosis after a coronary artery bypass grafting; reocclusion and restenosis after a reconstructive operation for the blood circulation such as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary recanalization (PTCR); and thrombus formation in the course of the extracorporeal circulation. As the habit of life is being westernized and people of advanced ages are increasing in Japan, thrombotic and embolismic patients such as those suffering from myocardial infarction, cerebral thrombosis and peripheral thrombosis are increasing in number year by year, and the treatment of patients with these diseases is becoming more and more important in the society. Anticoagulation treatment is included in the internal treatments for the remedy and prevention of thrombosis, like fibrinolytic therapy and antiplatelet therapy. Thrombin inhibitors were developed as thrombus-formation inhibitors in the prior art. However, it has been known that since thrombin not only controls the activation of fibrinogen to form fibrin, which is the last step of the coagulation reaction, but also deeply relates to the activation and aggregation of blood platelets, the inhibition of the action of thrombin causes a danger of causing hemorrhage. In addition, when thrombin inhibitors are orally administered, the bioavailability thereof is low. At present, no thrombin inhibitors which can be orally administered is available on the market. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Calcium salts of 1,5-benzodiazepine derivatives, process for producing the salts and drugs containing the same Inventor(s): Kawase, Nobuo; (Saitama, JP), Maeda, Kiyoto; (Saitama, JP), Miura, Naoyoshi; (Saitama, JP), Murata, Masakazu; (Saitama, JP), Shinozaki, Katsuo; (Saitama, JP), Taguchi, Hiroaki; (Saitama, JP) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20030096809 Date filed: August 15, 2002 Abstract: Provided are calcium salts of a 1,5-benzodiazepine derivative represented by the following formula (I): 1(wherein, R.sup.1 represents a lower alkyl group, R.sup.2 represents a phenyl or cyclohexyl group, and Y represents a single bond or a lower alkylene group); a process for preparing the salts; and drugs containing the same as the active ingredient.The compounds exhibit a potent inhibitory activity against the secretion of gastric acid and potent antagonism against gastrin and/or CCK-B receptor. Excerpt(s): The present invention relates to benzodiazepine derivatives having an important role in a medical field. More specifically, the invention relates to calcium salts of 1,5-benzodiazepine derivatives having a gastrin and/or CCK-B (cholecystokinin-B) receptor antagonism and at the same time having potent gastric acid secretion inhibitory action; preparation processes of the compounds; and drugs containing the compounds as an effective ingredient. Cholecystokinin (CCK) is a gastrointestinal hormone which is produced by and released from duodenal and jejunal mucous membranes, and is known to have actions such as secretion of pancreatic juice, gallbladder constriction, and stimulation of insulin secretion. CCK is also known to be present in the cerebral cortex, hypothalamus, and hippocampus at a high concentration and exhibit actions such as inhibition of eating and hunger, augmentation of memory, and generation of anxiety. Gastrin is a gastrointestinal hormone which is produced by and released from G-cells distributed in the pylorus and is known to exhibit actions such as secretion of gastric acid and constriction of the pylorus and gallbladder. CCK and gastrin, having the same five amino acids in their C-terminals, express actions via receptors. CCK receptors are classified into CCK-A which are peripheral type receptors distributed in the pancreas, gallbladder, and intestines; and CCK-B which are central type receptors distributed in the brain. Since gastrin receptors and CCK-B receptors show similar properties in receptor-binding tests and have high homology, they are often called CCK-B/gastrin receptors. Compounds having antagonism to these receptors, for example, gastrin or CCK-B receptor, are presumed to be useful for prevention or treatment of gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, pancreatitis, Zollinger-Ellison syndrome, vacuolating G-cell hyperplasia, basal-mucous-membrane hyperplasia, cholecystitis, attack of biliary colic, dysmotilities of alimentary canal, irritable bowel syndrome, certain types of tumors, eating disorders, anxiety, panic disorder, depression, schizophrenia, Parkinson's disease, tardive dyskinesia, Gilles de la Tourette syndrome, drug dependence, and drug-withdrawal symptoms. Moreover, the compounds are expected to induce pain relief or to accelerate induction of pain relief by opioid medications (Folia Pharmacologica Japonica, Vol. 106, 171-180 (1995), Drugs of the Future, Vol. 18. 919-931 (1993), American Journal of Physiology, Vol. 269, G628-G646 (1995), American Journal of Physiology, Vol. 259, G184-G190 (1990), European Journal of Pharmacology, 261, 257-263 (1994), Trends in Pharmacological Science, Vol. 15, 65-66 (1994)). As a gastrin receptor antagonist, proglumide is known as a remedy for gastric ulcer and gastritis. Proglumide's affinity with gastrin or CCK-B receptors is however
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very low, and its curative effect is weak. It is reported that some benzodiazepine derivatives such as L-364,718 (devazepide, Japanese Patent Application Laid-Open (kokai) No. 63666/1986) and L-365,260 (Japanese Patent Application Laid-Open (kokai) No. 238069/1988) exhibit CCK-A receptor antagonism or CCK-B receptor antagonism. It is also disclosed that compounds having strong CCK-B receptor antagonism suppress pentagastrin-stimulated secretion of gastric acid (WO 94/438 and Wo 95/18110). Administration in vivo of these compounds however does not always bring about satisfactory effects. In W098/25911 and W099/64403, the present inventors therefore disclosed 1,5-benzodiazepine derivatives having potent gastrin and/or CCK-B receptor antagonism and at the same time, having strong gastric acid secretion inhibitory action. There is however a demand for compounds which have potent gastrin and/or CCK-B receptor antagonism and gastric acid secretion inhibitory action, particularly strong in gastric acid secretion inhibitory action, and are suited for clinical use. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Compositions and methods relating to novel benzodiazepine compounds and targets thereof Inventor(s): Glick, Gary D.; (Ann Arbor, MI), Opipari, Anthony W.; (Ann Arbor, MI) Correspondence: Medlen & Carroll, Llp; 101 Howard Street, Suite 350; San Francisco; CA; 94105; US Patent Application Number: 20030119029 Date filed: August 13, 2002 Excerpt(s): This application is a Continuation in Part of U.S. patent application Ser. No. 09/767,283, filed Jan. 22, 2001, which is a continuation of U.S. patent application Ser. No. 09/700,101, filed Nov. 8, 2000, which is the National entry of PCTUS00/11599 filed Apr. 27, 2000, which claims priority to U.S. Provisional Application Serial No. 60/131,761, filed Apr. 30, 1999, to U.S. Provisional Application Serial No. 60/165,511, filed Nov. 15, 1999, and to U.S. Provisional Application Serial No. 60/191,855, filed Mar. 24, 2000. This application also claims priority to U.S. Provisional Application Serial No. 60/312,560, filed Aug. 15, 2001, to U.S. Provisional Application Serial No. 60/313,689, filed Aug. 20, 2001, and to U.S. Provisional Application Express Mail No.: EV092300423, filed Jul. 18, 2002. Each aforementioned application is specifically incorporated herein by reference in it entirety. The present invention relates to novel chemical compounds, methods for their discovery, and their therapeutic use. In particular, the present invention provides benzodiazepine derivatives and methods of using benzodiazepine derivatives as therapeutic agents to treat a number of conditions associated with the faulty regulation of the processes of programmed cell death, autoimmunity, inflammation, and hyperproliferation, and the like. Multicellular organisms exert precise control over cell number. A balance between cell proliferation and cell death achieves this homeostasis. Cell death occurs in nearly every type of vertebrate cell via necrosis or through a suicidal form of cell death, known as apoptosis. Apoptosis is triggered by a variety of extracellular and intracellular signals that engage a common, genetically programmed death mechanism. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compounds and methods for the treatment of urogenital disorders Inventor(s): Grayson, Stephen; (San Rafael, CA), Mak, Vivien H.W.; (Palo Alto, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20020198136 Date filed: March 6, 2002 Abstract: The present invention provides methods for treating a variety of urogenital disorders, such as, for example, vaginismus, dyspareunia, vulvodynia (including vulvar vestibulitis), interstitial cystitis, nonspecific urethriris (i.e., nonspecific pain and/or burning of the urinary tract) and sexual dysfunctions, such as, for example, female sexual arousal disorders and female sexual orgasmic disorders, using a variety of compounds, including, but not limited to, NO donors, calcium channel blockers, cholinergic modulators,.alpha.-adrenergic receptor antagonists,.beta.-adrenergic receptor agonists, phosphodiesterase inhibitors, cAMP-dependent protein kinase activators (e.g., cAMP mimetics), superoxide scavengers, potassium channel activators, estrogen-like compounds, testosterone-like compounds, benzodiazepines, adrenergic nerve inhibitors, antidiarrheal agents, HMG-CoA reductase inhibitors, smooth muscle relaxants, adenosine receptor modulators, adenylyl cyclase activators, endothelin receptor antagonists, bisphosphonates and cGMP-dependent protein kinase activators (e.g., cGMP mimetics). Excerpt(s): The present application claims priority to U.S. Provisional Pat. Application Nos. 60/273,901, filed Mar. 6, 2001, and 60/334,903, filed Oct. 24, 2001, the teachings of both of which are incorporated herein by reference for all purposes. Urogenital disorders affect a large number of women and can have profound effects on life quality. Although a number of treatments are available for some of the most serious gynecological and urinary tract diseases, many urogenital disorders are still poorly understood. As a consequence, treatments are often nonexistent, inefficient and/or invasive. One example of a relatively rare, yet highly debilitating, urogenital disorder is vaginismus. Vaginismus results from the involuntary spasm of the pelvic muscles surrounding the outer third of the vagina, and interferes with a woman's ability to have a sexual relationship. This disorder is a major cause of unconsummated marriage, and can result in marked distress, interpersonal difficulty, and infertility. In addition, women suffering from vaginismus are sometimes unable to undergo a routine gynecological exam. Typical treatments of vaginismus include, for example, psychological therapy, Kegel exercises, and the use of a plastic dilator to progressively stretch the contracted muscles of the vagina. Although often effective, these treatments are time-consuming and cause high levels of anxiety. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Delivery of benzodiazepines through an inhalation route Inventor(s): Kim, John J.; (San Jose, CA), Rabinowitz, Joshua D.; (Mountain View, CA), Zaffaroni, Alejandro C.; (Atherton, CA) Correspondence: Richard R. Eckman; Morrison & Foerster Llp; 755 Page Mill Road; Palo Alto; CA; 94304-1018; US Patent Application Number: 20030032638 Date filed: May 21, 2002
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Abstract: The present invention relates to the delivery of benzodiazepines through an inhalation route. Specifically, it relates to aerosols containing benzodiazepines that are used in inhalation therapy. In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of a benzodiazepine. In a method aspect of the present invention, a benzodiazepine is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of a benzodiazepine, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. In a kit aspect of the present invention, a kit for delivering a benzodiazepine through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of a benzodiazepine; and, b) a device that forms a benzodiazepine containing aerosol from the composition, for inhalation by the mammal. Excerpt(s): This application claims priority to U.S. provisional application Ser. No. 60/294,203 entitled "Thermal Vapor Delivery of Drugs," filed May 24, 2001, Rabinowitz and Zaffaroni, the entire disclosure of which is hereby incorporated by reference. This application further claims priority to U.S. provisional application Ser. No. 60/317,479 entitled "Aerosol Drug Delivery," filed Sep. 5, 2001, Rabinowitz and Zaffaroni, the entire disclosure of which is hereby incorporated by reference. This application further claims priority to U.S. provisional application Ser. No. 60/345,145 entitled "Delivery of Clonazepam, Flunitrazepam and Flurazepam Through an Inhalation Route," filed Nov. 9, 2001, Kim, the entire disclosure of which is hereby incorporated by reference. The present invention relates to the delivery of benzodiazepines through an inhalation route. Specifically, it relates to aerosols containing benzodiazepines that are used in inhalation therapy. It is desirable to provide a new route of administration for such compositions that rapidly produces peak plasma concentrations of the active ingredient. The provision of such a route is an object of the present invention. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Drug treatment for restless leg syndrome Inventor(s): Brecht, Hans Michael; (Ingelheim, DE) Correspondence: Boehringer Ingelheim Corporation; 900 Ridgebury Road; P. O. Box 368; Ridgefield; CT; 06877; US Patent Application Number: 20010053777 Date filed: August 1, 2001 Abstract: A method for the treatment of Restless Leg Syndrome (RLS), which comprises administering an.alpha.2-agonist and a second agent selected from the group consisting of the dopamine agonists, opioids, benzodiazepines and the combination of L-DOPA plus a decarboxylase inhibitor. Excerpt(s): This application is a division of Ser. No. 09/639,291 filed Aug. 15, 2000. The invention relates to a new combination of active substances for more effective treatment of Restless Leg Syndrome (RLS) consisting of an.alpha.2-agonist and another neuropsychic drug which reduces the symptoms of RLS as a monotherapy. Restless Leg Syndrome is a neurological disorder which manifests itself chiefly as sensory disorders of the legs such as tingling, dragging, tearing, itching, burning, cramp or pain and in those affected triggers an irresistible compulsion to move. Frequently these disorders occur when the affected person is resting. Particularly at night, during sleep, these
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sensory disorders and the consequent compulsive movements lead to restlessness and sleep disorders. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Genes and proteins for the biosynthesis of anthramycin Inventor(s): Farnet, Chris M.; (Outremont, CA), Staffa, Alfredo; (Saint-Laurent, CA) Correspondence: Ywe J. Looper; Ecopia Biosciences INC.; 7290 Frederick-banting; Saintlaurent; QC; H4s 2a1; CA Patent Application Number: 20030077767 Date filed: June 11, 2002 Abstract: Genes and proteins involved in the biosynthesis of benzodiazepines by microorganisms, including the genes and proteins forming the biosynthetic loci for the benzodiazepine anthramycin from Streptomyces refuineus subsp. thermotolerans. The genes and proteins allow direct manipulation of benzodiazepines and related chemical structures via chemical engineering of the enzymes involved in the biosynthesis of anthramycin. Excerpt(s): This application claims benefit under 35 USC.sctn.119 of provisional application U.S. Ser. No. 60/296,744 filed on Jun. 11, 2001 which is hereby incorporated by reference in its entirety for all purposes. The present invention relates to nucleic acids molecules that encode proteins that direct the synthesis of benzodiazepines, and in particular anthramycin. The present invention also is directed to use of DNA to produce compounds exhibiting antibiotic activity based on the anthramycin structures. Precursor feeding studies have established the biosynthetic building blocks for anthramycin (Hurley et al., 1975). The anthranilate moieties of these antibiotics are derived from tryptophan via the kynurenine pathway, with the three antibiotics differing in the pattern of substitution at the aromatic ring (Hurley & Gariola, 1979 Antimicrob. Agents Chemother. 15:42-45). The 2-carbon and 3-carbon proline units of the antibiotics are derived from catabolism of L-tyrosine. The additional carbon atom found in the 3carbon proline unit of anthramycin and sibiromycin is derived from methionine and is absent in the 2-carbon proline unit of tomaymycin. Despite the precursor feeding studies, the genes and proteins forming the biosynthetic locus for producing anthramycin have remained unidentified. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Ginkgolides for inhibition of membrane expression of benzodiazepine receptors Inventor(s): Drieu, Katy; (Paris, FR) Correspondence: Biomeasure, Incorporated; 27 Maple Street; Milford; MA; 01757-3650; US Patent Application Number: 20020006955 Date filed: June 12, 2001 Abstract: Ginkgolides may be used to inhibit the membrane expression of a benzodiazepine receptor in a patient and in treatments to combat excess glucocorticoid production.
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Excerpt(s): The invention relates to the inhibition of membrane expression of benzodiazepine receptors and in particular to the use of ginkgolides for the manufacture of medicaments for such membrane expression inhibition. Studies have been conducted to examine the beneficial effects of extract of the leaves of the gymnosphermus tree ginkgo biloba (e.g., EGb 761) on "antistress" activity by lowering corticosterine levels in stressed rat models. See, Rapin, et al., Gen. Pharmac. 25(5):1009 (1994). EGb 761 had previously been shown to have activity in the cardiovascular system (e.g., reduction of platelet adhesion and thrombi growth), central nervous system (e.g., neuroprotective activity), and neurosensory system (e.g., retinal protection). See, e.g., DeFeudis, et al., Ginkgo Biloba Extract (EGb 761): Pharmaceutical Activities and Clinical Applications (Elsevier, Paris, 1991). It has now been found that ginkgolides are effective at inhibiting membrane expression of benzodiazepine receptors, eg. adrenal benzodiazepine receptors, and that, having this effect, they can be used to inhibit glucocorticoid release. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Method for the production of imidazo-(1,2-C)(2,3)-benzodiazepines and intermediates in the production thereof Inventor(s): Schneider, Matthias; (Berlin, DE), Tilstam, Ulf; (Berlin, DE), Winter, Eric; (Braunschweig, DE) Correspondence: Millen, White, Zelano & Branigan, P.C.; 2200 Clarendon BLVD.; Suite 1400; Arlington; VA; 22201; US Patent Application Number: 20040019041 Date filed: August 21, 2003 Abstract: The invention relates to a method for the preparation of compound of formula (1). The invention further relates to the previously unknown compounds of formulas (5 and 6) as intermediates in the production of benzodiazepines of formula (1). Excerpt(s): n=1, 2 or 3. C.sub.1-C.sub.6-Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Methods for identifying peripheral benzodiazepine receptor binding agents Inventor(s): Sjoberg, Eric Richard; (San Diego, CA), Velicelebi, Gonul; (San Diego, CA) Correspondence: Seed Intellectual Property Law Group Pllc; 701 Fifth Ave; Suite 6300; Seattle; WA; 98104-7092; US Patent Application Number: 20020039746 Date filed: January 16, 2001 Abstract: The invention provides methods for screening for agents that modulate mitochondrial membrane potential. Such agents generally bind to a peripheral benzodiazepine receptor and may be detected by direct binding assays or by indirect or functional assays. Agents identified using the screens provided herein have application in the prevention and treatment of a variety of diseases associated with abnormal mitochondrial function.
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Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/176,180 filed Jan. 14, 2000, which is incorporated herein by reference in its entirety. The invention relates generally to assays for screening for agents that alter mitochondrial function. More specifically, the invention relates to compositions and screening methods for use in identifying agents that bind a peripheral benzodiazepine receptor, including cell lines that constitutively or inducibly overexpress a peripheral benzodiazepine receptor. Mitochondria are organelles that are the main energy source in cells of higher organisms. These organelles provide direct and indirect biochemical regulation of a wide array of cellular respiratory, oxidative and metabolic processes, including metabolic energy production, aerobic respiration and intracellular calcium regulation. For example, mitochondria are the site of electron transport chain (ETC) activity, which drives oxidative phosphorylation to produce metabolic energy in the form of adenosine triphosphate (ATP), and which also underlies a central mitochondrial role in intracellular calcium homeostasis. These processes require the maintenance of a mitochondrial membrane electrochemical potential, and defects in such membrane potential can result in a variety of disorders. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Methods of treating benzodiazepine site (BZD-S) associated syndromes using 2' hydroxyflavonoids Inventor(s): Huen, Shing Yan Michael; (Hong Kong, CN), Hui, Kwok Min; (Hong Kong, CN), Wang, Hongyan; (Liaoning, CN), Xue, Hong; (Hong Kong, CN) Correspondence: Hamilton, Brook, Smith & Reynolds, P.C.; 530 Virginia Road; P.O. Box 9133; Concord; MA; 01742-9133; US Patent Application Number: 20040034092 Date filed: August 19, 2002 Abstract: Methods for preventing or for treating benzodiazepine site (BZD-S) associated syndromes comprising administering 2' hydroxyflavone and flavone derivatives thereof which contain a hydroxyl group at the 2' position to a patient in need thereof in an effective dose. Methods for extracting certain of the compounds from plant material are also described. Excerpt(s): Benzodiazepines (BZDS) which bind to the benzodiazepine site (BZD-S) of the GABA.sub.A receptor are extremely effective anxiolytics, and are among the most widely prescribed psychoactive drugs in current therapeutic use. BZDs, however, also exhibit undesirable side effects including sedative and myorelaxant activity. Treatment with BZDs can also become considerably less effective over time (Woods et al., 1992, Pharmacol. Rev., 44:151-347). Certain flavonoid compounds, for example, 5,7dihydroxyflavone (also known as chrysin) and some chrysin derivatives, also bind to the BZD-S and are known to exhibit central nervous system effects including anticonvulsant effects and anxiolytic effects without also inducing either sedative or myorelaxant effects (U.S. Pat. No. 5,756,538 to Cassels et al. (1998)). Moreover, Scutellaria baicalensis Georgi (commonly known as Huang Qin in Chinese and Ougon in Japanese), an important medicinal herb in traditional Chinese medicine used in the treatment of anxiety, is known to contain chrysin and other naturally-occurring flavonoid compounds. However, most flavonoids do not bind to the BZD-S with an affinity comparable to that of the BZDs. For example, chrysin demonstrates much weaker binding to the BZD-S than does diazepam. In addition, the identification and testing of those flavonoids with optimal binding properties has been hampered by the
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difficulty of preparing some of them in sufficient quantity. Many naturally-occurring flavonoids are present in plant materials only in minimal amounts. Moreover, the synthesis of highly active flavonoid compounds, such as those with a plurality of hydroxyl groups, has been particularly difficult because such compounds tend to form as intermediates in the synthesis of less active compounds, rather than as an end product. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Nonpeptide substituted spirobenzoazepines as vasopressin antagonists Inventor(s): Chen, Robert H.K.; (Belle Mead, NJ), Xiang, Min A.; (Bridgewater, NJ) Correspondence: Audley A. Ciamporcero JR.; Johnson & Johnson; One Johnson & Johnson Plaza; New Brunswick; NJ; 08933-7003; US Patent Application Number: 20030045517 Date filed: July 2, 2001 Abstract: The invention is directed to nonpeptide substituted benzodiazepines of Formula I, 1wherein A, X, n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, a and b are as described in the specification, which are useful as vasopressin receptor antagonists for treating conditions associated with vasopressin receptor activity such as those involving increased vascular resistance and cardiac insufficiency. Pharmaceutical compositions comprising a compound of Formula I and methods of treating conditions such as hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention are also disclosed. Excerpt(s): This application claims priority from U.S. Ser. No. 60/216,220, filed Jul. 5, 2000. This invention relates to novel nonpeptide substituted vasopressin receptor antagonists. More particularly, the compounds of the present invention interrupt the binding of the peptide hormone vasopressin to its receptors and are therefore useful for treating conditions involving increased vascular resistance and cardiac insufficiency. Vasopressin is a nonapeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through the vascular V-1 and renal V-2 receptor subtypes. The functions of vasopressin include contraction of uterine, bladder, and smooth muscle; stimulation of glycogen breakdown in the liver; induction of platelet aggregation; release of corticotropin from the anterior pituitary and stimulation of renal water reabsorption. As a neurotransmitter within the central nervous system (CNS), vasopressin can affect aggressive behavior, sexual behavior, the stress response, social behavior and memory. The V-1a receptor mediates central nervous system effects, contraction of smooth muscle and hepatic glycogenolytic effects of vasopressin, while the V-1b receptor mediates anterior pituitary effects of vasopressin. The V-2 receptor, presumably found only in the kidney, effects the antidiuretic actions of vasopressin via stimulation of adenylate cyclase. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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PERIPHERAL-TYPE BENZODIAZEPINE RECEPTOR: A TOOL FOR DETECTION, DIAGNOSIS, PROGNOSIS, AND TREATMENT OF CANCER Inventor(s): CULTY, MARTINE; (NORTH POTOMAC, MD), PAPADOPOULOS, VASSILIOS; (NORTH POTOMAC, MD) Correspondence: Pillsbury Winthrop, Llp; P.O. Box 10500; Mclean; VA; 22102; US Patent Application Number: 20030157095 Date filed: March 25, 1998 Abstract: The expression and subcellular localization of peripheral-type benzodiazepine receptors (PBR) is shown in this application to correlate with the metastatic potential of cells, and increased cell proliferation. Inhibition of PBR expression, function or stability results in a decrease in cell proliferation. Compositions and methods for regulating and/or monitoring PBR and its expression are useful for the detection, diagnosis, prognosis and treatment of solid tumors, in particular, breast cancer. Excerpt(s): Tumor progression is a multi-step process in which normal cells gradually acquire more malignant phenotypes, including the ability to invade tissues and form metastases, the primary cause of mortality in breast cancer. During this process, the "aberrant" expression of a number of gene products may be the cause or the result of tumorigenesis. Considering that the first step of tumor progression is cell proliferation, it can be proposed that tumorigenesis and malignancy are related to the proliferative potential of tumoral cells. Studies in a number of tumors such as rat brain containing glioma tumors [Richfield, E. K. et al. (1988) Neurology 38:1255-1262], colonic adenocarcinoma and ovarian carcinoma [Katz, Y. et al. (1988) Eur. J. Pharmacol. 148: 483-484 and Katz, Y. et al. (1990) Clinical Sci. 78:155-158] have shown an abundance of peripheral-type benzodiazepine receptors (PBR) compared to normal tissue. All documents cited herein infra and supra are hereby incorporated in their entirety by reference thereto. Moreover, a 12-fold increase in PBR density relative to normal parenchyma, was found in human brain glioma or astrocytoma [Cornu, P. et al. (1992) Acta Neurochir. 119:146-152]. The authors suggested that PBR densities may reflect the proliferative activity of the receptor in these tissues. Recently, the involvement of PBR in cell proliferation was further shown [Neary, J. T. et al. (1995) Brain Research 675:27-30; Miettinen, H. et al. (1995) Cancer Research 55:2691-2695], and its expression in human astrocytic tumors was found to be associated with tumor malignancey and proliferative index [Miettinen, H. et al. supra; Alho, H. (1994) Cell Growth Different. 5:1005-1014]. PBR is an 18-kDa protein discovered as a class of binding sites for benzodiazepines distinct from the GABA neurotransmitter receptor (Papadopoulos, V. (1993) Endocr. Rev. 14:222-240]. PBR are extremely abundant in steroidogenic cells and found primarily on outer mitochondrial membranes [Anholt, R. et al. (1986) J. Biol. Chem. 261:576-583]. PBR is thought to be associated with a multimeric complex composed of the 18-kDa isoquinoline-binding protein and the 34-kDa pore-forming voltage-dependent anion channel protein, preferentially located on the outer/inner mitochondrial membrane contact sites [McEnery, M. W. et al. Proc. Natl. Acad. Sci. U.S.A. 89:3170-3174; Garnier, M. et al. (1994) Mol. Pharmacol. 45:201-211; Papadopoulos, V. et al. (1994) Mol. Cel. Endocr. 104:R5-R9]. Drug ligands of PBR, upon binding to the receptor, simulate steroid synthesis in steroidogenic cells in vitro [Papadopoulos, V. et al. (1990) J. Biol. Chem. 265:3772-3779; Ritta, M. N. et al. (1989) Neuroendocrinology 49: 262-266; Barnea, E. R. et al. (1989) Mol. Cell. Endocr. 64:155-159; Amsterdam, A. and Suh, B. S. (1991) Endocrinology 128:503-510; Yanagibashi, K. et al. (1989) J. Biochem. (Tokyo) 106: 10261029]. Likewise, in vivo studies showed that high affinity PBR ligands increase steroid plasma levels in hypophysectomized rats [Amri, H. et al. (1996) Endocrinology 137:5707-
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5718]. Further in vitro studies on isolated mitochondria provided evidence that PBR ligands, drug ligands, or the endogenous PBR ligand, the polypeptide diazepambinding inhibitor (BDI) [Papadopoulos, V. et al. (1997) Steroids 62:21-28], stimulate pregnenolone formation by increasing the rate of cholesterol transfer from the outer to the inner mitochondrial membrane [Krueger, K. E. and Papadopoulos, V. (1990) J. Biol. Chem. 265:15015-15022; Yanagibashi, K. et al. (1988) Endocrinology 123: 2075-2082; Besman, M. J. et al. (1989) Proc. Natl. Acad. Sci. U.S.A. 86: 4897-4901; Papadopoulos, V. et al. (1991) Endocrinology 129: 1481-1488]. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Pharmaceutical composition and method of modulating cholinergic function in a mammal Inventor(s): Coe, Jotham W.; (Niantic, CT), Sands, Steven B.; (Stonington, CT) Correspondence: Pfizer Inc; 150 East 42nd Street; 5th Floor - Stop 49; New York; NY; 10017-5612; US Patent Application Number: 20030008892 Date filed: March 25, 2002 Abstract: A pharmaceutical composition and method of modulating cholinergic function in a mammal comprising administration of a NRPA compound or a pharmaceutically acceptable salt thereof; and an anti-emetic/anti-nausea agent or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The NRPA compound and the anti-emetic/anti-nausea agent are present in amounts that render the composition effective modulating cholinergic function or in the treatment of a diorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multiinfarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome. The method of using these compositions is also disclosed. Excerpt(s): The present invention relates to pharmaceutical compositions for modulating cholinergic function in a mammal comprising a nicotinic receptor partial agonist compound in combination with an anti-emetic/anti-nausea agent and a pharmaceutically acceptable carrier. The nicotinic receptor partial agonists (NRPAs) included herein are aryl fused azapolycyclic compounds. NRPAs are not limited to those described here. The term NRPA refers to all chemical compounds which bind at neuronal nicotinic acetylcholine specific receptor sites in mammalian tissue and elicit a partial agonist response. A partial agonist response is defined here to mean a partial, or incomplete functional effect in a given functional assay. Additionally, a partial agonist will also exhibit some degree of antagonist activity by its ability to block the action of a
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full agonist (Feldman, R. S., Meyer, J. S. & Quenzer, L. F. Principles of Neuropsychopharmacology, 1997; Sinauer Assoc. Inc.). The present invention may be used to treat mammals (e.g. humans) for inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multiinfarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome with a decrease in the incidence and severity of unwanted side effects such as nausea and/or stomach upset. The present invention also relates to the combination use of NRPAs and anti-emetic/anti-nausea agents resulting in modulation of cholinergic function without nausea. The combination will provide an improved treatment paradigm than NRPAs alone. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Pharmaceutical composition for treatment of acute, chronic pain and/or neuropathic pain and migraines Inventor(s): Coe, Jotham W.; (Niantic, CT), Harrigan, Edmund P.; (Old Lyme, CT), O'Neill, Brian T.; (Old Saybrook, CT), Sands, Steven B.; (Stonington, CT), Watsky, Eric J.; (Stonington, CT) Correspondence: Paul H. Ginsburg; Pfizer Inc; 20th Floor; 235 East 42nd Street; New York; NY; 10017-5755; US Patent Application Number: 20010036943 Date filed: December 18, 2000 Abstract: Pharmaceutical compositions are disclosed for the treatment of acute, chronic and/or neuropathic pain. The pharmaceutical compositions are comprised of a therapeutically effective combination of a nicotine receptor partial agonist and an analgesic agent and a pharmaceutically acceptable carrier. The analgesic agent is selected from opioid analgesics, NMDA antagonists, substance P antagonists, COX 1 and COX 2 inhibitors , tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), capsaicin receptor agonists, anesthetic agents, benzodiazepines, skeletal muscle relaxants, migraine therapeutic agents, anti-convulsants, antihypertensives, anti-arrythmics, antihistamines, steroids, caffeine, and botulinum toxin. The method of using these compounds and a method of treating acute, chronic and/or neuropathic pain and migraine in a mammal including a human is also disclosed. Excerpt(s): The present invention relates to pharmaceutical compositions for the treatment of acute, chronic and/or neuropathic pain and migraine in a mammal (e.g. human) comprising a nicotine receptor partial agonist (NRPA) and analgesic agents, including opioid analgesics, NMDA antagonists, substance P antagonists, COX 1 and COX 2 inhibitors , tricyclic antidepressants (TCA), selective serotonin reuptake
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inhibitors (SSRI), capsaicin receptor agonists, anesthetic agents, benzodiazepines, skeletal muscle relaxants, migraine therapeutic agents, anti-convulsants, antihypertensives, anti-arrythmics, antihistamines, steroids, caffeine, N-type calcium channel antagonists and botulinum toxin. The term NRPA refers to all chemical compounds which bind at neuronal nicotinic acetylcholine specific receptor sites in mammalian tissue and elicit a partial agonist response. A partial agonist response is defined here to mean a partial, or incomplete functional effect in a given functional assay. Additionally, a partial agonist will also exhibit some degree of antagonist activity by its ability to block the action of a full agonist (Feldman, R. S., Meyer, J. S. & Quenzer, L. F. Principles of Neuropsychopharmacology, 1997; Sinauer Assoc. Inc.). The present invention may be used to treat mammals (e.g. humans) for acute, chronic and/or neuropathic pain with a decrease in the severity of unwanted side effects such as causing nausea and/or stomach upset. The invention also relates to aryl fused azapolycylic compounds that bind to neuronal nicotinic acetylcholine specific receptor sites and are useful in modulating cholinergic function and are referred to in WO 9818798-A1, WO 9935131-A1 and WO 9955680-A1. The foregoing applications are owned in common with the present application and are incorporated herein by reference in their entireties. Analgesic agents decrease pain perception. In animal models of pain states, the above compounds inhibit acute pain perception. These compounds also inhibit pain sensitization processes in which the perception of the painfulness of a given stimulus is increased without any change in stimulus intensity. In humans, analgesic agents have also been found to decrease both acute pain perception and sensitization. Opioid analgesic agents, in particular, remain the most effective means of alleviating severe pain across a broad spectrum, including inflammatory as well as neuropathic pain states. However, even though analgesic agents have therapeutic utility in the treatment of pain, there are significant liabilities to the use of analgesic compounds. Specifically, many of these compounds that have been tested in humans can cause potentially serious side effects such as gastrointestinal complications including nausea, emesis, ulcers, and constipation, respiratory depression, and psychological and physical dependence. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Process for the preparation benzodiazepine compounds
of
3,7-disubstituted-2,3,4,5-tetrahydro-1H-1,4-
-
Inventor(s): Bhandaru, Rao S.; (Belle Mead, NJ), Kronenthal, David R.; (Yardley, PA), Mudryk, Boguslaw M.; (East Windsor, NJ), Shi, Zhongping; (West Windsor, NJ) Correspondence: Stephen B. Davis; Bristol-myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20030162965 Date filed: November 12, 2002 Abstract: Methods for the synthesis of benzodiazepine compounds having farnesyl protein transferase inhibitory activity. Excerpt(s): This application claims a benefit of priority based on U.S. provisional application No. 60/350,674, filed Nov. 13, 2001, the entire disclosure of which is herein incorporated by reference. This invention relates to methods for the synthesis of 3,7disubstituted-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine compounds, particularly to methods in which the use of hazardous starting materials and reagents is avoided or minimized. The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a
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signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to guanosine diphosphate (GDP). Upon growth factor receptor activation Ras is induced to exchange GDP for guanosine triphosphate (GTP) and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal. The signal is terminated by the intrinsic GTPase activity of Ras, facilitated by the GTPase activating protein (GAP), which returns the protein to its inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GAP-assisted GTPase activity and transmit an uncontrolled growth stimulatory signal. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Production of tertiary amines by reductive amination Inventor(s): Chen, Chien-Kuang; (Marlboro, NJ), Gao, Zhinong; (Plainsboro, NJ) Correspondence: Stephen B. Davis; Bristol-myers Squibb Company; Patent Department; P O Box 4000; Princeton; NJ; 08543-4000; US Patent Application Number: 20020169313 Date filed: April 11, 2002 Abstract: A process for the production of tertiary amines by reductive amination of carbonyl compounds with secondary amines in the presence of a water scavenger, preferably trifluoroacetic acid anhydride, is disclosed. This process has applications in the preparation of imidazole-containing benzodiazepines, which are inhibitors of farnesyl protein transferase. Excerpt(s): This application claims benefit of U.S. Provisional application Serial No. 60/284,854 filed Apr. 19, 2001, the contents of which are hereby incorporated by reference. The present invention concerns an improved process for the production of tertiary amines by reductive amination. This improved process can be applied to the preparation of imidazole-containing benzodiazepines, which are inhibitors of farnesyl protein transferase that find utility in the treatment of a variety of cancers and other diseases (Ding, C. Z.; Hunt, J. T.; Kim, S. -h.; Mitt, T.; Bhide, R.; Leftheris, K. WO 9730992; Chem. Abstr. 1998, 127, 278213). A number of methods have been previously reported for the reductive amination of carbonyl compounds with secondary amines in the presence of a reducing agent. The reducing agents previously used include: zinc (Lockemann, G. DE 503113; Chem. Abstr. 1931, 25, 522), H.sub.2/Pd(or Pt, Ni) (Emerson, W. S. Org. React. 1948, 4, 174; Schaus, J. M.; Huser, D. L.; Titus, R. D. Synth. Commun. 1990, 20, 3553), organoselenides, such as selenophenol (Fujimori, K.; Yoshimoto, H.; Oae, S. Tetrahedron Left. 1980, 21, 3385), NaBH.sub.4 (Verardo, G.; Giumanini, A. G.; Strazzolini, P. Synth. Commun. 1994, 24, 609), and NaCNBH.sub.3 (Lee, M.; Garbiras, B. J. Synth. Commun. 1994, 24, 3129). All these reducing agents are subject to one or more drawbacks. They are either toxic, or else they are not selective, with the result that a number of other reducible groups could be affected by sidereactions with these reagents. Reducing agents such as the organoselenides and NaCNBH.sub.3 are highly toxic, while zinc, NaBH.sub.4, and H.sub.2 over Pt, Pd, or Ni, for example, suffer from poor selectivity. NaBH(OAc).sub.3 was subsequently introduced to address these problems (Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
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Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849) and this reagent was used in the preparation of the aforementioned imidazole-containing benzodiazepine compounds (Ding, C. Z.; Hunt, J. T.; Kim, S. -h.; Mitt, T.; Bhide, R.; Leftheris, K., WO 9730992; Chem. Abstr. 1998, 127, 278213). Although the desired products were obtained from 1 H-benzodiazepine starting materials, a large excess of aldehyde was required for a satisfactory conversion. In addition, expensive chromatographic separation of products was necessary, so that this method was not readily adaptable to large scale preparation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Sedative non-benzodiazepine formulations Inventor(s): Fogarty, Siobhan; (Blackrock, IE), O'Toole, Edel; (Marino, IE) Correspondence: Crowell & Moring, L.L.P.; Intellectual Property Group; P.O. Box 14300; Washington; DC; 20044-4300; US Patent Application Number: 20030165566 Date filed: January 9, 2003 Abstract: The invention provides for an enhanced absorption pharmaceutical composition comprising a plurality of microparticles, each microparticle comprising at least one sedative non-benzodiazepine, at least one spheronization aid and at least one solubility enhancer. The microparticles of the invention are further incorporated into an oral fast-dispersing dosage form. Excerpt(s): This application claims priority from U.S. provisional patent application No. 60/346,613 filed Jan. 10, 2002. The present invention relates to enhanced absorption fastdispersing oral dosage pharmaceutical preparations comprising at least one sedative non-benzodiazepine agent. Insomnia is defined as difficulty falling asleep, or maintaining sleep, which interferes with a patient's daytime functioning. Insomnia is the most common sleep complaint with a prevalence of 26% to 50% in adult populations (Erman M E, Insomnia. Rakel: Conn's Current Therapy. (Ed.) 52.sup.nd ed. Saunders Co. 2000; Shader R I. Sedative-Hypnotics. Tasman: Psychiatry, 1.sup.st ed. Saunders Co. 1997). Although widely prevalent in the general population, it is estimated that only 5% to 20% of patients suffering from insomnia seek help from their clinicians (Erman M E, Insomnia. Rakel: Conn's Current Therapy. 52.sup.nd ed. Saunders Co. 2000). It has been reported that in the United States, 10% to 16% of adults suffer from serious short-term to sub-acute insomnia (i.e., <6 months in duration) and 9% to 10% complain of serious chronic insomnia (i.e., >6 months in duration) (Insomnia. Goetz:Textbook of Clinical Neurology. 1.sup.st ed. Saunders Co. 1999). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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•
Substituted 1,4-benzodiazepines and uses thereof Inventor(s): Calvo, Raul R.; (Royersford, PA), Carver, Theodore E. JR.; (Downingtown, PA), Cummings, Maxwell D.; (Wayne, PA), Grasberger, Bruce L.; (Trappe, PA), Kim, Alexander J.; (Philadelphia, PA), Lafrance, Louis V. III; (West Chester, PA), Lu, Tianbao; (Kennett Square, PA), Milkiewicz, Karen L.; (Exton, PA), Parks, Daniel J.; (Exton, PA) Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W., Suite 600; Washington; DC; 20005-3934; US Patent Application Number: 20030109518 Date filed: November 13, 2002 Abstract: The present invention is directed to novel 1,4-benzodiazepines, pharmaceutical compositions thereof, and the use thereof as inhibitors of HDM2-p53 interactions. Compounds have Formula I: 1or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:X and Y are independently --C(O)--, --CH.sub.2-- or -C(S)--;R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.8, R.sup.b, R.sup.c, R.sup.d and M are defined herein;R.sup.5 is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;R.sup.6 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;R.sup.9 is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; andR.sup.10 is --(CH.sub.2).sub.n--CO.sub.2R.sup.b, --(CH.sub.2).sub.m--CO.su- b.2M, -(CH.sub.2).sub.i--OH or --(CH.sub.2).sub.j--CONR.sup.cR.sup.dn is 0-8, m is 0-8, i is 1-8 and j is 0-8. Excerpt(s): This application claims priority under 35 U.S.C.sctn.119(e) to U.S. Provisional Application No. 60/331,235, filed Nov. 13, 2001, which is fully incorporated by reference herein. The present invention is in the area of novel 1,4-benzodiazepines and salts thereof, their syntheses, and their use as inhibitors of MDM2 and HDM2 oncoproteins. This invention relates to compounds that bind to the human protein HDM2 and interfere with its interaction with other proteins, especially the tumor suppressor protein p53. HDM2 is the expression product of hdm2, an oncogene that is overexpressed in a variety of cancers, especially soft tissue sarcomas (Momand, J., et al., Nucl. Acids Res. 26:3453-3459 (1998)). 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 benzodiazepines, 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 “benzodiazepines” (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 benzodiazepines.
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You can also use this procedure to view pending patent applications concerning benzodiazepines. 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 6. BOOKS ON BENZODIAZEPINES Overview This chapter provides bibliographic book references relating to benzodiazepines. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on benzodiazepines include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print®). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “benzodiazepines” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “benzodiazepines” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “benzodiazepines” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •
5-Ht1a Agonists, 5-Ht3 Antagonists and Benzodiazepines: Their Comparative Behavioural Pharmacology by S.J. Cooper (Editor), R. J. Rodgers (Editor); ISBN: 0471927937; http://www.amazon.com/exec/obidos/ASIN/0471927937/icongroupinterna
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A History of the Benzodiazepines by Jorge Alberto Costa e Silva; ISBN: 1853154415; http://www.amazon.com/exec/obidos/ASIN/1853154415/icongroupinterna
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Actions and Interactions of Gaba and Benzodiazepines by Norman G. Bowery (Editor); ISBN: 0890042985; http://www.amazon.com/exec/obidos/ASIN/0890042985/icongroupinterna
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Aggression: Individual Differences, Alcohol And Benzodiazepines (Maudsley Monograph Series) by Alyson J. Bond, et al; ISBN: 0863774822; http://www.amazon.com/exec/obidos/ASIN/0863774822/icongroupinterna
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Analytical Profiles of Benzodiazepines; ISBN: 9991083847; http://www.amazon.com/exec/obidos/ASIN/9991083847/icongroupinterna
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Benzodiazepine Dependence (Oxford Medical Publications) by Cosmo Hallstrom (Editor); ISBN: 0192620940; http://www.amazon.com/exec/obidos/ASIN/0192620940/icongroupinterna
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Benzodiazepine Receptor Inverse Agonists by Martin Sarter (Editor), et al; ISBN: 0471561738; http://www.amazon.com/exec/obidos/ASIN/0471561738/icongroupinterna
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Benzodiazepine Receptor Ligands, Memory and Information Processing: Psychometric, Psychopharmacological and Clinical Issues; ISBN: 3540187022; http://www.amazon.com/exec/obidos/ASIN/3540187022/icongroupinterna
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Benzodiazepine Receptor Ligands, Memory, and Information Processing (Psychopharmacology Series, Vol 6) by I. Hindmarch, H. Ott (Editor); ISBN: 0387187022; http://www.amazon.com/exec/obidos/ASIN/0387187022/icongroupinterna
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Benzodiazepine/Gaba Receptors and Chloride Channels; ISBN: 0845137042; http://www.amazon.com/exec/obidos/ASIN/0845137042/icongroupinterna
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Benzodiazepine/Gaba Receptors and Chloride Channels: Structural and Functional Properties (Receptor Biochemistry and Methodology, Vol 5) by Richard W. Olsen (Editor), J. Craig Venter (Editor); ISBN: 0471856215; http://www.amazon.com/exec/obidos/ASIN/0471856215/icongroupinterna
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Benzodiazepines by Michael R. Trimble (Editor), et al; ISBN: 1871816432; http://www.amazon.com/exec/obidos/ASIN/1871816432/icongroupinterna
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Benzodiazepines and Ghb: Detection and Pharmacology by Salvatore J. Salamone (Editor); ISBN: 0896039811; http://www.amazon.com/exec/obidos/ASIN/0896039811/icongroupinterna
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Benzodiazepines and Therapeutic Counselling: Report from WHO Collaborative Study; ISBN: 3540192891; http://www.amazon.com/exec/obidos/ASIN/3540192891/icongroupinterna
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Benzodiazepines Divided: A Multidisciplinary Review by Michael R. Trimble (Editor); ISBN: 0471901997; http://www.amazon.com/exec/obidos/ASIN/0471901997/icongroupinterna
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Benzodiazepines II: A Handbook. Basic Data, Analytical Methods, Pharmacokinetics, and Comprehensive Literature by H. Schutz; ISBN: 0387502491; http://www.amazon.com/exec/obidos/ASIN/0387502491/icongroupinterna
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Benzodiazepines in clinical practice by David J. Greenblatt; ISBN: 0911216529; http://www.amazon.com/exec/obidos/ASIN/0911216529/icongroupinterna
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Benzodiazepines in Clinical Practice: Risks and Benefits (Clinical Practice, No 17) by Peter P. Roy-Byrne, Deborah S. Cowley (Editor); ISBN: 0880484535; http://www.amazon.com/exec/obidos/ASIN/0880484535/icongroupinterna
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Benzodiazepines in Current Clinical Practice: Proceedings of a Symposium January 20 1987 No 114 by Y. Rue (Editor), Hugh L. Freeman; ISBN: 0905958454; http://www.amazon.com/exec/obidos/ASIN/0905958454/icongroupinterna
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Benzodiazepines Today and Tomorrow by R.G. Priest (Editor), U. Vianna Filho (Editor); ISBN: 0852003684; http://www.amazon.com/exec/obidos/ASIN/0852003684/icongroupinterna
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Benzodiazepines: Current Concepts: Biological, Clinical and Social Perspectives by G. Beaumont (Editor), et al; ISBN: 0471926043; http://www.amazon.com/exec/obidos/ASIN/0471926043/icongroupinterna
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Benzodiazepines: Use, Overuse, Misuse, Abuse (111P) by John Marks; ISBN: 0839112661; http://www.amazon.com/exec/obidos/ASIN/0839112661/icongroupinterna
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Calming the Brain: benzodiazepines and related drugs from laboratory to clinic by Adam Doble, et al; ISBN: 1841840521; http://www.amazon.com/exec/obidos/ASIN/1841840521/icongroupinterna
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Essential and Non-Essential Metals-Metabolites With Antibiotic ActivityPharmacology of Benzodiazepines-Interferon Gamma Research (Progress in Clinic) by M. Costa (Compiler), D. T. Forman (Editor); ISBN: 0387136053; http://www.amazon.com/exec/obidos/ASIN/0387136053/icongroupinterna
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Gaba and Benzodiazepine Receptors by Squires; ISBN: 0849358760; http://www.amazon.com/exec/obidos/ASIN/0849358760/icongroupinterna
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GABA and benzodiazepine receptors; ISBN: 0890045305; http://www.amazon.com/exec/obidos/ASIN/0890045305/icongroupinterna
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Good Chemistry: The Life and Legacy of Valium Inventor Leo Sternbach by Alex Baenninger, Alex Baenninger; ISBN: 0071426175; http://www.amazon.com/exec/obidos/ASIN/0071426175/icongroupinterna
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Hangover Effects of Alcohol & Carry-Over Effects of Certain Benzodiazepine Hypnotics on Driving Performance by Jan Tornros; ISBN: 9155450296; http://www.amazon.com/exec/obidos/ASIN/9155450296/icongroupinterna
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History Tolerance Benzodiazepines: Volume 13 by A. Higgitt (Author), et al; ISBN: 0521369711; http://www.amazon.com/exec/obidos/ASIN/0521369711/icongroupinterna
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Mechanism of action of benzodiazepines; ISBN: 0890040397; http://www.amazon.com/exec/obidos/ASIN/0890040397/icongroupinterna
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Naturally Occurring Benzodiazepines: Structure, Distribution and Function (Ellis Horwood Series in Pharmaceutical Technology) by Ivan Izquierdo, Jorge Medina (Editor); ISBN: 0130154881; http://www.amazon.com/exec/obidos/ASIN/0130154881/icongroupinterna
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Peripheral Benzodiazepine Receptors by Eva Giesen-Crouse (Author); ISBN: 0122826302; http://www.amazon.com/exec/obidos/ASIN/0122826302/icongroupinterna
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Pharmacology of Benzodiazepines by Earl Usdin, et al; ISBN: 3527261265; http://www.amazon.com/exec/obidos/ASIN/3527261265/icongroupinterna
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Pharmacology of Benzodiazepines: Proceedings of a Conference Held in the Masur Auditorium, National Institute of Health, Bethesda, Maryland, USA, on April 12-14 1982 by Earl Usdin (Editor); ISBN: 0333340248; http://www.amazon.com/exec/obidos/ASIN/0333340248/icongroupinterna
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Reducing Benzodiazepine Consumption; ISBN: 3540970355; http://www.amazon.com/exec/obidos/ASIN/3540970355/icongroupinterna
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Reducing Benzodiazepine Consumption: Psychological Contribution to General Practice (Recent Research in Psychology) by Margaret A. Cormack, et al; ISBN: 0387970355; http://www.amazon.com/exec/obidos/ASIN/0387970355/icongroupinterna
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Sleep, Benzodiazepines and Performance: Experimental Methodologies and Research Prospects by I. Hindmarch (Editor); ISBN: 0387132910; http://www.amazon.com/exec/obidos/ASIN/0387132910/icongroupinterna
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Stopping anxiety medication : panic control therapy for benzodiazepine discontinuation : therapist guide; ISBN: 0158131460; http://www.amazon.com/exec/obidos/ASIN/0158131460/icongroupinterna
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Stopping Anxiety Medication : Panic Control Therapy for Benzodiazepine Discontinuation Patient Workbook by David H. Barlow, et al; ISBN: 0158131290; http://www.amazon.com/exec/obidos/ASIN/0158131290/icongroupinterna
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Stopping Valium and Ativan, Centrax, Dalmane, Librium, Paxipam, Restoril, Serax, Tranxene, Xanax by Eve Bargman; ISBN: 0937188123; http://www.amazon.com/exec/obidos/ASIN/0937188123/icongroupinterna
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Stopping Valium: And Ativan, Centrax, Dalmane, Librium, Paxipam, Restoril, Serax, Tranxene, Xanax by Eve and Bargmann, et al; ISBN: 0446375829; http://www.amazon.com/exec/obidos/ASIN/0446375829/icongroupinterna
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The analysis of benzodiazepines in forensic urine samples (SuDoc TD 4.210:96/14) by Thomas C. Kupiec; ISBN: B00010SJXO; http://www.amazon.com/exec/obidos/ASIN/B00010SJXO/icongroupinterna
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The Benzodiazepine Receptor : Drug Acceptor Only or a Physiologically Relevant Part of our Central Nervous System? by Walter Erhard Müller (Author); ISBN: 0521304180; http://www.amazon.com/exec/obidos/ASIN/0521304180/icongroupinterna
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The Benzodiazepines; ISBN: 0911216251; http://www.amazon.com/exec/obidos/ASIN/0911216251/icongroupinterna
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The benzodiazepines, patterns of use : an annotated bibliography by C. E. Weise; ISBN: 0888680120; http://www.amazon.com/exec/obidos/ASIN/0888680120/icongroupinterna
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The Benzodiazepines: Current Standards for Medical Practice by D.E. Smith (Editor); ISBN: 0852007833; http://www.amazon.com/exec/obidos/ASIN/0852007833/icongroupinterna
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The effects of tranquillization : benzodiazepine use in Canada by R. Cooperstock; ISBN: 0662119983; http://www.amazon.com/exec/obidos/ASIN/0662119983/icongroupinterna
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The Gabaa/Benzodiazepine Receptor as a Target for Psychoactive Drugs by Adam Doble, Ian L. Martin; ISBN: 3540605657; http://www.amazon.com/exec/obidos/ASIN/3540605657/icongroupinterna
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Valium and Other Tranquilizers by Gail Winger; ISBN: 0685522571; http://www.amazon.com/exec/obidos/ASIN/0685522571/icongroupinterna
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Valium, Librium, & the Benzodiazepine Blues by Jim Parker; ISBN: 0892301635; http://www.amazon.com/exec/obidos/ASIN/0892301635/icongroupinterna
Chapters on Benzodiazepines In order to find chapters that specifically relate to benzodiazepines, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and benzodiazepines using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “benzodiazepines” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on benzodiazepines: •
Chemical Dependence Source: in Scully, C. and Cawson, R.A. Medical Problems in Dentistry. 4th ed. Woburn, MA: Butterworth-Heinemann. 1998. p. 488-505. Contact: Available from Butterworth-Heinemann. 225 Wildwood Avenue, Woburn, MA 01801-2041. (800) 366-2665 or (781) 904-2500. Fax (800) 446-6520 or (781) 933-6333. E-mail:
[email protected]. Website: www.bh.com. PRICE: $110.00. ISBN: 0723610568. Summary: Chemical dependence (substance or drug abuse) is a growing problem worldwide. Abuse of a drug is defined as self-administration in a manner that deviates from the cultural norm and is harmful. Addiction is defined as the continued use of a specific psychoactive substance despite physical, psychological, or social harm. This chapter on chemical dependence is from a text that covers the general medical and surgical conditions relevant to the oral health care sciences. Topics include aspects of chemical dependence, the consumption of alcohol, fetal alcohol syndrome, alcohol withdrawal, nicotine and tobacco, benzodiazepines, barbiturates, opioids (narcotics), amphetamines, cocaine, psychedelic drugs (cannabis, LSD, PCP, ketamine), anesthetic abuse, and anabolic steroids. For each condition, the authors discuss general aspects, diagnosis and management issues, dental aspects, and patient care strategies. The chapter includes a summary of the points covered. One appendix lists street names and other terms for drugs of abuse. 4 tables. 38 references.
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Substance Abuse Source: in Ciancio, S.G., ed. ADA Guide to Dental Therapeutics. 2nd ed. Chicago, IL: American Dental Association (ADA). 2000. p. 559-568. Contact: Available from American Dental Association (ADA). Catalog Sales, P.O. Box 776, St. Charles, IL 60174-0776. (800) 947-4746. Fax (888) 476-1880 or (630) 443-9970. Website: www.ada.org. PRICE: $44.95 for members; $64.95 for nonmembers, plus shipping and handling. Summary: Dentists are prescribing more medications than ever before and patients seeking dental care are using a wide range of medications for medical problems. And both dentists and patients have choices to make about the variety of nonprescription products available for treating various disorders of the mouth. This chapter on substance abuse is from a detailed guide to dental therapeutics. The author offers information to help practitioners safely manage patients who have or are suspected of
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having substance abuse problems, including alcohol abuse. Topics include defining addiction, the dentist's role with addicted patients, recognizing addicted patients, guarding against drug theft, and actions dentists should take after recognizing an addicted patient. One table provides a summary of some prescribing considerations for dentists who have patients with a history of substance abuse or dependence; another table reviews the dental implications of substances of abuse, including alcohol, amphetamines, barbituates, benzodiazepines, cocaine, inhalants, lysergic acid diethylamide (LSD), marijuana, nicotine, opioids, and phenycyclidine hydrochloride (PCP). 2 tables. 6 references. •
Treatment of the Sphincter: Medical Therapy Source: in Corcos, J.; Schick, E., eds. Urinary Sphincter. New York, NY: Marcel Dekker, Inc. 2001. p. 483-496. Contact: Available from Marcel Dekker, Inc. Cimarron Road, P.O. Box 5005, Monticello, NY 12701. (800) 228-1160 or (845) 796-1919. Fax (845) 796-1772. E-mail:
[email protected]. International E-mail:
[email protected]. Website: www.dekker.com. PRICE: $225.00 plus shipping and handling. ISBN: 0824704770. Summary: Medical treatment for sphincteric (the controlling muscles of the bladder opening) pathology is often pursued as a first line approach for the patient with either incontinence (involuntary loss of urine) or obstructive voiding. The decision to pursue medical therapy may be patient or physician driven and based on the desire to avoid more aggressive invasive procedures. This chapter on medical therapy for treatment of the sphincter is from a textbook that presents a detailed and systematic account of the current knowledge on the anatomy, physiology, functional relationships, and range of dysfunctions that affect the urinary sphincter. The medical approach to the treatment of the dysfunctional sphincter may be divided practically into medications that are used to either enhance sphincteric function (as in stress incontinence) or weaken sphincteric function (as in dyssynergia or voiding dysfunction) and promote bladder emptying. The author reviews medical therapy for the hyperactive sphincter, including the use of alpha adrenergic blockers, benzodiazepines, beta adrenergic agents, dantrolene sodium, botulinum toxin, phenol block, and baclofen; and medical therapy for the incompetent sphincter, including the use of alpha adrenergic agonists, imipramine, and estrogen therapy. The author concludes that for the smooth sphincter, alpha adrenergic agonists and antagonists represent an effective way to modulate sphincteric function. Although many different drugs have been tried to target striated sphincteric dysfunction, few have been selective enough to warrant widespread clinical use. Too commonly, adverse systemic side effects limit their clinical effectiveness. For a select group of patients, however, these drugs allow them to overcome striated sphincteric dysfunction, without resorting to surgery. 2 tables. 107 references.
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Nausea and Vomiting Source: in Brandt, L., et al., eds. Clinical Practice of Gastroenterology. Volume One. Philadelphia, PA: Current Medicine. 1999. p. 215-225. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. Website: www.wbsaunders.com. PRICE: $235.00 plus shipping and handling. ISBN: 0443065209 (two volume set); 0443065217 (volume 1); 0443065225 (volume 2). Summary: Most occasional nausea and vomiting is associated with a viral gastroenteritis or a bacterial infection, usually from preformed enterotoxins (foodborne). Nausea is a
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debilitating symptom and, whether persistent or intermittent, is always the expression of underlying organic disease. It is generally associated either with primary gastrointestinal (GI) neuromuscular (motility) disorders of unknown cause, or with disorders secondary to other diseases that fall into systemic groups, such as mechanical, inflammatory, endocrine, immune complex, metabolic, neurologic, iatrogenic, environmental, psychogenic, or idiopathic. This chapter on nausea and vomiting is from a lengthy textbook that brings practitioners up to date on the complexities of gastroenterology practice, focusing on the essentials of patient care. The authors focus on the recognized mechanisms of nausea and vomiting; discuss methods of evaluation, diagnosis, and treatment; and suggest that a new field of gastroenterology is in the making, i.e., neurogastroenterology. The authors provide a patient care algorithm for the evaluation of acute nausea and vomiting with headache or diarrhea, one for the evaluation of chronic nausea and vomiting, and one for the evaluation of nausea and vomiting associated with chronic unexplained abdominal pain. Treatment options include phenathizines, antihistamines, anticholinergics, butyrophenones, substituted benzamides, serotonin antagonists, macrolide antibiotics, benzodiazepines, cannabinoids, diet, acupuncture, biofeedback, and relaxation techniques. 8 figures. 3 tables. 15 references. •
Respiratory Disorders Source: in Scully, C. and Cawson, R.A. Medical Problems in Dentistry. 4th ed. Woburn, MA: Butterworth-Heinemann. 1998. p. 154-172. Contact: Available from Butterworth-Heinemann. 225 Wildwood Avenue, Woburn, MA 01801-2041. (800) 366-2665 or (781) 904-2500. Fax (800) 446-6520 or (781) 933-6333. E-mail:
[email protected]. Website: www.bh.com. PRICE: $110.00. ISBN: 0723610568. Summary: Respiratory disorders are common and may significantly affect dental treatment, especially general anesthesia. Respiratory diseases are often also a contraindication to opioids, benzodiazepines and other respiratory depressants. This chapter on respiratory disorders is from a text that covers the general medical and surgical conditions relevant to the oral health care sciences. Topics include upper respiratory tract viral infections, sinusitis, lower respiratory tract infections, pulmonary tuberculosis, Legionnaire's disease (legionellosis), lung abscess, bronchiectasis, cystic fibrosis, chronic obstructive airways diseases, asthma, bronchogenic carcinoma (lung cancer), occupational lung disease, sarcoidosis, postoperative respiratory complications (including aspiration of gastric contents), obstructive sleep apnea syndrome, and respiratory distress syndromes (RDS). For each disease, the authors discuss general aspects, diagnosis and management issues, dental aspects, and patient care strategies. The chapter includes a summary of the points covered. 1 figure. 5 tables. 51 references.
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Chapter 55: Disorders of the Muscles, Bursas, and Tendons Source: in Berkow, R., ed. The Merck Manual of Medical Information: Home Edition (online version). Rahway, NJ: Merck and Company, Inc. 2000. 6 p. Contact: Available online from Merck and Company, Inc. (800) 819-9456. Website: www.merck.com/pubs/mmanual_home/contents.htm. Also available from your local book store. PRICE: $29.95 plus shipping. Summary: This chapter provides the general public and people who have disorders of muscles, bursas, and tendons with information on their symptoms, diagnosis, and treatment. Spasmodic torticollis is a painful intermittent or continuous spasm of the neck muscles that forces the head to rotate and tilt forward, backward, or sideways.
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Torticollis varies from mild to severe, and it may persist for life. Diagnosis is based on the medical history, a physical examination, and imaging tests. When a cause is identified, the torticollis can usually be treated successfully. However, treatment is less likely to be effective when the cause is a nervous system disorder or is unknown. Physical therapy or massage can sometimes relieve the spasm temporarily. Drugs such as anticholinergics and benzodiazepines are commonly used. Muscle relaxants and antidepressants may also be prescribed. Fibromyalgia syndromes are a group of disorders characterized by achy pain and stiffness in soft tissues throughout the body or only in certain locations. Widespread fibromyalgia is more common in women, whereas localized fibromyalgia is more common in men. The cause is unknown. The most commonly affected areas include the fibrous tissues or muscles of the neck, shoulders, chest, rib cage, lower back, and thighs. Diagnosis is based on the pattern and location of the pain. Nondrug treatments are usually more effective than drugs. Bursitis, which may be either acute or chronic, is the painful inflammation of a bursa caused by chronic overuse, injury, gout, pseudogout, rheumatoid arthritis, or infections. General symptoms include pain and limited movement. Specific symptoms depend on the location of the inflamed bursa. Bursitis is suspected if the area around a bursa is sore when touched and specific joint movements are painful. Antibiotics are used to treat infected bursas, whereas conservative measures and nonsteroidal antiinflammatory drugs are usually used to treat noninfectious acute bursitis. Chronic bursitis is treated similarly. Tendinitis is the inflammation of a tendon, and tenosynovitis is tendinitis accompanied by an inflammation of the sheath around the tendon. Symptoms of both disorders include pain and swelling. Treatment options that may alleviate the symptoms of tendinitis include conservative measures, nonsteroidal antiinflammatory drugs, and injection of corticosteroids and local anesthetics. 1 figure. •
Treatment of Non-Cognitive Features of Dementia Source: in Levy, R.; Howard, R.; Burns, A.; eds. Treatment and Care in Old Age Psychiatry. Petersfield, Hampshire, UK: Wrightson Biomedical Publishing Ltd. 1993. p. 47-57. Contact: Available from Taylor and Francis. 1900 Frost Road, Suite 101, Bristol, PA 19007-1598. (800) 821-8312 or (215) 785-5515 (FAX). PRICE: $85.00. Summary: This chapter, in a text concerning recent advances in the psychiatry of the aged, describes the psychiatric symptoms and behavioral disturbances that occur in patients with dementia, outlines their importance, and discusses their treatment. Noncognitive features, including delusions, hallucinations, mood changes, sleep disturbances, appetite changes, sexual changes, psychomotor changes, and personality changes, may have diagnostic value and may help to indicate subgroups of Alzheimer's disease. The chapter focuses on pharmacological treatment of these symptoms, with discussion of neuroleptic agents in general and specific discussion of non-neuroleptics. The latter include antidepressants, anticonvulsants, beta blockers, benzodiazepines, and psychostimulants. General recommendations for drug treatment are given, along with discussions of the drug and behavioral treatment of specific behaviors, including depression, delusions, anxiety, insomnia, aggression, shouting, wandering, and agitation. 27 references.
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Pharmacologic Management of Patient Behavior Source: in McDonald, R.E. and Avery, D.A., eds. Dentistry for the Child and Adolescent. 7th ed. St. Louis, MO: Mosby, Inc. 2000. p. 297-324.
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Contact: Available from Harcourt Health Sciences. 11830 Westline Industrial Drive, St. Louis, MO 63146. (800) 325-4177. Fax (800) 874-6418. Website: www.harcourthealth.com. PRICE: $72.00 plus shipping and handling. ISBN: 0815190174. Summary: To perform the highest quality dental service for the pediatric patient, one may need to use pharmacologic (drug) means to obtain a quiescent, cooperative patient. This chapter on the pharmacologic management of patient behavior is from a textbook on dentistry for the child and adolescent that is designed to help undergraduate dental students and postdoctoral pediatric dentistry students provide comprehensive oral health care for infants, children, teenagers, and individuals with various disabilities. The goals of conscious sedation for the pediatric patient are to provide the most comfortable, most efficient, and highest quality dental service for the patient; to control inappropriate behavior; to produce in the patient a positive attitude toward future care; to promote patient welfare and safety; and to return the patient to a physiologic state in which safe discharge is possible. Topics covered include the differences between conscious sedation and deep sedation or general anesthesia; patient selection and preparation, including informed consent and instructions to parents; documentation; sedation techniques, including inhalation, oral, intramuscular, submucosal, and intravenous; combinations of methods and agents; facilities and equipment; common agents employed, including gases, antihistamines, benzodiazepines, benzodiazepine antagonists, sedative hypnotics, narcotics, and narcotic antagonists; monitoring; and risk management. 14 figures. 3 tables. 26 references.
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CHAPTER 7. MULTIMEDIA ON BENZODIAZEPINES Overview In this chapter, we show you how to keep current on multimedia sources of information on benzodiazepines. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.
Video Recordings An excellent source of multimedia information on benzodiazepines is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “benzodiazepines” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “benzodiazepines” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on benzodiazepines: •
Problem Behaviors in Geriatrics: Agitation and Restlessness Source: Indianapolis, IN: Geriatric Video Productions. 1996. Contact: Available from Geriatric Video Productions. PO Box 55741, Indianapolis, IN 46205. (800) 621-9181; FAX: (317) 579-0402. Internet: http://www.geriatricvideo.com. PRICE: $139.00 plus $2.00 shipping and handling. Summary: This videotape is intended to help nursing home staff identify and manage agitated and restless behavior in elderly people. The narrator defines agitation and describes the four ways in which it can manifest itself: psychomotor activity, such as pacing, wandering, and accelerated movements; physiological disturbances, such as incontinence and refusal of food; speech patterns, such as yelling and repeated vocalizations; and social behaviors, such as hitting and biting. Agitation may be the result of internal or external stimuli or a medical disorder, such as delirium, dementia, or depression. The narrator discusses how to prevent or reduce different types of
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agitation, focusing on staff-patient interaction, environmental design, and other nonrestrictive techniques. If non-restrictive techniques are unsuccessful in controlling agitation, medication may be added to the treatment plan. The narrator discusses conditions under which medications should be given and provides information on antipsychotic agents, long-acting benzodiazepines, and short-acting benzodiazepines. A 21-page manual accompanies the video. •
Psychotropic Medication and the Home Health Patient Source: Tuscaloosa, AL: Dementia Education and Training Program. 1995. (videocassette). Contact: Alabama Department of Public Health. Bureau of Geriatric Psychology. Dementia Education and Training Program. 200 University Boulevard, Tuscaloosa, AL 35401. (800) 457-5679; (205) 759-0820; FAX (205) 759-0891. PRICE: $15.00. Summary: This videotape, featuring Dr. Richard Powers, is one of a series of educational programs for home health nurses. Other health professionals may find it useful as well. Information is provided about the effects of aging on pharmacokinetics, the indications for use of neuroleptics in the elderly, and the cause and treatment of neuroleptic side effects. Other topics include anticholinergics, benzodiazepines, and the causes and treatment of sleep disorders in older people.
Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Sound Recordings.” Type “benzodiazepines” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on benzodiazepines: •
Behavior Management With Psychotropic Medications Source: Redmond, WA: Tree Farm Cassettes. 1993. (audiocassette). Contact: Available from Tree Farm Cassettes. 23703 N.E. 4th Street, Redmond, WA 98053. (800) 468-0464 or (206) 868-2495 (FAX). PRICE: $9.00. Order Number: AP34060. Complete conference on cassettes available for $225.00. Summary: This audiocassette recording session at the 11th Annual Convention of the National Association of Activity Professionals, which took place in Milwaukee, Wisconsin, on April 14-17, 1993. The speaker discusses the principles of using psychotropic medications to treat behavioral disorders secondary to dementia. He emphasizes that Alzheimer's disease is incurable but that its symptoms are treatable, and that treating behavioral symptoms can improve the quality of life for patients and caregivers. Activity professionals can be part of a team that helps make decisions about the appropriate medications for individual patients, and they need to understand the effects that medications have on a patient's behavior. The author discusses the misuse of psychotropic medications, including excessive dosing, inadequate monitoring, inadequate indications, and excess duration, and the need to balance benefits and adverse effects. Federal guidelines for prescribing psychotropic drugs are examined.
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Some principles for prescribing psychotropics are outlined, including the need to document and quantify target behaviors, to define therapeutic objectives, to exhaust nonpharmacologic therapies before prescribing, to screen for underlying illness and drug effects, to consider pharmacokinetic and pharmacodynamic processes and how they are influenced by aging, to simplify the drug regimen, and to make changes in treatment strategies carefully and appropriately. The effects, acceptable and unacceptable uses, and regulatory guidelines for antipsychotics, antidepressants, and benzodiazepines are covered in detail, and general side effects are listed.
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CHAPTER 8. PERIODICALS BENZODIAZEPINES
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Overview In this chapter, we suggest a number of news sources and present various periodicals that cover benzodiazepines.
News Services and Press Releases One of the simplest ways of tracking press releases on benzodiazepines 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 “benzodiazepines” (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 benzodiazepines. 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 “benzodiazepines” (or synonyms). The following was recently listed in this archive for benzodiazepines: •
Benzodiazepines found to be overprescribed in UK nursing homes Source: Reuters Medical News Date: February 10, 2003
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Symptom-triggered benzodiazepine effectively treats alcohol withdrawal Source: Reuters Medical News Date: May 28, 2002
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OraSure oral test for benzodiazepines cleared by FDA Source: Reuters Medical News Date: April 19, 2002
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Valproate may substitute for benzodiazepines in treatment of alcohol withdrawal Source: Reuters Medical News Date: September 27, 2001
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Benzodiazepine given by paramedics is safe and effective for out-of-hospital status epilepticus Source: Reuters Medical News Date: August 30, 2001
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Melatonin helps sleep quality in diabetics, facilitates withdrawal from benzodiazepines Source: Reuters Medical News Date: July 06, 2001
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Caution required when using even low-dose benzodiazepines in elderly Source: Reuters Medical News Date: July 02, 2001
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Benzodiazepine use not linked to hip fractures in elderly Source: Reuters Medical News Date: March 27, 2001
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Imipramine eases benzodiazepine withdrawal in long-term users Source: Reuters Medical News Date: December 22, 2000
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Amitriptyline, long-acting benzodiazepines inappropriately prescribed for elderly Source: Reuters Medical News Date: October 03, 2000
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Different receptor subtypes mediate different benzodiazepine effects Source: Reuters Medical News Date: May 17, 2000
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GABA(A)/benzodiazepine receptor function altered in premenstrual dysphoric disorder Source: Reuters Medical News Date: May 04, 2000
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Benzodiazepine detoxification successful in long run Source: Reuters Medical News Date: May 04, 2000
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Recent benzodiazepine use for anxiety disorder affects buspirone effectiveness Source: Reuters Medical News Date: March 22, 2000
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Melatonin helps patients discontinue benzodiazepine treatment for insomnia Source: Reuters Medical News Date: November 16, 1999
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Use of anxiolytic benzodiazepines associated with UK highway accidents Source: Reuters Medical News Date: October 23, 1998
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Individualized benzodiazepine dosing effective in alcohol withdrawal Source: Reuters Medical News Date: July 24, 1998
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Sleeping-Pill And Benzodiazepine Use Common In Elderly Source: Reuters Medical News Date: April 20, 1998
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FDA Committee Revisits Halcion, Backs IOM Recommendations Source: Reuters Medical News Date: December 05, 1997
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Anxiety Linked To Maldistribution Of Cerebral Benzodiazepine Receptors Source: Reuters Medical News Date: November 04, 1997
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DEA and FDA Consider Rescheduling Of Benzodiazepines Source: Reuters Medical News Date: September 15, 1997
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Benzodiazepine Use Among Elderly Linked To Risk Of Motor Vehicle Crash Source: Reuters Medical News Date: July 02, 1997
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Stroke Rehabilitation Requires Specialized Care; Benzodiazepines Hinder Recovery From Stroke In Some Patients Source: Reuters Medical News Date: June 30, 1995 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
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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 “benzodiazepines” (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 “benzodiazepines” (or synonyms). If you know the name of a company that is relevant to benzodiazepines, 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 “benzodiazepines” (or synonyms).
Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “benzodiazepines” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on benzodiazepines: •
Tired and the Restless: Taming Restless Legs Syndrome Source: Mayo Clinic Women's HealthSource. 1(10): 6. November 1997. Contact: Available from Mayo Foundation for Medical Education and Research. P.O. Box 56931, Boulder, CO 80322-6931. (800) 876-8633. Summary: This brief newsletter article explores the use of drug therapy to treat restless legs syndrome (RLS), a condition that affects as much as 10 percent of the population. Its symptoms include a jittery, tingling, burning, or aching feeling in the lower legs or thighs. However, proper treatment can reduce or eliminate these symptoms. Some physical conditions may lead to RLS, including a pinched nerve in the back, damage to nerves in the legs associated with diabetes or kidney failure, iron deficiency anemia (which can be a side effect of hemodialysis), vitamin B12 deficiency, and rheumatoid arthritis. Pregnancy or stress can also worsen the condition. The author suggests the use of over the counter pain relievers, such as ibuprofen, or warm baths to calm the legs
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before bed. Leg massage may also work. Moderate, regular exercise can help, but exercise within 4 to 6 hours of bedtime can intensify the symptoms. Alcohol and caffeine can also make the condition worse. The author briefly reviews how four groups of medications can be used for RLS: Parkinson's medications, opioid drugs, benzodiazepines, and antiseizure medications. One sidebar offers a strategy for reducing the stress associated with worrying. •
ECT for Agitation in Patients With Dementia Source: American Association for Geriatric Psychiatry Newsletter. 11(11): 15-16. September-October 1990. Contact: Available from American Association for Geriatric Psychiatry, Central Office. P.O. Box 376A, Greenbelt, MD 20768. (301) 220-0952. PRICE: Call for price information. Summary: This newsletter article for the geriatric psychiatrist examines the use of electroconvulsive therapy (ECT) for agitated depressive symptoms in patients who are not responsive to tricyclics, heterocyclic antidepressants, neuroleptics, or benzodiazepines. ECT generally produces a good outcome and is looked upon as the treatment of choice for delusional depression which is often accompanied by an agitated state. However, it has not been established as to whether ECT is indicated for used in agitation associated with dementia without a depressive component. ECT has not been definitely indicated for chronic organic brain syndromes without a depressive component. A problem in assessment and treatment of agitation in patients with dementia but without major depression is obtaining the special informed consent needed for ECT use. Assessment of the patient's ability to provide informed consent as well as a conference with the patient and family can assist in determining the use of ECT. 20 references.
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Prescribed Medications Source: Fibromyalgia Frontiers. 9(3): 17-22. 2001. Contact: Available from National Fibromyalgia Partnership, Inc. 140 Zinn Way, Linden, VA 22642-5609. (866) 725-4404 toll-free. Fax (540) 622-2998. E-mail:
[email protected]. Website: www.fmpartnership.org. Summary: This newsletter article provides health professionals and people who have fibromyalgia (FM) with information on prescription and nonprescription medications that can relieve pain and improve sleep and mood. Categories of drugs used in the treatment of fibromyalgia are analgesics, antiinflammatory drugs, antidepressant medications, muscle relaxants, sleep modifiers, antianxiety medicines, and other medicines used to treat chronic pain. Analgesics are pain killers and can include nonprescription medicines such as aspirin and acetaminophen or prescription strength pain pills such as narcotics, codeine, Vicodin, Darvocet, Oxycontin, and Percocet. Antiinflammatory medicines include aspirin, nonsteroidal antiinflammatory drugs, and corticosteroids. Antidepressant medications include tricyclics and selective serotonin reuptake inhibitors. Muscle relaxants can decrease pain in people who have FM and include Flexeril, Soma, Skelaxin, and Robaxin. Various medications can be used to treat insomnia, including benzodiazepines and hypnotic nonbenzodiazepines. Anxiety is a common problem in FM, but various medicines, including antidepressants and muscle relaxants, can treat it. Other medicines used to treat pain include antiseizure medicines, headache medications, and antibiotics. The article highlights the beneficial and adverse effects of each drug category. In addition, the article presents basic strategies regarding medication use and discusses the use of trigger point injections to manage pain.
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Academic Periodicals covering Benzodiazepines Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to benzodiazepines. In addition to these sources, you can search for articles covering benzodiazepines 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 9. 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 benzodiazepines. 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 non-profit 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 benzodiazepines. 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.).
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The following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to benzodiazepines: Benzodiazepines •
Systemic - U.S. Brands: Alprazolam Intensol; Ativan; Dalmane; Diastat; Diazepam Intensol; Dizac; Doral; Halcion; Klonopin; Librium; Lorazepam Intensol; Paxipam; ProSom; Restoril; Serax; Tranxene T-Tab; Tranxene-SD; Tranxene-SD Half Strength; Valium; Xanax http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202084.html
Chlordiazepoxide and Clidinium •
Systemic - U.S. Brands: Clindex; Clinoxide; Clipoxide; Librax; Lidox; Lidoxide; Zebrax http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202130.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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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 Institute10: •
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/
10
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.11 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:12 •
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
•
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
11
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). 12 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
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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 Gateway13 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.14 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “benzodiazepines” (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 46123 169 428 49 200 46969
HSTAT15 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.16 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.17 Simply search by “benzodiazepines” (or synonyms) at the following Web site: http://text.nlm.nih.gov.
13
Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.
14
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). 15 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 16 17
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 Biologists18 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.19 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.20 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.
Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •
CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.
•
Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.
The Genome Project and Benzodiazepines In the following section, we will discuss databases and references which relate to the Genome Project and benzodiazepines. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).21 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 18 Adapted 19
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. 20 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. 21 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.
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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “benzodiazepines” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for benzodiazepines: •
Benzodiazepine Receptor, Peripheral Type Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109610 Genes and Disease (NCBI - Map)
The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •
Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html
•
Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html
•
Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html
•
Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html
•
Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html
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•
Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html
•
Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez
Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •
3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
•
Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books
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Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome
•
NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/
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Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide
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OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
•
PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset
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ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo
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Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein
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PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
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Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure
•
Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy
To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then
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select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “benzodiazepines” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database22 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html.
The Genome Database23 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “benzodiazepines” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).
22
Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 23 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.
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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 benzodiazepines 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 benzodiazepines. 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 benzodiazepines. 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 “benzodiazepines”:
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Other guides Amphetamine Abuse http://www.nlm.nih.gov/medlineplus/amphetamineabuse.html Bipolar Disorder http://www.nlm.nih.gov/medlineplus/bipolardisorder.html Club Drugs http://www.nlm.nih.gov/medlineplus/clubdrugs.html Gastroesophageal Reflux/Hiatal Hernia http://www.nlm.nih.gov/medlineplus/gastroesophagealrefluxhiatalhernia.html Interstitial Cystitis http://www.nlm.nih.gov/medlineplus/interstitialcystitis.html Multiple Sclerosis http://www.nlm.nih.gov/medlineplus/multiplesclerosis.html Neuromuscular Disorders http://www.nlm.nih.gov/medlineplus/neuromusculardisorders.html Panic Disorder http://www.nlm.nih.gov/medlineplus/panicdisorder.html Prescription Drug Abuse http://www.nlm.nih.gov/medlineplus/prescriptiondrugabuse.html
You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on benzodiazepines. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •
Medical Bulletin of the Restless Legs Syndrome Foundation, Inc Source: Rochester, MN: Restless Legs Syndrome Foundation, Inc. 1998. 15 p. Contact: Available from Restless Legs Syndrome Foundation, Inc. P.O. Box 7050, Rochester, MN 55903-7050. E-mail:
[email protected]. Website: www.rls.org. PRICE: Single copy free. Requires a self-addressed, stamped, business-sized envelope. Summary: Restless legs syndrome (RLS) is a distinctive but often misdiagnosed sensorymotor disorder. The features include paresthesias (uncomfortable sensations) in the
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limbs that compel the person to move in order to relieve the sensations, which occur when the afflicted individual is at rest, primarily in the evening and at night. This document is the annual medical bulletin from the Restless Legs Syndrome Foundation, a nonprofit agency that provides information about RLS, helps develop patient support groups, supports research to find better treatments, and publishes a quarterly patient newsletter. The bulletin describes the features of RLS, including dysesthesias, relief with movement, and increase in symptoms at rest; associated features, including limb movements in sleep, sleep disturbance, dyskinesias, positive family history, and disease course; the causes of the disorder (including anemia and iron deficiency accompanying end-stage renal disease, or ESRD); prevalence; diagnosis; treatment options, including nonpharmacologic therapies, treating underlying conditions including renal disease, and drug therapy. Drugs discussed include dopamine precursors and dopaminereceptor agonists, benzodiazepines, opioids, and anticonvulsants. The bulletin concludes that the diagnosis is generally easy if one is familiar with the syndrome. Therefore, it is incumbent upon clinicians to familiarize themselves with the symptoms of this common disorder to aid their patients in finding suitable treatments. The bulletin includes a lengthy bibliography, a list of references, and a brief description of the RLS Foundation. 64 references. •
Getting the Most Out of Your Medicines: A Guide for Patients With FMS/CFS (Fibromyalgia Syndrome/Chronic Fatigue Syndrome) Source: Tucson, AZ: Fibromyalgia Network. 2000. 82 p. Contact: Available from Fibromyalgia Network. P.O. Box 31750, Tucson, AZ 85751-1750. (800) 853-2929 or (520) 290-5508. Fax (520) 290-5550. Website: www.fmnetnews.com. PRICE: $10.00. Summary: This booklet provides people who have fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) with information on medications used to improve sleep, reduce pain, and minimize fatigue. The booklet explains the role of the central nervous system in controlling pain, sleep, and neuroendocrine/stress functions. This is followed by a discussion of the mechanism of action, dosage, and side effects of various drugs, including tricyclic antidepressants, benzodiazepines, muscle relaxants, sleeping aids, selective serotonin reuptake inhibitors, mild stimulants and neuromodulating drugs, nonsteroidal anti-inflammatory drugs, immune system modulators, calcium and sodium channel blockers, pain relievers, and antiyeast regimens. Other treatment modalities discussed include combination therapies, trigger point injections, and nutritive supplements. In addition, the booklet describes common associated syndromes and their treatment, including temporomandibular dysfunction syndrome, chronic headaches, irritable bowel and bladder syndromes, and dysautonomia. The booklet concludes with information on medicines for the future. A list of additional information resources is included. 6 figures, 4 tables, and 82 references.
•
Living with Restless Legs Source: Rochester, MN: Restless Legs Syndrome Foundation, Inc. 1998. 20 p. Contact: Available from Restless Legs Syndrome Foundation, Inc. P.O. Box 7050, Rochester, MN 55903-7050. E-mail:
[email protected]. PRICE: Single copy free. Requires a 55 cent self-addressed, business-sized envelope. Also available for free at www.rls.org/patient.htm. Summary: This brochure offers information about restless legs syndrome (RLS) and its impact on quality of life. RLS is a neurologic disorder with four primary features:
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bothersome sensations in the legs that produce an irresistible urge to move, symptoms that are worse at rest and lessened by voluntary movement, symptoms that are worse in the evening and at night, and movement of the toes, feet, or legs (restlessness) typically seen when the affected individual is sitting or lying down in the evening. The brochure begins with a checklist of symptoms to help readers determine if they have RLS. The brochure lists associated features, research in the cause of RLS, typical age of onset, diagnostic tests used to determine the presence of RLS, treatment options, and drug therapy, including that with dopaminergic agents, benzodiazepines, opioids, and anticonvulsants. The brochure emphasizes that choosing a healthy lifestyle, eliminating symptom-producing substances, taking vitamin and mineral supplements as necessary, and engaging in self-directed activities can all work toward reducing or eliminating the need for pharmacologic intervention. The centerfold of the brochure describes the Restless Legs Syndrome Foundation, a nonprofit agency that provides information about RLS, helps develop support groups, funds research to find better treatments, and publishes a quarterly newsletter; an envelope and donation form for supporting the foundation are included. The brochure concludes with a list of the members of the foundation's board of directors, a list of strategies for coping with RLS, and a list of additional resources. 12 references. •
Interstitial Cystitis and Pain Source: Rockville, MD: Interstitial Cystitis Association (ICA). 2003. [2 p.]. Contact: Available from Interstitial Cystitis Association (ICA). 110 North Washington Street, Suite 340, Rockville, MD 20850. (301) 610-5300. Fax (301) 610-5308. E-mail:
[email protected]. Website: www.ichelp.org. PRICE: $1.00 for members; $1.25 for nonmembers; plus shipping and handling. Item number: RFIP01. Summary: This fact sheet reviews the treatment guidelines for the pain associated with interstitial cystitis (IC), a chronic, painful inflammatory condition of the bladder wall. Although there is no cure for IC, many treatment options are currently available, and there have been many recent advances in pain research and therapies. Leading pain specialists in the United States believe that nonmalignant pain, such as the pain caused by IC, is as serious and debilitating as malignant pain (that due to cancer) and should be treated just as aggressively. This aggressive treatment includes opiate therapy when more conservative approaches fail. The fact sheet reviews drugs used, including non opioid pain medications (aspirin, acetominophen, and nonsteroidal antiinflammatory drugs), tricyclic antidepressants, Pentosan polysulfate sodium (Elmiron), local anesthetics, anticonvulsants, benzodiazepines, antihistamines, tramadol (Ultram), and opioid pain medications. In each category, the fact sheet reviews the use of the drug and the potential side effects. The author notes that nonpharmacologic treatments for IC pain (diet modification, physical therapy, acupuncture, transcutaneous electric nerve stimulation, biofeedback, hypnosis, cognitive therapy) can play a valuable, complementary role in the treatment of IC pain. The fact sheet includes the contact information for the Interstitial Cystitis Association (ICA). 2 references.
•
Recreational Drugs and HIV Antivirals: A Guide to Interactions for Clinicians Contact: US Department of Health and Human Services, Public Health Service, Health Resources and Services Administration, HIV/AIDS Bureau, Office of Communications, 5600 Fishers Ln Rm 14-15, Rockville, MD, 20857, (301) 443-6652, http://hab.hrsa.gov/. Summary: This pamphlet is intended for use by clinicians and other health care professionals to provide advice that may reduce harm to patients who use recreational
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drugs in conjunction with antiretroviral agents. The pamphlet identifies the general and pharmacokinetic effects of alcohol, amphetamines, amyl nitrite, benzodiazepines, cocaine, ecstasy, gamma-hydroxy-butyrate, heroin, ketamine, LSD, marijuana, and methadone. The pamphlet also describes the known interactions of these substances with antiretroviral agents. 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 benzodiazepines. 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
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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
Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to benzodiazepines. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with benzodiazepines. 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 benzodiazepines. 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.
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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 “benzodiazepines” (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 “benzodiazepines”. 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 “benzodiazepines” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “benzodiazepines” (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.24
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
24
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)25: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
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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
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
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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
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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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/
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Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
25
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/
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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
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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
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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/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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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
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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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/
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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
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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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
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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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/
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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). The NIH suggests the following Web sites in the ADAM Medical Encyclopedia when searching for information on benzodiazepines: •
Basic Guidelines for Benzodiazepines Librium overdose Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002665.htm
•
Signs & Symptoms for Benzodiazepines Abdominal pain Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003120.htm Anxiety Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm Bluish skin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm Blurred vision Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003029.htm
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Coma Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Confusion Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003205.htm Convulsions Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003200.htm Depression Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003213.htm Dizziness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003093.htm Drowsiness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003208.htm Emesis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Incoordination Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003198.htm Memory loss Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003257.htm Muscle contractions Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003193.htm Rash Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Stupor Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003202.htm Upset stomach Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Vomiting Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003117.htm Weakness Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003174.htm •
Diagnostics and Tests for Benzodiazepines Gastric lavage Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003882.htm
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•
Background Topics for Benzodiazepines Labored breathing Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000007.htm Respiratory Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002290.htm Unconscious Web site: http://www.nlm.nih.gov/medlineplus/ency/article/000022.htm
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/
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Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine
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BENZODIAZEPINES DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abacavir: A nucleoside analog reverse transcriptase inhibitor (NARTIs) developed by Glaxo Wellcome. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abscess: A localized, circumscribed collection of pus. [NIH] Abulia: Impairment or loss of will power. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] 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] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acupuncture Analgesia: Analgesia produced by the insertion of acupuncture needles at certain points in the body. These activate the small myelinated nerve fibers in the muscle which transmit impulses to the spinal cord and then activate three centers - the spinal cord, midbrain and pituitary hypothalamus - to produce analgesia. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH]
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Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of cyclic AMP and pyrophosphate from ATP. EC 4.6.1.1. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenergic Agents: Drugs that act on adrenergic receptors or affect the life cycle of adrenergic transmitters. Included here are adrenergic agonists and antagonists and agents that affect the synthesis, storage, uptake, metabolism, or release of adrenergic transmitters. [NIH]
Adrenergic Agonists: Drugs that bind to and activate adrenergic receptors. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]
Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds
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specifically to the molecule to be purified. [NIH] AFP: Alpha-fetoprotein. A protein normally produced by a developing fetus. AFP levels are usually undetectable in the blood of healthy nonpregnant adults. An elevated level of AFP suggests the presence of either a primary liver cancer or germ cell tumor. [NIH] 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] Ageing: A physiological or morphological change in the life of an organism or its parts, generally irreversible and typically associated with a decline in growth and reproductive vigor. [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] Agoraphobia: Obsessive, persistent, intense fear of open places. [NIH] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [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] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Alexia: The inability to recognize or comprehend written or printed words. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. [NIH]
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Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (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] Amenorrhea: Absence of menstruation. [NIH] Amination: The creation of an amine. It can be produced by the addition of an amino group to an organic compound or reduction of a nitro group. [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 Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [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] Amnesia: Lack or loss of memory; inability to remember past experiences. [EU] 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] Ampulla: A sac-like enlargement of a canal or duct. [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]
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Amyl Nitrite: A vasodilator that is administered by inhalation. It is also used recreationally due to its supposed ability to induce euphoria and act as an aphrodisiac. [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anabolic Steroids: Chemical derivatives of testosterone that are used for anabolic promotion of growth and repair of body tissues and the development of male sexual characteristics. [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] Analeptic: A drug which acts as a restorative, such as caffeine, amphetamine, pentylenetetrazol, etc. [EU] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analgesics, Opioid: Narcotic or opioid substances, synthetic or semisynthetic agents producing profound analgesia, drowsiness, and changes in mood. Mood changes may be pleasurable, therefore creating a potential for the abuse of these agents; the prototype of these is morphine to which all other analgesics are compared. [NIH] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Anaphylatoxins: The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgenic: Producing masculine characteristics. [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] Angina: Chest pain that originates in the heart. [NIH] Anginal: Pertaining to or characteristic of angina. [EU] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH]
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Animal Husbandry: The science of breeding, feeding, and care of domestic animals; includes housing and nutrition. [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] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [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] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]
Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Anthramycin: A broad-spectrum spectrum antineoplastic antibiotic isolated from Streptomyces refuineus var. thermotolerans. It has low toxicity, some activity against Trichomonas and Endamoeba, and inhibits RNA and DNA synthesis. It binds irreversibly to DNA. [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] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on 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] Anticonvulsive: An agent that prevents or relieves convulsions. [NIH] Antidepressant: A drug used to treat depression. [NIH]
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Antidepressive Agents: Mood-stimulating drugs used primarily in the treatment of 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] Antidiuretic: Suppressing the rate of urine formation. [EU] Antidote: A remedy for counteracting a poison. [EU] Antiemetic: An agent that prevents or alleviates nausea and vomiting. Also antinauseant. [EU]
Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antigen-Antibody Complex: The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] 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
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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] Antispasmodic: An agent that relieves spasm. [EU] Antitumour: Counteracting tumour formation. [EU] Antitussive: An agent that relieves or prevents cough. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiety Disorders: Disorders in which anxiety (persistent feelings of apprehension, tension, or uneasiness) is the predominant disturbance. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Apathy: Lack of feeling or emotion; indifference. [EU] Apnea: A transient absence of spontaneous respiration. [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] Aqueous: Having to do with water. [NIH] Arachidonate 12-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in platelets. EC 1.13.11.31. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Aromatic: Having a spicy odour. [EU]
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Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Aspartate: A synthetic amino acid. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Asphyxia: A pathological condition caused by lack of oxygen, manifested in impending or actual cessation of life. [NIH] Aspiration: The act of inhaling. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [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] Astrocytoma: A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] 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] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH]
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Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Auditory: Pertaining to the sense of hearing. [EU] Auditory Perception: The process whereby auditory stimuli are selected, organized and interpreted by the organism; includes speech discrimination. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Baclofen: A GABA derivative that is a specific agonist at GABA-B receptors. It is used in the treatment of spasticity, especially that due to spinal cord damage. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. [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] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as sedatives and anesthetics, and they have been used to treat the convulsions associated with epilepsy. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH]
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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] Baths: The immersion or washing of the body or any of its parts in water or other medium for cleansing or medical treatment. It includes bathing for personal hygiene as well as for medical purposes with the addition of therapeutic agents, such as alkalines, antiseptics, oil, etc. [NIH] Behavioral Symptoms: Observable manifestions of impaired psychological functioning. [NIH]
Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
Benzaldehyde: A colorless oily liquid used as a flavoring agent and to make dyes, perfumes, and pharmaceuticals. Benzaldehyde is chemically related to benzene. [NIH] Benzamides: Benzoic acid amides. [NIH] Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Benzoquinones: Benzene rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups. [NIH] Beta blocker: A drug used to slow the heart rate and reduce pressure inside blood vessels. It also can regulate heart rhythm. [NIH] Betahistine: N-Methyl-2-pyridineethanamine. A physiological histamine analog vasodilator agent that also acts as a histamine H1 receptor agonist. It is used in Meniere's disease and in vascular headaches but may exacerbate bronchial asthma and peptic ulcers. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bicuculline: Isoquinoline alkaloid from Dicentra cucullaria and other plants that is a competitive antagonist at GABA-A receptors and thus causes convulsions. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH]
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Binding agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] 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] Biological Assay: A method of measuring the effects of a biologically active substance using an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc. [NIH] Biological Factors: Compounds made by living organisms that contribute to or influence a phenomenon or process. They have biological or physiological activities. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [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] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [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] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood 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,
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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 Fluids: Liquid components of living organisms. [NIH] Body Regions: Anatomical areas of the body. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] 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] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Brain Ischemia: Localized reduction of blood flow to brain tissue due to arterial obtruction or systemic hypoperfusion. This frequently occurs in conjuction with brain hypoxia. Prolonged ischemia is associated with brain infarction. [NIH] Brain Stem: The part of the brain that connects the cerebral hemispheres with the spinal cord. It consists of the mesencephalon, pons, and medulla oblongata. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]
Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchiectasis: Persistent abnormal dilatation of the bronchi. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Burning Mouth Syndrome: A group of painful oral symptoms associated with a burning or similar sensation. There is usually a significant organic component with a degree of functional overlay; it is not limited to the psychophysiologic group of disorders. [NIH]
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Bursitis: Inflammation of a bursa, occasionally accompanied by a calcific deposit in the underlying supraspinatus tendon; the most common site is the subdeltoid bursa. [EU] 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] Butyric Acid: A four carbon acid, CH3CH2CH2COOH, with an unpleasant odor that occurs in butter and animal fat as the glycerol ester. [NIH] Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [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] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Cannabidiol: Compound isolated from Cannabis sativa extract. [NIH] Cannabinoids: Compounds extracted from Cannabis sativa L. and metabolites having the cannabinoid structure. The most active constituents are tetrahydrocannabinol, cannabinol, and cannabidiol. [NIH] Cannabinol: A physiologically inactive constituent of Cannabis sativa L. [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] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas
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(tight junctions) which may limit large molecule movement. [NIH] Capsaicin: Cytotoxic alkaloid from various species of Capsicum (pepper, paprika), of the Solanaceae. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] 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-, polyand heterosaccharides. [EU] Carbolines: A group of pyridoindole compounds. Allowed are any points of fusion of pyridine with the five-membered ring of indole and any derivatives of these compounds. [NIH]
Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Cardiovascular System: The heart and the blood vessels by which blood is pumped and circulated through the body. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotid Arteries: Either of the two principal arteries on both sides of the neck that supply blood to the head and neck; each divides into two branches, the internal carotid artery and the external carotid artery. [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-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship
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of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspases: A family of intracellular cysteine endopeptidases. They play a key role in inflammation and mammalian apoptosis. They are specific for aspartic acid at the P1 position. They are divided into two classes based on the lengths of their N-terminal prodomains. Caspases-1,-2,-4,-5,-8, and -10 have long prodomains and -3,-6,-7,-9 have short prodomains. EC 3.4.22.-. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Communication: Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell Extracts: Preparations of cell constituents or subcellular materials, isolates, or substances. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cellobiose: A disaccharide consisting of two glucose units in beta (1-4) glycosidic linkage. Obtained from the partial hydrolysis of cellulose. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange
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materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] 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 Arteries: The arteries supplying the cerebral cortex. [NIH] Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]
Cerebral Palsy: Refers to a motor disability caused by a brain dysfunction. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrovascular Disorders: A broad category of disorders characterized by impairment of blood flow in the arteries and veins which supply the brain. These include cerebral infarction; brain ischemia; hypoxia, brain; intracranial embolism and thrombosis; intracranial arteriovenous malformations; and vasculitis, central nervous system. In common usage, the term cerebrovascular disorders is not limited to conditions that affect the cerebrum, but refers to vascular disorders of the entire brain including the diencephalon; brain stem; and cerebellum. [NIH] 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] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] 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] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH]
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Chimeras: Organism that contains a mixture of genetically different cells. [NIH] Chlorine: A greenish-yellow, diatomic gas that is a member of the halogen family of elements. It has the atomic symbol Cl, atomic number 17, and atomic weight 70.906. It is a powerful irritant that can cause fatal pulmonary edema. Chlorine is used in manufacturing, as a reagent in synthetic chemistry, for water purification, and in the production of chlorinated lime, which is used in fabric bleaching. [NIH] Cholecystitis: Inflammation of the gallbladder. [NIH] Cholecystokinin: A 33-amino acid peptide secreted by the upper intestinal mucosa and also found in the central nervous system. It causes gallbladder contraction, release of pancreatic exocrine (or digestive) enzymes, and affects other gastrointestinal functions. Cholecystokinin may be the mediator of satiety. [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] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Cholinergic Agonists: Drugs that bind to and activate cholinergic receptors. [NIH] Cholinesterase Inhibitors: Drugs that inhibit cholinesterases. The neurotransmitter acetylcholine is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. [NIH] Chorea: Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. [NIH] Choreatic Disorders: Acquired and hereditary conditions which feature chorea as a primary manifestation of the disease process. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromaffin Cells: Cells that store epinephrine secretory vesicles. During times of stress, the nervous system signals the vesicles to secrete their hormonal content. Their name derives from their ability to stain a brownish color with chromic salts. Characteristically, they are located in the adrenal medulla and paraganglia (paraganglia, chromaffin) of the sympathetic nervous system. [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] Chromic: Catgut sterilized and impregnated with chromium trioxide. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Fatigue Syndrome: Fatigue caused by the combined effects of different types of prolonged fatigue. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or
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transplantation to replace the work of the kidneys. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Citalopram: A selective neuronal serotonin reuptake inhibitor and a clinically effective antidepressant with tolerable side effects. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia (TD) in preference to tricyclic antidepressants, which aggravate this condition. [NIH]
Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical 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] Clozapine: A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Coal: A natural fuel formed by partial decomposition of vegetable matter under certain environmental conditions. [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 thought to involve inhibition of dopamine uptake. [NIH]
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Cochlear: Of or pertaining to the cochlea. [EU] Cochlear Diseases: Diseases of the cochlea, the part of the inner ear that is concerned with hearing. [NIH] Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [NIH] 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] Cognitive restructuring: A method of identifying and replacing fear-promoting, irrational beliefs with more realistic and functional ones. [NIH] Cognitive Therapy: A direct form of psychotherapy based on the interpretation of situations (cognitive structure of experiences) that determine how an individual feels and behaves. It is based on the premise that cognition, the process of acquiring knowledge and forming beliefs, is a primary determinant of mood and behavior. The therapy uses behavioral and verbal techniques to identify and correct negative thinking that is at the root of the aberrant behavior. [NIH] Colic: Paroxysms of pain. This condition usually occurs in the abdominal region but may occur in other body regions as well. [NIH] Coliphages: Viruses whose host is Escherichia coli. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Combinatorial Chemistry Techniques: A chemistry-based technology in which sets of reactions, for solution or solid-phase synthesis, are used to create molecular libraries for analysis of compounds on a large scale. [NIH] Comorbidity: The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity
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may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, 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] Compulsion: 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 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] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congestion: Excessive or abnormal accumulation of blood in a part. [EU]
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Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Conscious Sedation: An alternative to general anesthesia in patients for whom general anesthesia is refused or considered inadvisable. It involves the administering of an antianxiety drug (minor tranquilizer) and an analgesic or local anesthetic. This renders the patient free of anxiety and pain while allowing the patient to remain in verbal contact with the physician or dentist. [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] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [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]
Convulsants: Substances that act in the brain stem or spinal cord to produce tonic or clonic convulsions, often by removing normal inhibitory tone. They were formerly used to stimulate respiration or as antidotes to barbiturate overdose. They are now most commonly used as experimental tools. [NIH] Convulsion: A violent involuntary contraction or series of contractions of the voluntary muscles. [EU] 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]
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Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Artery Bypass: Surgical therapy of ischemic coronary artery disease achieved by grafting a section of saphenous vein, internal mammary artery, or other substitute between the aorta and the obstructed coronary artery distal to the obstructive lesion. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronary Vasospasm: Spasm of the large- or medium-sized coronary arteries. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroids: Hormones that have antitumor activity in lymphomas and lymphoid leukemias; in addition, corticosteroids (steroids) may be used for hormone replacement and for the management of some of the complications of cancer and its treatment. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Cranial Nerves: Twelve pairs of nerves that carry general afferent, visceral afferent, special afferent, somatic efferent, and autonomic efferent fibers. [NIH] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Curare: Plant extracts from several species, including Strychnos toxifera, S. castelnaei, S. crevauxii, and Chondodendron tomentosum, that produce paralysis of skeletal muscle and are used adjunctively with general anesthesia. These extracts are toxic and must be used with the administration of artificial respiration. [NIH] 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] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH]
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Cysteine Endopeptidases: Endopeptidases which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by sulfhydryl reagents. EC 3.4.22. [NIH] Cystitis: Inflammation of the urinary bladder. [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] Cytotoxic: Cell-killing. [NIH] Dangerous Behavior: Actions which have a high risk of being harmful or injurious to oneself or others. [NIH] Dantrolene: Skeletal muscle relaxant that acts by interfering with excitation-contraction coupling in the muscle fiber. It is used in spasticity and other neuromuscular abnormalities. Although the mechanism of action is probably not central, dantrolene is usually grouped with the central muscle relaxants. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] 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
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also acute confusional state and acute brain syndrome. [EU] Delusions: A false belief regarding the self or persons or objects outside the self that persists despite the facts, and is not considered tenable by one's associates. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Dental Care: The total of dental diagnostic, preventive, and restorative services provided to meet the needs of a patient (from Illustrated Dictionary of Dentistry, 1982). [NIH] Dental Caries: Localized destruction of the tooth surface initiated by decalcification of the enamel followed by enzymatic lysis of organic structures and leading to cavity formation. If left unchecked, the cavity may penetrate the enamel and dentin and reach the pulp. The three most prominent theories used to explain the etiology of the disase are that acids produced by bacteria lead to decalcification; that micro-organisms destroy the enamel protein; or that keratolytic micro-organisms produce chelates that lead to decalcification. [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] Dentists: Individuals licensed to practice dentistry. [NIH] Depersonalization: Alteration in the perception of the self so that the usual sense of one's own reality is lost, manifested in a sense of unreality or self-estrangement, in changes of body image, or in a feeling that one does not control his own actions and speech; seen in depersonalization disorder, schizophrenic disorders, and schizotypal personality disorder. Some do not draw a distinction between depersonalization and derealization, using depersonalization to include both. [EU] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Deprivation: Loss or absence of parts, organs, powers, or things that are needed. [EU] Derealization: Is characterized by the loss of the sense of reality concerning one's surroundings. [NIH] DES: Diethylstilbestrol. A synthetic hormone that was prescribed from the early 1940s until 1971 to help women with complications of pregnancy. DES has been linked to an increased risk of clear cell carcinoma of the vagina in daughters of women who used DES. DES may also increase the risk of breast cancer in women who used DES. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by
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administration of graded immunotherapy. [EU]
doses
of
allergen;
called
also
hyposensitization
and
Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Devazepide: A derivative of benzodiazepine that acts on the cholecystokinin A (CCKA) receptor to antagonize CCK-8's (sincalide) physiological and behavioral effects, such as pancreatic stimulation and inhibition of feeding. [NIH] 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 Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diamines: Organic chemicals which have two amino groups in an aliphatic chain. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diarrhoea: Abnormal frequency and liquidity of faecal discharges. [EU] Diastolic: Of or pertaining to the diastole. [EU] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dihydroprogesterone: 20 alpha-Hydroxypregn-4-en-3-one. progesterone derivative with progestational activity. [NIH]
A
naturally
occurring
Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation: The act of dilating. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] Diphenhydramine: A histamine H1 antagonist used as an antiemetic, antitussive, for dermatoses and pruritus, for hypersensitivity reactions, as a hypnotic, an antiparkinson, and as an ingredient in common cold preparations. It has some undesired antimuscarinic and sedative effects. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU]
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Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] 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] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Donepezil: A drug used in the treatment of Alzheimer's disease. It belongs to the family of drugs called cholinesterase inhibitors. It is being studied as a treatment for side effects caused by radiation therapy to the brain. [NIH] 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] Dopamine Agents: Any drugs that are used for their effects on dopamine receptors, on the life cycle of dopamine, or on the survival of dopaminergic neurons. [NIH] Dopamine Agonists: Drugs that bind to and activate dopamine receptors. [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] Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] 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] Dracunculus: A genus of nematode parasites which inhabit the body cavity, serous membranes, and connective tissues of vertebrates. The species parasitic in man is Dracunculus medinensis. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNA-
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binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [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] Duct: A tube through which body fluids pass. [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] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyslexia: Partial alexia in which letters but not words may be read, or in which words may be read but not understood. [NIH] Dyspareunia: Painful sexual intercourse. [NIH] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystonia: Disordered tonicity of muscle. [EU] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Ejaculation: The release of semen through the penis during orgasm. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH]
Dictionary 199
Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electroconvulsive Therapy: Electrically induced convulsions primarily used in the treatment of severe affective disorders and schizophrenia. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [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] Electrophysiological: Pertaining to electrophysiology, that is a branch of physiology that is concerned with the electric phenomena associated with living bodies and involved in their functional activity. [EU] Emboli: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] 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] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH]
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Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endoscope: A thin, lighted tube used to look at tissues inside the body. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] Enterotoxins: Substances that are toxic to the intestinal tract causing vomiting, diarrhea, etc.; most common enterotoxins are produced by bacteria. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Enucleation: Removal of the nucleus from an eucaryiotic cell. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]
Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Ergot: Cataract due to ergot poisoning caused by eating of rye cereals contaminated by a fungus. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus.
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Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Escalation: Progressive use of more harmful drugs. [NIH] Esophagitis: Inflammation, acute or chronic, of the esophagus caused by bacteria, chemicals, or trauma. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Estazolam: A benzodiazepine with anticonvulsant, hypnotic, and muscle relaxant properties. It has been shown in some cases to be more potent than diazepam or nitrazepam. [NIH]
Estrogen: One of the two female sex hormones. [NIH] Estrogen Replacement Therapy: The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, dyspareunia, and progressive development of osteoporosis. This may also include the use of progestational agents in combination therapy. [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] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Euphoria: An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. [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] Excitability: Property of a cardiac cell whereby, when the cell is depolarized to a critical level (called threshold), the membrane becomes permeable and a regenerative inward current causes an action potential. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] 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] Excitatory Amino Acids: Endogenous amino acids released by neurons as excitatory
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neurotransmitters. Glutamic acid is the most common excitatory neurotransmitter in the brain. Aspartic acid has been regarded as an excitatory transmitter for many years, but the extent of its role as a transmitter is unclear. [NIH] Excrete: To get rid of waste from the body. [NIH] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extracellular: Outside a cell or cells. [EU] Extracorporeal: Situated or occurring outside the body. [EU] Extracorporeal Circulation: Diversion of blood flow through a circuit located outside the body but continuous with the bodily circulation. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Facial: Of or pertaining to the face. [EU] Facial Pain: Pain in the facial region including orofacial pain and craniofacial pain. Associated conditions include local inflammatory and neoplastic disorders and neuralgic syndromes involving the trigeminal, facial, and glossopharyngeal nerves. Conditions which feature recurrent or persistent facial pain as the primary manifestation of disease are referred to as facial pain syndromes. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Farnesyl: Enzyme which adds 15 carbon atoms to the Ras precursor protein. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]
Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Febrile: Pertaining to or characterized by fever. [EU] 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 Neck Fractures: Fractures of the short, constricted portion of the thigh bone between the femur head and the trochanters. It excludes intertrochanteric fractures which are hip fractures. [NIH] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fenfluramine: A centrally active drug that apparently both blocks serotonin uptake and provokes transport-mediated serotonin release. [NIH] Fentanyl: A narcotic opioid drug that is used in the treatment of pain. [NIH] Fetal Alcohol Syndrome: A disorder occurring in children born to alcoholic women who
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continue to drink heavily during pregnancy. Common abnormalities are growth deficiency (prenatal and postnatal), altered morphogenesis, mental deficiency, and characteristic facies - small eyes and flattened nasal bridge. Fine motor dysfunction and tremulousness are observed in the newborn. [NIH] Fetoprotein: Transabdominal aspiration of fluid from the amniotic sac with a view to detecting increases of alpha-fetoprotein in maternal blood during pregnancy, as this is an important indicator of open neural tube defects in the fetus. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [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] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flumazenil: A potent benzodiazepine receptor antagonist. Since it reverses the sedative and other actions of benzodiazepines, it has been suggested as an antidote to benzodiazepine overdoses. [NIH] Flunitrazepam: Benzodiazepine with pharmacologic actions similar to those of diazepam. The United States Government has banned the importation of this drug. Steps are being taken to reclassify this substance as a Schedule 1 drug with no accepted medical use. [NIH] Fluorine: A nonmetallic, diatomic gas that is a trace element and member of the halogen family. It is used in dentistry as flouride to prevent dental caries. [NIH] Fluoxetine: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. [NIH]
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Flurazepam: A benzodiazepine derivative used mainly as a hypnotic. [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] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] GABA: The most common inhibitory neurotransmitter in the central nervous system. [NIH] Galanthamine: A cholinesterase inhibitor. It has been used to reverse the muscular effects of gallamine and tubocurarine and has been studied as a treatment for Alzheimer's disease and other central nervous system disorders. [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] Gasoline: Volative flammable fuel (liquid hydrocarbons) derived from crude petroleum by processes such as distillation reforming, polymerization, etc. [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]
Gastritis: Inflammation of the stomach. [EU] 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] Gastroenterology: A subspecialty of internal medicine concerned with the study of the physiology and diseases of the digestive system and related structures (esophagus, liver, gallbladder, and pancreas). [NIH] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes
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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] General practitioner: A medical practitioner who does not specialize in a particular branch of medicine or limit his practice to a specific class of diseases. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genital: Pertaining to the genitalia. [EU] Genitourinary: Pertaining to the genital and urinary organs; urogenital; urinosexual. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Giant Cells: Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. [NIH] Ginkgo biloba: Exclusive species of the genus Ginkgo, family Ginkgoacea. It produces extracts of medicinal interest. Ginkgo may refer to the genus or species. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]
Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glossopharyngeal Nerve: The 9th cranial nerve. The glossopharyngeal nerve is a mixed motor and sensory nerve; it conveys somatic and autonomic efferents as well as general, special, and visceral afferents. Among the connections are motor fibers to the
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stylopharyngeus muscle, parasympathetic fibers to the parotid glands, general and taste afferents from the posterior third of the tongue, the nasopharynx, and the palate, and afferents from baroreceptors and chemoreceptors of the carotid sinus. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] 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] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glucuronides: Glycosides of glucuronic acid formed by the reaction of uridine diphosphate glucuronic acid with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and bilirubin metabolism to a more water-soluble compound that can be eliminated in the urine and bile. [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]
Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]
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] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Gonadal: Pertaining to a gonad. [EU] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Grafting: The operation of transfer of tissue from one site to another. [NIH] Granule: A small pill made from sucrose. [EU]
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Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Guanosine Diphosphate: Guanosine 5'-(trihydrogen diphosphate). A guanine nucleotide containing two phosphate groups esterified to the sugar moiety. Synonyms: GRPP; guanosine pyrophosphate. [NIH] Guanosine Triphosphate: Guanosine 5'-(tetrahydrogen triphosphate). A guanine nucleotide containing three phosphate groups esterified to the sugar moiety. [NIH] Habituation: Decline in response of an organism to environmental or other stimuli with repeated or maintained exposure. [NIH] Haematemesis: The vomiting of blood. [EU] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] 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] 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] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Services: Services for the diagnosis and treatment of disease and the maintenance of health. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [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] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level
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may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhoids: Varicosities of the hemorrhoidal venous plexuses. [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] Hepatic Encephalopathy: A condition that may cause loss of consciousness and coma. It is usually the result of advanced liver disease. Also called hepatic coma. [NIH] Hepatocytes: The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
Hip Fractures: Fractures of the femur head, the femur neck, the trochanters, or the inter- or subtrochanteric region. Excludes fractures of the acetabulum and fractures of the femoral shaft below the subtrochanteric region. For the fractures of the femur neck the specific term femoral neck fractures is available. [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] Holidays: Days commemorating events. Holidays also include vacation periods. [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] 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]
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Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridization: The genetic process of crossbreeding to produce a hybrid. Hybrid nucleic acids can be formed by nucleic acid hybridization of DNA and RNA molecules. Protein hybridization allows for hybrid proteins to be formed from polypeptide chains. [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] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxamic Acids: A class of weak acids with the general formula R-conhoh. [NIH] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperkinesia: Abnormally increased motor function or activity; hyperactivity. [EU] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersecretion: Excessive secretion. [EU] 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] 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] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycaemia: An abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache, accompanied by irritability, confusion, hallucinations, bizarre behaviour, and ultimately, convulsions and coma. [EU] Hypotension: Abnormally low blood pressure. [NIH] 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] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate
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perfusion of the tissue by blood. [EU] Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Ibuprofen: A nonsteroidal anti-inflammatory agent with analgesic properties used in the therapy of rheumatism and arthritis. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Illusions: The misinterpretation of a real external, sensory experience. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Imipramine: The prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group. [NIH]
Immersion: The placing of a body or a part thereof into a liquid. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunoenzyme Techniques: Immunologic techniques based on the use of: (1) enzymeantibody conjugates; (2) enzyme-antigen conjugates; (3) antienzyme antibody followed by its homologous enzyme; or (4) enzyme-antienzyme complexes. These are used histologically for visualizing or labeling tissue specimens. [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] Immunosuppressive: Describes the ability to lower immune system responses. [NIH]
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Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [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] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] 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]
Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [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]
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Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]
Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [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] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inlay: In dentistry, a filling first made to correspond with the form of a dental cavity and then cemented into the cavity. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] 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] Intensive Care: Advanced and highly specialized care provided to medical or surgical patients whose conditions are life-threatening and require comprehensive care and constant monitoring. It is usually administered in specially equipped units of a health care facility. [NIH]
Interindividual: Occurring between two or more individuals. [EU] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] 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]
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Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intervention Studies: Epidemiologic investigations designed to test a hypothesized causeeffect relation by modifying the supposed causal factor(s) in the study population. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intracranial Embolism: The sudden obstruction of a blood vessel by an embolus. [NIH] Intracranial Embolism and Thrombosis: Embolism or thrombosis involving blood vessels which supply intracranial structures. Emboli may originate from extracranial or intracranial sources. Thrombosis may occur in arterial or venous structures. [NIH] Intracranial Hypertension: Increased pressure within the cranial vault. This may result from several conditions, including hydrocephalus; brain edema; intracranial masses; severe systemic hypertension; pseudotumor cerebri; and other disorders. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Intrinsic Factor: A glycoprotein secreted by the cells of the gastric glands that is required for the absorption of vitamin B 12. Deficiency of intrinsic factor results in pernicious anemia. [NIH]
Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
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] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isopropyl: A gene mutation inducer. [NIH] Jealousy: An irrational reaction compounded of grief, loss of self-esteem, enmity against the rival and self criticism. [NIH] Jet lag: Symptoms produced in human beings by fast travel through large meridian difference. [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that
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surround and support it. [NIH] Kainic Acid: (2S-(2 alpha,3 beta,4 beta))-2-Carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid. Ascaricide obtained from the red alga Digenea simplex. It is a potent excitatory amino acid agonist at some types of excitatory amino acid receptors and has been used to discriminate among receptor types. Like many excitatory amino acid agonists it can cause neurotoxicity and has been used experimentally for that purpose. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH] Kava: Dried rhizome and roots of Piper methysticum, a shrub native to Oceania and known for its anti-anxiety and sedative properties. Heavy usage results in some adverse effects. It contains alkaloids, lactones, kawain, methysticin, mucilage, starch, and yangonin. Kava is also the name of the pungent beverage prepared from the plant's roots. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] 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] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually 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] Kynurenic Acid: A broad-spectrum excitatory amino acid antagonist used as a research tool. [NIH]
Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lag: The time elapsing between application of a stimulus and the resulting reaction. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no
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troublesome effect. [NIH] Lavage: A cleaning of the stomach and colon. Uses a special drink and enemas. [NIH] Legionellosis: Infections with bacteria of the genus Legionella. [NIH] Length of Stay: The period of confinement of a patient to a hospital or other health facility. [NIH]
Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] 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] Library Services: Services offered to the library user. They include reference and circulation. [NIH]
Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] 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] Linkages: 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] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5-
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lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Lipoxygenase Inhibitors: Compounds or agents that combine with lipoxygenase and thereby prevent its substrate-enzyme combination with arachidonic acid and the formation of the eicosanoid products hydroxyeicosatetraenoic acid and various leukotrienes. [NIH] Lithium: An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight 6.94. Salts of lithium are used in treating manic-depressive disorders. [NIH]
Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]
Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [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] Long-Term Care: Care over an extended period, usually for a chronic condition or disability, requiring periodic, intermittent, or continuous care. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH]
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Lysergic acid: A compound close in chemical structure to LSD-25 but without hallucinogenic effects; one of the direct chemical predecessors of LSD-25. Sometimes LSD-25 is erroneously called by this name. [NIH] Lysergic Acid Diethylamide: Semisynthetic derivative of ergot (Claviceps purpurea). It has complex effects on serotonergic systems including antagonism at some peripheral serotonin receptors, both agonist and antagonist actions at central nervous system serotonin receptors, and possibly effects on serotonin turnover. It is a potent hallucinogen, but the mechanisms of that effect are not well understood. [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] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mania: Excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behaviour, and elevation of mood. [EU] Manic: Affected with mania. [EU] Manic-depressive psychosis: One of a group of psychotic reactions, fundamentally marked by severe mood swings and a tendency to remission and recurrence. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] 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] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH]
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Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental deficiency: A condition of arrested or incomplete development of mind from inherent causes or induced by disease or injury. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mescaline: Hallucinogenic alkaloid isolated from the flowering heads (peyote) of Lophophora (formerly Anhalonium) williamsii, a Mexican cactus used in Indian religious rites and as an experimental psychotomimetic. Among its cellular effects are agonist actions at some types of serotonin receptors. It has no accepted therapeutic uses although it is legal for religious use by members of the Native American Church. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH] Mesolimbic: Inner brain region governing emotion and drives. [NIH] Meta-Analysis: A quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc., with application chiefly in the areas of research and medicine. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and
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viruses. [NIH] Microcirculation: The vascular network lying between the arterioles and venules; includes capillaries, metarterioles and arteriovenous anastomoses. Also, the flow of blood through this network. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Midazolam: A short-acting compound, water-soluble at pH less than 4 and lipid-soluble at physiological pH. It is a hypnotic-sedative drug with anxiolytic and amnestic properties. It is used for sedation in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. Because of its short duration and cardiorespiratory stability, it is particularly useful in poor-risk, elderly, and cardiac patients. [NIH]
Middle Cerebral Artery: The largest and most complex of the cerebral arteries. Branches of the middle cerebral artery supply the insular region, motor and premotor areas, and large regions of the association cortex. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [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] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
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] Monoamine Oxidase: An enzyme that catalyzes the oxidative deamination of naturally occurring monoamines. It is a flavin-containing enzyme that is localized in mitochondrial membranes, whether in nerve terminals, the liver, or other organs. Monoamine oxidase is important in regulating the metabolic degradation of catecholamines and serotonin in neural or target tissues. Hepatic monoamine oxidase has a crucial defensive role in inactivating circulating monoamines or those, such as tyramine, that originate in the gut and are
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absorbed into the portal circulation. (From Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 8th ed, p415) EC 1.4.3.4. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Mood Disorders: Those disorders that have a disturbance in mood as their predominant feature. [NIH] Morale: The prevailing temper or spirit of an individual or group in relation to the tasks or functions which are expected. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphogenesis: The development of the form of an organ, part of the body, or organism. [NIH]
Morphological: Relating to the configuration or the structure of live organs. [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH] Motor nerve: An efferent nerve conveying an impulse that excites muscular contraction. [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] Mucociliary: Pertaining to or affecting the mucus membrane and hairs (including eyelashes, nose hair, .): mucociliary clearing: the clearance of mucus by ciliary movement ( particularly in the respiratory system). [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscle relaxant: An agent that specifically aids in reducing muscle tension, as those acting at the polysynaptic neurons of motor nerves (e.g. meprobamate) or at the myoneural junction (curare and related compounds). [EU] Muscle tension: A force in a material tending to produce extension; the state of being stretched. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be
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induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] 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] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Naloxone: A specific opiate antagonist that has no agonist activity. It is a competitive antagonist at mu, delta, and kappa opioid receptors. [NIH] Naltrexone: Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of naloxone. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence. [NIH] Narcosis: A general and nonspecific reversible depression of neuronal excitability, produced by a number of physical and chemical aspects, usually resulting in stupor. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Narcotic Antagonists: Agents inhibiting the effect of narcotics on the central nervous system. [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] Neck Muscles: The neck muscles consist of the platysma, splenius cervicis, sternocleidomastoid(eus), longus colli, the anterior, medius, and posterior scalenes, digastric(us), stylohyoid(eus), mylohyoid(eus), geniohyoid(eus), sternohyoid(eus), omohyoid(eus), sternothyroid(eus), and thyrohyoid(eus). [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]
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Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nerve Fibers: Slender processes of neurons, especially the prolonged axons that conduct nerve impulses. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Networks: Pertaining to a nerve or to the nerves, a meshlike structure of interlocking fibers or strands. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuraminidase: An enzyme that catalyzes the hydrolysis of alpha-2,3, alpha-2,6-, and alpha-2,8-glycosidic linkages (at a decreasing rate, respectively) of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid, and synthetic substrate. (From Enzyme Nomenclature, 1992) EC 3.2.1.18. [NIH] Neuroanatomy: Study of the anatomy of the nervous system as a specialty or discipline. [NIH]
Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurogenic: Loss of bladder control caused by damage to the nerves controlling the bladder. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] 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] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as
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neurotransmitters and some functioning as hormones. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neuroprotective Agents: Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. [NIH] Neurosis: Functional derangement due to disorders of the nervous system which does not affect the psychic personality of the patient. [NIH] Neurotic: 1. Pertaining to or characterized by neurosis. 2. A person affected with a neurosis. [EU]
Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]
Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] 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] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful antianginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] Nitrazepam: A benzodiazepine derivative used as an anticonvulsant and hypnotic. [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] Nitrous Oxide: Nitrogen oxide (N2O). A colorless, odorless gas that is used as an anesthetic and analgesic. High concentrations cause a narcotic effect and may replace oxygen, causing death by asphyxia. It is also used as a food aerosol in the preparation of whipping cream. [NIH]
Nonmalignant: Not cancerous. [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]
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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] Nucleic Acid Hybridization: The process whereby two single-stranded polynucleotides form a double-stranded molecule, with hydrogen bonding between the complementary bases in the two strains. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [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 suppress it. Common obsessions involve thoughts of violence, contamination, and selfdoubt. [EU] Odour: A volatile emanation that is perceived by the sense of smell. [EU] Oligosaccharides: Carbohydrates consisting of between two and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [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] Organelles: Specific particles of membrane-bound organized living substances present in
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eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Orgasm: The crisis of sexual excitement in either humans or animals. [NIH] Orofacial: Of or relating to the mouth and face. [EU] Orphenadrine: A muscarinic antagonist used to treat drug-induced parkinsonism and to relieve pain from muscle spasm. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] 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] 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] Oxazepam: A benzodiazepine used in the treatment of anxiety, alcohol withdrawal, and insomnia. [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]
Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Palsy: Disease of the peripheral nervous system occurring usually after many years of increased lead absorption. [NIH]
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Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatic Juice: The fluid containing digestive enzymes secreted by the pancreas in response to food in the duodenum. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] 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] Paraganglia, Chromaffin: Small bodies containing chromaffin cells occurring outside of the adrenal medulla, most commonly near the sympathetic ganglia and in organs such as the kidney, liver, heart and gonads. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Paramedic: An emergency medical technician (EMT) who received further training for the delivery of some aspects of advanced life support (ALS) care. [NIH] Paranasal Sinuses: Air-filled extensions of the respiratory part of the nasal cavity into the frontal, ethmoid, sphenoid, and maxillary cranial bones. They vary in size and form in different individuals and are lined by the ciliated mucous membranes of the nasal cavity. [NIH]
Paranoia: A psychotic disorder marked by persistent delusions of persecution or delusional jealousy and behaviour like that of the paranoid personality, such as suspiciousness, mistrust, and combativeness. It differs from paranoid schizophrenia, in which hallucinations or formal thought disorder are present, in that the delusions are logically consistent and that there are no other psychotic features. The designation in DSM III-R is delusional (paranoid) disorders, with five types : persecutory, jealous, erotomanic, somatic, and grandiose. [EU] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal,
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intravenous, etc. [EU] Paresthesias: Abnormal touch sensations, such as burning or prickling, that occur without an outside stimulus. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxetine: A serotonin uptake inhibitor that is effective in the treatment of depression. [NIH]
Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Patch-Clamp Techniques: An electrophysiologic technique for studying cells, cell membranes, and occasionally isolated organelles. All patch-clamp methods rely on a very high-resistance seal between a micropipette and a membrane; the seal is usually attained by gentle suction. The four most common variants include on-cell patch, inside-out patch, outside-out patch, and whole-cell clamp. Patch-clamp methods are commonly used to voltage clamp, that is control the voltage across the membrane and measure current flow, but current-clamp methods, in which the current is controlled and the voltage is measured, are also used. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]
Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
Patient Selection: Criteria and standards used for the determination of the appropriateness of the inclusion of patients with specific conditions in proposed treatment plans and the criteria used for the inclusion of subjects in various clinical trials and other research protocols. [NIH] Pediatric Dentistry: The practice of dentistry concerned with the dental problems of children, proper maintenance, and treatment. The dental care may include the services provided by dental specialists. [NIH] Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third
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compartment below, the corpus spongiosum, houses the urethra. [NIH] Pentagastrin: A synthetic polypeptide that has effects like gastrin when given parenterally. It stimulates the secretion of gastric acid, pepsin, and intrinsic factor, and has been used as a diagnostic aid. [NIH] Pentylenetetrazole: A pharmaceutical agent that displays activity as a central nervous system and respiratory stimulant. It is considered a non-competitive GABA antagonist. Pentylenetetrazole has been used experimentally to study seizure phenomenon and to identify pharmaceuticals that may control seizure susceptibility. [NIH] Pepsin: An enzyme made in the stomach that breaks down proteins. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: Ulcer that occurs in those portions of the alimentary tract which come into contact with gastric juice containing pepsin and acid. It occurs when the amount of acid and pepsin is sufficient to overcome the gastric mucosal barrier. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Periventricular Leukomalacia: Rare form of epilepsy. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] 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] 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] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenprocoumon: 3-(1-Phenylpropyl)-4-hydroxycoumarin. Long acting oral anticoagulant. It may cause diarrhea. [NIH]
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Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phobia: A persistent, irrational, intense fear of a specific object, activity, or situation (the phobic stimulus), fear that is recognized as being excessive or unreasonable by the individual himself. When a phobia is a significant source of distress or interferes with social functioning, it is considered a mental disorder; phobic disorder (or neurosis). In DSM III phobic disorders are subclassified as agoraphobia, social phobias, and simple phobias. Used as a word termination denoting irrational fear of or aversion to the subject indicated by the stem to which it is affixed. [EU] Phobic Disorders: Anxiety disorders in which the essential feature is persistent and irrational fear of a specific object, activity, or situation that the individual feels compelled to avoid. The individual recognizes the fear as excessive or unreasonable. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phosphodiesterase Inhibitors: Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. [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] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Phototherapy: Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physical Medicine: A medical specialty concerned with the use of physical agents, mechanical apparatus, and manipulation in rehabilitating physically diseased or injured patients. [NIH] Physical Therapy: The restoration of function and the prevention of disability following disease or injury with the use of light, heat, cold, water, electricity, ultrasound, and exercise. [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
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cells, tissues, and organs. [NIH] Picrotoxin: A noncompetitive antagonist at GABA-A receptors and thus a convulsant. Picrotoxin blocks the GABA-activated chloride ionophore. Although it is most often used as a research tool, it has been used as a CNS stimulant and an antidote in poisoning by CNS depressants, especially the barbiturates. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placebo Effect: An effect usually, but not necessarily, beneficial that is attributable to an expectation that the regimen will have an effect, i.e., the effect is due to the power of suggestion. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] 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 Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form.
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Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]
Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] 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] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] 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] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-synaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Post-traumatic: Occurring as a result of or after injury. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH]
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Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practicability: A non-standard characteristic of an analytical procedure. It is dependent on the scope of the method and is determined by requirements such as sample throughout and costs. [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] Precipitation: The act or process of precipitating. [EU] 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] Pregnanolone: A pregnane found in the urine of pregnant women and sows. It has anesthetic, hypnotic, and sedative properties. [NIH] Pregnenolone: Steroid hormone. [NIH] Premedication: Preliminary administration of a drug preceding a diagnostic, therapeutic, or surgical procedure. The commonest types of premedication are antibiotics (antibiotic prophylaxis) and anti-anxiety agents. It does not include preanesthetic medication. [NIH] Premenstrual: Occurring before menstruation. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare
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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] Proglumide: 4-Benzamido-N,N-dipropylglutaramic acid. A drug that exerts an inhibitory effect on gastric secretion and reduces gastrointestinal motility. It is used clinically in the drug therapy of gastrointestinal ulcers. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Prone: Having the front portion of the body downwards. [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] 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] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential antithrombotic effects. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protective Agents: Synthetic or natural substances which are given to prevent a disease or disorder or are used in the process of treating a disease or injury due to a poisonous agent. [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 p53: Nuclear phosphoprotein encoded by the p53 gene whose normal function is to
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control cell proliferation. A mutant or absent p53 protein has been found in leukemia, osteosarcoma, lung cancer, and colorectal cancer. [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] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]
Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] 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] Psychogenic: Produced or caused by psychic or mental factors rather than organic factors. [EU]
Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychometric testing: Psychological and mental testing and quantitative analysis of an individual's psychological traits or attitudes or mental processes. [NIH] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychopathology: The study of significant causes and processes in the development of mental illness. [NIH] Psychophysiology: The study of the physiological basis of human and animal behavior. [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
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psychotic. [EU] Psychotherapy: A generic term for the treatment of mental illness or emotional disturbances primarily by verbal or nonverbal communication. [NIH] 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] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and 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] Puromycin: An antibiotic from Streptomyces alboniger that inhibits protein synthesis by binding to RNA. It is a antineoplastic and antitrypanosomal agent and is used in research as an inhibitor of protein synthesis. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Pyloric Sphincter: The muscle between the stomach and the small intestine. [NIH] Pylorus: The opening in a vertebrate from the stomach into the intestine. [EU] Pyoderma: Any purulent skin disease (Dorland, 27th ed). [NIH] Pyoderma Gangrenosum: An idiopathic, rapidly evolving, and severely debilitating disease occurring most commonly in association with chronic ulcerative colitis. It is characterized by the presence of boggy, purplish ulcers with undermined borders, appearing mostly on the
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legs. The majority of cases are in people between 40 and 60 years old. Its etiology is unknown. [NIH] 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] 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] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quiescent: Marked by a state of inactivity or repose. [EU] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] 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] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Ras gene: A gene that has been found to cause cancer when it is altered (mutated). Agents that block its activity may stop the growth of cancer. A ras peptide is a protein fragment produced by the ras gene. [NIH] Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego function. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular
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changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] 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] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflux: The term used when liquid backs up into the esophagus from the stomach. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [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] Relaxant: 1. Lessening or reducing tension. 2. An agent that lessens tension. [EU] Relaxation Techniques: The use of muscular relaxation techniques in treatment. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Research Design: A plan for collecting and utilizing data so that desired information can be obtained with sufficient precision or so that an hypothesis can be tested properly. [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] Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Restless legs: Legs characterized by or showing inability to remain at rest. [EU] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [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
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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] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk-Taking: Undertaking a task involving a challenge for achievement or a desirable goal in which there is a lack of certainty or a fear of failure. It may also include the exhibiting of certain behaviors whose outcomes may present a risk to the individual or to those associated with him or her. [NIH] Risperidone: A selective blocker of dopamine D2 and serotonin-5-HT-2 receptors that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative symptoms in the treatment of schizophrenia. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rotenone: A botanical insecticide that is an inhibitor of mitochondrial electron transport. [NIH]
Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Sabin: The unit of acoustic absorption. One Sabin is 1 sq. foot of perfect sound-absorbing material. [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]
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Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponin: A substance found in soybeans and many other plants. Saponins may help lower cholesterol and may have anticancer effects. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Scopolamine: An alkaloid from Solanaceae, especially Datura metel L. and Scopola carniolica. Scopolamine and its quaternary derivatives act as antimuscarinics like atropine, but may have more central nervous system effects. Among the many uses are as an anesthetic premedication, in urinary incontinence, in motion sickness, as an antispasmodic, and as a mydriatic and cycloplegic. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Secretory Vesicles: Vesicles derived from the golgi apparatus containing material to be released at the cell surface. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sedatives, Barbiturate: Those derivatives of barbituric or thiobarbituric acid that are used as
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hypnotics or sedatives. The structural class of all such derivatives, regardless of use, is barbiturates. [NIH] 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] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sensor: A device designed to respond to physical stimuli such as temperature, light, magnetism or movement and transmit resulting impulses for interpretation, recording, movement, or operating control. [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] Serotonin Agonists: Agents that have an affinity for serotonin receptors and are able to mimic the effects of serotonin by stimulating the physiologic activity at the cell receptors. These compounds are used as antidepressants, anxiolytics, and in the treatment of migraine. [NIH]
Serotonin Antagonists: Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or serotonin agonists. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [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]
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Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]
Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Sigmoid: 1. Shaped like the letter S or the letter C. 2. The sigmoid colon. [EU] Sigmoid Colon: The lower part of the colon that empties into the rectum. [NIH] Sigmoidoscope: A thin, lighted tube used to view the inside of the colon. [NIH] Sigmoidoscopy: Endoscopic examination, therapy or surgery of the sigmoid flexure. [NIH] 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] Sincalide: A polypeptide hormone present in the intestine and brain. When secreted from the gastric mucosa, it stimulates the release of both bile from the gallbladder, and the release of digestive enzymes from the pancreas. [NIH] Sinusitis: An inflammatory process of the mucous membranes of the paranasal sinuses that occurs in three stages: acute, subacute, and chronic. Sinusitis results from any condition causing ostial obstruction or from pathophysiologic changes in the mucociliary transport mechanism. [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]
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Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Sleep Deprivation: The state of being deprived of sleep under experimental conditions, due to life events, or from a wide variety of pathophysiologic causes such as medication effect, chronic illness, psychiatric illness, or sleep disorder. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]
Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Behavior: Any behavior caused by or affecting another individual, usually of the same species. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Social Support: Support systems that provide assistance and encouragement to individuals with physical or emotional disabilities in order that they may better cope. Informal social support is usually provided by friends, relatives, or peers, while formal assistance is provided by churches, groups, etc. [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] Soft tissue sarcoma: A sarcoma that begins in the muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] 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 in contrast to the viscera. [EU]
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Somnolence: Sleepiness; also unnatural drowsiness. [EU] Soporific: 1. Causing or inducing profound sleep. 2. A drug or other agent which induces sleep. [EU] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sphincter: A ringlike band of muscle fibres that constricts a passage or closes a natural orifice; called also musculus sphincter. [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] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splint: A rigid appliance used for the immobilization of a part or for the correction of deformity. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Sprue: A non febrile tropical disease of uncertain origin. [NIH] Stabilization: The creation of a stable state. [EU] Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Stavudine: A dideoxynucleoside analog that inhibits reverse transcriptase and has in vitro activity against HIV. [NIH] Steady state: Dynamic equilibrium. [EU] 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
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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] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stress incontinence: An involuntary loss of urine that occurs at the same time that internal abdominal pressure is increased, such as with laughing, sneezing, coughing, or physical activity. [NIH] Stress management: A set of techniques used to help an individual cope more effectively with difficult situations in order to feel better emotionally, improve behavioral skills, and often to enhance feelings of control. Stress management may include relaxation exercises, assertiveness training, cognitive restructuring, time management, and social support. It can be delivered either on a one-to-one basis or in a group format. [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] Stroke Volume: The amount of blood pumped out of the heart per beat not to be confused with cardiac output (volume/time). [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Other factors contributing to structure-activity relationship include chemical reactivity, electronic effects, resonance, and inductive effects. [NIH] Strychnine: An alkaloid found in the seeds of nux vomica. It is a competitive antagonist at glycine receptors and thus a convulsant. It has been used as an analeptic, in the treatment of nonketotic hyperglycinemia and sleep apnea, and as a rat poison. [NIH] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding
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only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Subiculum: A region of the hippocampus that projects to other areas of the brain. [NIH] 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] Subtrochanteric: Below a trochanter. [NIH] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] 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] Supraspinal: Above the spinal column or any spine. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synapses: Specialized junctions at which a neuron communicates with a target cell. At
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classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic 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] Systemic: Affecting the entire body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Taurine: 2-Aminoethanesulfonic acid. A conditionally essential nutrient, important during mammalian development. It is present in milk but is isolated mostly from ox bile and strongly conjugates bile acids. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Temazepam: A benzodiazepinone that acts as a GABA modulator and anti-anxiety agent. [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] Tendinitis: Inflammation of tendons and of tendon-muscle attachments. [EU] Tenosynovitis: Inflammation of a tendon sheath. [EU] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetrahydrocannabinol: A psychoactive compound extracted from the resin of Cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (THC) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound. Dronabinol is a synthetic form of delta-9-THC. [NIH]
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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] 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] Thrombocytes: Blood cells that help prevent bleeding by causing blood clots to form. Also called platelets. [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] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Time Management: Planning and control of time to improve efficiency and effectiveness. [NIH]
Tin: A trace element that is required in bone formation. It has the atomic symbol Sn, atomic number 50, and atomic weight 118.71. [NIH] Tinnitus: Sounds that are perceived in the absence of any external noise source which may take the form of buzzing, ringing, clicking, pulsations, and other noises. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases;
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vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] 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] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] 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] Topical: On the surface of the body. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Torticollis: Wryneck; a contracted state of the cervical muscles, producing twisting of the neck and an unnatural position of the head. [EU] 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] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Traction: The act of pulling. [NIH] Tramadol: A narcotic analgesic proposed for severe pain. It may be habituating. [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] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcutaneous: Transdermal. [EU] Transcutaneous Electric Nerve Stimulation: Electrical stimulation of nerves and/or muscles to relieve pain; it is used less frequently to produce anesthesia. The optimal placements of electrodes or "trigger points" may correspond with acupuncture analgesia points. TENS is sometimes referred to as acupuncture-like when using a low frequency stimulus. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case
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of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [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] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, practicability, etc., of these interventions in individual cases or series. [NIH]
Trees: Woody, usually tall, perennial higher plants (Angiosperms, Gymnosperms, and some Pterophyta) having usually a main stem and numerous branches. [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] Triazolam: A short-acting benzodiazepine used in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries. [NIH] 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] Trifluoroacetic Acid: A very strong halogenated derivative of acetic acid. It is used in acid catalyzed reactions, especially those where an ester is cleaved in peptide synthesis. [NIH] Trigeminal: Cranial nerve V. It is sensory for the eyeball, the conjunctiva, the eyebrow, the skin of face and scalp, the teeth, the mucous membranes in the mouth and nose, and is motor to the muscles of mastication. [NIH] Trigger zone: Dolorogenic zone (= producing or causing pain). [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] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of
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Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tubocurarine: A neuromuscular blocker and active ingredient in curare; plant based alkaloid of Menispermaceae. [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] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] 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] 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] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]
Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [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] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH]
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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] Urogenital: Pertaining to the urinary and genital apparatus; genitourinary. [EU] 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] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagal: Pertaining to the vagus nerve. [EU] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Valerian: Valeriana officinale, an ancient, sedative herb of the large family Valerianaceae. The roots were formerly used to treat hysterias and other neurotic states and are presently used to treat sleep disorders. [NIH] 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] Vascular Headaches: A group of disorders characterized by recurrent headaches associated with abnormal dilation and constriction of cerebral blood vessels. Representative disorders from this category include migraine, cluster headache, and paroxysmal hemicrania. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] 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]
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Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Veratridine: One of the components in the veratrine mixture of alkaloids. Found in the seed of Schoenocaulon officinale and in rhizome of Veratrum album L., Liliaceae. [NIH] Vestibulocochlear Nerve: The 8th cranial nerve. The vestibulocochlear nerve has a cochlear part (cochlear nerve) which is concerned with hearing and a vestibular part (vestibular nerve) which mediates the sense of balance and head position. The fibers of the cochlear nerve originate from neurons of the spiral ganglion and project to the cochlear nuclei (cochlear nucleus). The fibers of the vestibular nerve arise from neurons of Scarpa's ganglion and project to the vestibular nuclei. [NIH] Vestibulocochlear Nerve Diseases: Diseases of the vestibular and/or cochlear (acoustic) nerves, which join to form the vestibulocochlear nerve. Vestibular neuritis, cochlear neuritis, and acoustic neuromas are relatively common conditions that affect these nerves. Clinical manifestations vary with which nerve is primarily affected, and include hearing loss, vertigo, and tinnitus. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] 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] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Volition: Voluntary activity without external compulsion. [NIH] Vomica: The profuse and sudden expectoration of pus and putrescent matter. An abnormal cavity in an organ especially in the lung, caused by suppuration and the breaking down of tissue. [NIH] Wakefulness: A state in which there is an enhanced potential for sensitivity and an efficient responsiveness to external stimuli. [NIH] War: Hostile conflict between organized groups of people. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection
Dictionary 253
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]
255
INDEX A Abacavir, 21, 171 Abdominal, 129, 167, 171, 190, 204, 213, 226, 244, 250 Abdominal Pain, 129, 171, 204, 213, 250 Aberrant, 115, 171, 190 Abscess, 129, 171 Abulia, 10, 171 Acceptor, 126, 171, 225 Acetaminophen, 141, 171 Acetylcholine, 11, 36, 116, 118, 171, 188 Acoustic, 27, 81, 171, 238, 252 Acrylonitrile, 171, 238 Actin, 171, 220, 221 Acupuncture Analgesia, 171, 248 Acyl, 20, 91, 101, 171 Adaptability, 171, 186 Adaptation, 171, 230 Adduct, 90, 171 Adenine, 50, 172, 235 Adenocarcinoma, 115, 172 Adenosine, 76, 91, 109, 113, 172, 184, 229 Adenosine Triphosphate, 113, 172, 229 Adenylate Cyclase, 114, 172 Adrenal Cortex, 172, 193, 232 Adrenal Medulla, 172, 186, 188, 200, 223, 226 Adrenergic, 9, 11, 16, 109, 128, 172, 176, 177, 197, 200, 245 Adrenergic Agents, 128, 172 Adrenergic Agonists, 128, 172 Adverse Effect, 12, 35, 36, 40, 134, 141, 172, 189, 214, 241 Aerobic, 113, 172, 219 Aerobic Metabolism, 172 Aerobic Respiration, 113, 172 Aerosol, 36, 96, 110, 172, 223 Afferent, 94, 172, 193, 232 Affinity, 17, 35, 37, 44, 48, 79, 80, 99, 107, 113, 115, 172, 173, 179, 189, 215, 240, 242 Affinity Chromatography, 35, 172 AFP, 6, 173 Age Groups, 98, 173 Age of Onset, 158, 173, 250 Aged, 80 and Over, 173 Ageing, 94, 173 Agoraphobia, 52, 173, 210, 226, 229 Airway, 96, 173, 242
Akathisia, 173, 177 Alanine, 94, 173 Albumin, 73, 173, 230, 241 Aldehydes, 100, 173 Alertness, 32, 173, 184 Alexia, 173, 198 Algorithms, 173, 182 Alimentary, 107, 173, 226, 228 Alkaline, 173, 174, 184, 225 Alkaloid, 173, 180, 181, 185, 189, 218, 220, 223, 239, 244, 250 Alkylation, 99, 173 Allergen, 174, 196, 240 Allylamine, 174 Alternative medicine, 75, 86, 139, 174, 191 Amenorrhea, 174, 176 Amination, 119, 174 Amine, 92, 99, 100, 174, 208 Amino Acid Sequence, 174, 176, 205 Amino Acid Substitution, 22, 174 Ammonia, 5, 174, 250 Amnesia, 37, 174 Amnestic, 174, 204, 219 Amphetamine, 9, 16, 156, 174, 175, 196 Ampulla, 174, 200 Amygdala, 45, 174, 181, 215, 247 Amyl Nitrite, 159, 175 Anabolic, 25, 127, 175, 196 Anabolic Steroids, 127, 175 Anaesthesia, 175, 211 Anal, 71, 72, 73, 107, 175, 203, 226 Analeptic, 175, 244 Analgesic, 35, 72, 91, 117, 171, 175, 190, 192, 210, 220, 223, 224, 248 Analgesics, Opioid, 7, 175 Analog, 171, 175, 181, 243 Analogous, 43, 175, 198, 249 Anaphylatoxins, 175, 191 Anatomical, 18, 33, 175, 179, 183, 192, 211, 226, 239 Androgenic, 25, 175 Anemia, 140, 153, 157, 175, 213 Anesthesia, 62, 129, 131, 173, 175, 176, 192, 193, 199, 214, 219, 248 Anesthetics, 7, 17, 33, 36, 84, 130, 158, 175, 180, 200 Angina, 106, 175 Anginal, 175, 223
256
Benzodiazepines
Angiogenesis, 98, 175 Angioplasty, 106, 175 Animal Husbandry, 97, 176 Animal model, 4, 29, 104, 118, 176 Anions, 173, 176, 213, 241 Anorexia, 7, 8, 116, 117, 176, 204, 250 Anorexia Nervosa, 7, 8, 176 Antagonism, 21, 107, 176, 184, 189, 217 Anterior Cerebral Artery, 176, 187 Anthramycin, 111, 176 Anti-Anxiety Agents, 176, 232, 235, 248 Antibacterial, 176, 243 Antibiotic, 50, 111, 125, 176, 183, 200, 227, 232, 235, 243 Antibodies, 42, 70, 176, 207, 210, 216, 230 Antibody, 172, 176, 177, 191, 207, 208, 210, 211, 217, 236, 240, 243 Anticholinergic, 11, 96, 176 Anticoagulant, 106, 176, 228, 233 Anticonvulsant, 13, 27, 31, 39, 42, 77, 81, 91, 93, 95, 113, 176, 185, 201, 223, 251 Anticonvulsive, 77, 176 Antidepressant, 7, 11, 40, 56, 141, 176, 189, 203, 210 Antidepressive Agents, 177, 235 Antidiuretic, 114, 177 Antidote, 177, 203, 230 Antiemetic, 177, 196 Antigen, 172, 176, 177, 191, 205, 208, 209, 210, 211, 217, 240 Antigen-Antibody Complex, 177, 191 Anti-inflammatory, 7, 12, 157, 171, 177, 179, 206, 210 Anti-Inflammatory Agents, 12, 177, 179 Antineoplastic, 176, 177, 235 Antioxidant, 11, 177 Antipsychotic, 9, 10, 13, 14, 93, 95, 96, 134, 177, 189, 222, 238, 248 Antipsychotic Agents, 9, 13, 134, 177, 248 Antipyretic, 171, 178 Antispasmodic, 178, 224, 239 Antitumour, 48, 64, 178 Antitussive, 178, 196, 224 Anuria, 178, 214 Anus, 4, 175, 178 Anxiety, 6, 11, 12, 14, 17, 18, 20, 21, 23, 25, 27, 29, 32, 39, 40, 41, 42, 44, 45, 57, 66, 78, 82, 87, 90, 93, 96, 97, 103, 107, 109, 113, 116, 117, 126, 130, 138, 139, 141, 167, 173, 176, 178, 192, 204, 214, 225, 226, 229, 232, 235, 246, 248 Anxiety Disorders, 42, 178, 226
Anxiolytic, 13, 16, 18, 19, 23, 26, 33, 36, 39, 42, 63, 70, 76, 93, 95, 113, 139, 178, 184, 219 Aorta, 178, 193, 251 Apathy, 178, 222 Apnea, 129, 178, 242, 244 Apoptosis, 34, 49, 77, 108, 178, 186 Applicability, 15, 178 Aqueous, 178, 181, 194, 199 Arachidonate 12-Lipoxygenase, 178, 216 Arachidonate 15-Lipoxygenase, 178, 216 Arachidonate Lipoxygenases, 178, 215 Arachidonic Acid, 178, 215, 216, 233 Aromatic, 111, 178, 229, 245 Arterial, 106, 174, 179, 183, 187, 192, 209, 213, 234, 246 Arteries, 104, 178, 179, 182, 183, 185, 187, 193, 218, 219, 221, 235 Arteriolar, 179, 183 Arterioles, 179, 183, 184, 219, 251 Arteriovenous, 179, 187, 219 Aspartate, 104, 179, 214 Aspartic, 179, 186, 200, 202 Aspartic Acid, 179, 186 Asphyxia, 179, 223 Aspiration, 129, 179, 203 Aspirin, 141, 158, 179 Assay, 48, 71, 72, 116, 118, 179, 182, 210 Astrocytes, 38, 179, 219 Astrocytoma, 115, 179 Asymptomatic, 179, 226 Ataxia, 152, 153, 179, 187, 247 Atrial, 179, 192, 249 Atrioventricular, 179, 192 Atrium, 179, 192, 249, 251 Atrophy, 54, 152, 179, 220 Atropine, 180, 239 Attenuation, 76, 80, 180 Atypical, 3, 7, 13, 40, 180, 189, 238 Auditory, 59, 79, 180, 232, 251 Auditory Perception, 59, 79, 180 Autodigestion, 180, 226 Autoimmune disease, 180 Autoimmunity, 108, 180 Autonomic, 16, 58, 96, 171, 177, 180, 193, 205, 223, 228, 242, 245 Autonomic Nervous System, 16, 180, 228, 242, 245 Autoradiography, 21, 180 Autosuggestion, 180, 210 Axons, 180, 195, 212, 222, 224, 236
Index 257
B Baclofen, 30, 128, 180 Bacteria, 171, 176, 177, 180, 195, 199, 200, 201, 202, 215, 218, 219, 243, 249, 251 Bactericidal, 180, 201 Bacteriophage, 79, 180, 230, 249 Bacteriostatic, 180, 200 Barbiturate, 180, 192, 239 Basal Ganglia, 177, 179, 180, 181, 188, 215 Basal Ganglia Diseases, 179, 181, 188 Base, 44, 98, 102, 103, 172, 181, 194, 195, 205, 214, 231, 236, 246, 250 Baths, 140, 181 Behavioral Symptoms, 9, 134, 181 Benign, 16, 27, 181, 207 Benzaldehyde, 102, 181 Benzamides, 129, 181 Benzene, 36, 181 Benzoquinones, 181 Beta blocker, 130, 181 Betahistine, 8, 181 Bewilderment, 181, 191 Bicuculline, 17, 181 Bile, 181, 204, 206, 216, 241, 244, 246 Bile Acids, 181, 244, 246 Bile Ducts, 181 Biliary, 107, 181, 184, 226 Biliary Tract, 181, 184, 226 Bilirubin, 173, 181, 206 Binding agent, 112, 182 Binding Sites, 19, 46, 62, 115, 182 Bioassay, 182 Bioavailability, 106, 182 Bioavailable, 101, 182 Biochemical, 16, 19, 38, 55, 75, 76, 78, 79, 80, 113, 119, 182, 214, 240 Biological Assay, 38, 182 Biological Factors, 16, 182 Biopsy, 182, 228 Biosynthesis, 40, 51, 111, 178, 182, 229, 233, 240 Biotechnology, 48, 51, 139, 149, 151, 152, 153, 182 Biotin, 71, 182 Bipolar Disorder, 9, 41, 116, 117, 156, 182 Bladder, 114, 128, 157, 158, 182, 188, 194, 211, 222, 233, 250, 251 Bloating, 182, 213 Blood Coagulation, 182, 184, 247 Blood Platelets, 106, 182, 240 Blood pressure, 30, 182, 185, 187, 209, 219, 223, 235, 242
Blood-Brain Barrier, 183, 215 Blot, 31, 45, 183 Body Fluids, 183, 184, 198, 242 Body Regions, 183, 190 Bone Marrow, 181, 183, 193, 210, 216, 242 Bowel, 107, 116, 117, 157, 175, 183, 196, 212, 213, 244, 250 Bradykinin, 54, 183, 214, 230 Brain Ischemia, 183, 187 Brain Stem, 183, 187, 192 Branch, 70, 98, 165, 183, 199, 205, 216, 227, 235, 243, 247 Breakdown, 114, 183, 196, 204, 224 Breeding, 176, 183 Broad-spectrum, 176, 183, 214 Bronchi, 183, 200 Bronchial, 181, 183, 208 Bronchiectasis, 129, 183 Buccal, 183, 216 Bulimia, 7, 8, 116, 117, 183 Burning Mouth Syndrome, 6, 8, 183 Bursitis, 130, 184 Buspirone, 6, 8, 9, 11, 13, 59, 138, 184 Butyric Acid, 18, 23, 184 Bypass, 106, 184, 193 C Caffeine, 14, 71, 95, 117, 118, 141, 175, 184, 235 Calcium, 36, 107, 109, 113, 118, 157, 184, 191, 223, 234, 241 Calcium channel blocker, 109, 184 Calcium Channel Blockers, 109, 184 Calculi, 184, 206 Cannabidiol, 184 Cannabinoids, 71, 95, 129, 184 Cannabinol, 184 Cannabis, 127, 184, 246 Capillary, 183, 184, 252 Capillary Permeability, 183, 184 Capsaicin, 6, 117, 118, 185 Capsules, 53, 185, 204 Carbamazepine, 6, 8, 9, 12, 13, 27, 185 Carbohydrate, 46, 185, 206, 231 Carbolines, 38, 185 Carbon Dioxide, 184, 185, 194, 203, 230, 237, 251 Carcinogen, 171, 185 Carcinogenic, 181, 185, 212, 244 Carcinoma, 115, 119, 129, 185, 189, 195 Cardiac, 11, 16, 55, 105, 114, 116, 117, 174, 184, 185, 192, 199, 200, 201, 219, 221, 244 Cardiac Output, 105, 185, 244
258
Benzodiazepines
Cardiorespiratory, 185, 219 Cardiovascular, 16, 112, 174, 185, 215, 240, 242 Cardiovascular disease, 16, 185 Cardiovascular System, 112, 185 Carotene, 185, 238 Carotid Arteries, 104, 185 Case report, 52, 185 Case-Control Studies, 49, 185 Caspases, 35, 186 Catabolism, 111, 186, 250 Catecholamine, 70, 177, 186, 197, 228 Catheterization, 175, 186 Cations, 186, 213 Caudal, 186, 196, 209, 231 Causal, 186, 213 Cell, 20, 24, 26, 29, 30, 31, 33, 34, 36, 42, 45, 49, 72, 94, 105, 107, 108, 113, 115, 119, 152, 153, 171, 172, 173, 175, 178, 179, 180, 182, 184, 186, 188, 189, 191, 194, 195, 198, 200, 201, 202, 204, 205, 210, 211, 212, 213, 216, 217, 219, 220, 221, 222, 224, 225, 227, 229, 230, 231, 233, 234, 236, 237, 239, 240, 241, 242, 245, 246, 247, 248, 249, 250, 251, 252 Cell Communication, 42, 186 Cell Death, 34, 108, 178, 186, 205, 221 Cell Differentiation, 186, 241 Cell Division, 152, 180, 186, 217, 219, 230, 233 Cell Extracts, 42, 186 Cell membrane, 33, 184, 186, 195, 204, 227, 229, 231, 242 Cell proliferation, 108, 115, 186, 212, 234, 241 Cell Respiration, 172, 186, 219, 237 Cellobiose, 186 Cellulose, 99, 186, 230 Central Nervous System Infections, 187, 207 Cerebellar, 179, 187, 237, 249 Cerebellar Diseases, 179, 187, 249 Cerebellum, 25, 187, 237 Cerebral Arteries, 187, 219 Cerebral Infarction, 106, 187 Cerebral Palsy, 187, 243 Cerebrovascular, 106, 181, 184, 185, 187, 247 Cerebrovascular Disorders, 106, 187, 247 Cerebrum, 187, 250 Cervical, 187, 248 Character, 187, 194
Chemoreceptor, 177, 187 Chemotactic Factors, 187, 191 Chimeras, 38, 188 Chlorine, 90, 94, 188 Cholecystitis, 107, 188 Cholecystokinin, 93, 107, 188, 196 Cholesterol, 50, 73, 116, 181, 188, 193, 239, 244 Cholinergic, 11, 13, 38, 109, 116, 118, 177, 188, 223 Cholinergic Agonists, 11, 188 Cholinesterase Inhibitors, 11, 93, 95, 188, 197 Chorea, 116, 117, 177, 188 Choreatic Disorders, 188 Choroid, 188, 237 Chromaffin Cells, 70, 188, 226 Chromatin, 178, 188 Chromic, 188 Chromosomal, 22, 28, 188 Chronic Fatigue Syndrome, 82, 157, 188 Chronic renal, 188, 231, 250 Circadian, 50, 189 CIS, 189, 238 Citalopram, 13, 189 Clamp, 36, 45, 72, 189, 227 Clear cell carcinoma, 189, 195 Clinical Medicine, 189, 232 Clinical trial, 14, 47, 149, 189, 192, 193, 227, 234, 236 Clonic, 189, 192 Cloning, 29, 35, 182, 189 Clozapine, 13, 55, 189 Coagulation, 106, 182, 184, 189, 208, 230, 247 Coal, 181, 189 Coca, 189 Cocaine, 14, 23, 52, 73, 95, 116, 117, 127, 128, 159, 189 Cochlear, 190, 247, 252 Cochlear Diseases, 190, 247 Codeine, 141, 190, 224 Cofactor, 190, 234, 247 Cognition, 40, 43, 190, 222 Cognitive restructuring, 190, 244 Cognitive Therapy, 158, 190 Colic, 107, 190 Coliphages, 180, 190 Colitis, 4, 116, 117, 190, 212, 213, 235, 250 Collagen, 94, 190, 204, 230, 233 Collapse, 183, 190, 242 Colloidal, 173, 190, 241
Index 259
Colonoscopy, 4, 190 Colorectal, 4, 119, 190, 234 Colorectal Cancer, 4, 190, 234 Combination Therapy, 190, 201 Combinatorial, 51, 92, 100, 101, 190 Combinatorial Chemistry Techniques, 92, 190 Comorbidity, 40, 44, 190 Complement, 35, 175, 191, 205, 230, 240 Complementary and alternative medicine, 75, 86, 191 Complementary medicine, 75, 191 Compulsion, 110, 191, 252 Computational Biology, 149, 151, 191 Concomitant, 26, 45, 56, 191 Cones, 191, 238 Confusion, 12, 168, 191, 197, 209, 222, 250 Congestion, 177, 191 Congestive heart failure, 114, 192 Conjugated, 102, 192, 194 Connective Tissue, 183, 190, 192, 197, 203, 204, 216, 218, 238, 239 Conscious Sedation, 131, 192 Consciousness, 4, 175, 176, 192, 194, 195, 197, 200, 208, 243 Constipation, 118, 177, 192, 213 Constriction, 107, 192, 213, 251 Constriction, Pathologic, 192, 251 Consumption, 47, 96, 103, 126, 127, 192, 204, 225, 237 Continuous infusion, 21, 35, 192 Contraindications, ii, 7, 192 Controlled study, 60, 70, 192 Convulsants, 117, 118, 192 Convulsion, 182, 192 Coordination, 35, 187, 192 Cor, 50, 114, 192 Coronary, 52, 106, 114, 185, 193, 218, 221 Coronary Artery Bypass, 106, 193 Coronary heart disease, 185, 193 Coronary Thrombosis, 193, 218, 221 Coronary Vasospasm, 114, 193 Corpus, 193, 227, 232, 247 Corpus Luteum, 193, 232 Cortex, 29, 30, 32, 54, 107, 172, 179, 187, 193, 200, 201, 203, 208, 219, 232, 236, 237 Cortical, 12, 37, 42, 104, 193, 201, 232, 236, 240, 247 Corticosteroids, 3, 7, 130, 141, 193, 206 Cortisol, 70, 173, 193 Cranial, 6, 187, 193, 205, 207, 213, 224, 226, 228, 249, 251, 252
Cranial Nerves, 6, 193 Craniocerebral Trauma, 181, 193, 207, 247, 248 Curare, 193, 220, 250 Curative, 108, 193, 223, 247 Cutaneous, 94, 193, 216 Cyclic, 64, 172, 184, 186, 193, 229, 239 Cyclosporine, 28, 193 Cysteine, 186, 193, 194, 200, 245 Cysteine Endopeptidases, 186, 194, 200 Cystitis, 109, 156, 158, 194 Cytochrome, 27, 194, 225 Cytokine, 35, 194 Cytoplasm, 178, 186, 194, 207, 238, 246 Cytotoxic, 34, 185, 194, 211, 241 D Dangerous Behavior, 14, 194 Dantrolene, 128, 194 Databases, Bibliographic, 149, 194 Deamination, 194, 219, 250 Decarboxylation, 194, 208 Degenerative, 5, 194, 220 Deletion, 178, 194 Delirium, 6, 10, 11, 133, 177, 194 Delusions, 130, 195, 226, 234 Dementia, 5, 6, 8, 9, 10, 11, 12, 13, 14, 83, 116, 117, 130, 133, 134, 141, 177, 195 Dendrites, 195, 222, 236 Dendritic, 58, 195, 217 Density, 42, 99, 115, 195, 224 Dental Care, 127, 195, 227 Dental Caries, 195, 203 Dentate Gyrus, 18, 195, 208 Dentists, 3, 127, 195 Depersonalization, 195, 226, 239 Depolarization, 24, 195, 241 Depressive Disorder, 195, 216 Deprivation, 12, 195, 242 Derealization, 195, 226 DES, 50, 95, 175, 195 Desensitization, 17, 19, 45, 47, 195 Detoxification, 16, 98, 138, 196, 206 Deuterium, 196, 209 Devazepide, 108, 196 Dextroamphetamine, 174, 196 Diabetes Mellitus, 8, 196, 206, 207, 212 Diagnostic procedure, 89, 140, 196 Dialyzer, 196, 207 Diamines, 102, 196 Diarrhea, 129, 196, 200, 213, 228 Diarrhoea, 196, 204 Diastolic, 196, 209
260
Benzodiazepines
Diencephalon, 187, 196, 209, 232, 247 Digestion, 173, 181, 183, 196, 213, 216, 228, 244, 251 Digestive system, 196, 204 Dihydroprogesterone, 40, 196 Dihydrotestosterone, 196, 237 Dihydroxy, 75, 102, 196 Dilatation, 175, 183, 196, 232 Dilation, 183, 196, 251 Dilator, 109, 196 Diphenhydramine, 78, 196 Direct, iii, 11, 23, 56, 71, 100, 111, 112, 113, 143, 186, 189, 190, 196, 197, 217, 237, 246 Discrimination, 15, 23, 78, 180, 197 Disinfectant, 197, 201 Disorientation, 191, 194, 197, 243 Dissociation, 172, 197 Distal, 4, 193, 197, 199, 228, 234 Diuresis, 184, 197 Dizziness, 12, 168, 197, 226 Donepezil, 10, 11, 197 Dopa, 197, 215 Dopamine, 32, 44, 81, 110, 157, 174, 177, 189, 196, 197, 215, 219, 229, 238 Dopamine Agents, 32, 197 Dopamine Agonists, 110, 197 Dorsal, 39, 197, 231 Dorsum, 197 Dose-dependent, 36, 197 Dracunculus, 79, 197 Drug Design, 16, 197 Drug Interactions, 9, 24, 144, 198 Drug Monitoring, 44, 198 Drug Tolerance, 198, 248 Duct, 174, 186, 198, 202, 238 Duodenal Ulcer, 107, 198 Duodenum, 181, 198, 200, 226, 244 Dyes, 181, 198 Dyskinesia, 54, 107, 116, 117, 177, 189, 198 Dyslexia, 116, 117, 198 Dyspareunia, 109, 198, 201 Dysphoric, 138, 195, 198 Dysplasia, 153, 198 Dyspnea, 198, 226 Dystonia, 12, 116, 117, 177, 198 Dystrophy, 152, 198, 221 E Eating Disorders, 107, 198 Edema, 114, 188, 198, 213, 214, 235, 250 Effector, 50, 171, 191, 198, 223, 229 Effector cell, 198, 223
Efficacy, 9, 13, 14, 16, 18, 21, 34, 41, 46, 70, 73, 78, 184, 198, 249 Ejaculation, 44, 198, 240 Elastin, 190, 198 Elective, 199, 231, 242 Electrocoagulation, 189, 199 Electroconvulsive Therapy, 13, 141, 199 Electrode, 36, 199 Electrolyte, 194, 199, 214, 231, 242, 250 Electrons, 177, 181, 199, 213, 225, 236 Electrophysiological, 17, 26, 30, 38, 46, 199 Emboli, 106, 199, 213 Embolism, 106, 187, 199, 213, 235 Embolus, 199, 211, 213 Embryo, 186, 199, 211 Emesis, 118, 168, 178, 199 Emetic, 116, 199 Empirical, 10, 199 Emulsion, 180, 199, 203 Encephalopathy, 4, 49, 59, 61, 199, 208 Endarterectomy, 175, 199 Endocrine System, 200, 222 Endopeptidases, 186, 194, 200, 233 Endoscope, 200 Endoscopic, 4, 190, 200, 219, 241 Endotoxin, 200, 250 End-stage renal, 157, 188, 200, 231 Enhancer, 103, 120, 200 Enterotoxins, 128, 200 Entorhinal Cortex, 200, 208 Enucleation, 76, 200 Environmental Exposure, 200, 224 Environmental Health, 148, 150, 200 Enzymatic, 57, 71, 101, 184, 185, 191, 195, 200, 203, 208, 238 Epidemiological, 41, 52, 200 Epigastric, 200, 226 Epilepticus, 26, 61, 62, 138, 200, 243 Epinephrine, 16, 172, 188, 197, 200, 223, 250 Epithelial, 172, 200, 208 Epithelial Cells, 200, 208 Ergot, 200, 217 Erythrocytes, 175, 183, 200, 240 Erythromycin, 28, 200 Escalation, 17, 60, 201 Esophagitis, 107, 201 Esophagus, 196, 201, 204, 237, 244 Essential Tremor, 152, 201 Estazolam, 73, 201 Estrogen, 11, 109, 128, 201 Estrogen Replacement Therapy, 11, 201
Index 261
Ethanol, 20, 22, 23, 24, 25, 28, 29, 36, 59, 189, 201 Ether, 90, 102, 201 Ethnic Groups, 98, 201 Eukaryotic Cells, 201, 211, 225 Euphoria, 175, 201 Evacuation, 192, 201 Evoke, 70, 201, 244 Excitability, 42, 70, 201, 221 Excitation, 38, 187, 194, 201 Excitatory, 21, 24, 30, 31, 38, 104, 180, 201, 206, 214, 223 Excitatory Amino Acid Agonists, 201, 214 Excitatory Amino Acids, 104, 201, 223 Excrete, 178, 202, 214 Exhaustion, 176, 202 Exocrine, 119, 188, 202, 226 Exogenous, 31, 202, 206, 250 Expiration, 202, 237 Extracellular, 19, 108, 179, 192, 202, 242 Extracorporeal, 106, 202 Extracorporeal Circulation, 106, 202 Extraction, 46, 71, 78, 202 Extrapyramidal, 173, 177, 197, 202 F Facial, 8, 202, 227, 242 Facial Pain, 8, 202 Family Planning, 149, 202 Farnesyl, 99, 118, 119, 202 Fat, 178, 183, 184, 185, 192, 193, 199, 202, 215, 238, 242 Fathers, 22, 202 Fatigue, 12, 82, 157, 188, 202, 207 Fatty acids, 173, 202, 215, 233 Febrile, 202, 243 Feces, 192, 202, 244 Femoral, 202, 208 Femoral Neck Fractures, 202, 208 Femur, 202, 208 Fenfluramine, 8, 202 Fentanyl, 35, 202 Fetal Alcohol Syndrome, 127, 202 Fetoprotein, 173, 203 Fetus, 173, 203, 230, 232, 251 Fibrin, 106, 182, 203, 247 Fibrinogen, 98, 106, 203, 230, 247 Fibrinolytic, 106, 203 Fibrosis, 129, 153, 174, 203, 239 Fissure, 195, 203, 232 Fixation, 203, 240 Flumazenil, 15, 20, 23, 37, 60, 203 Flunitrazepam, 15, 34, 73, 110, 203
Fluorine, 37, 203 Fluoxetine, 13, 39, 203 Flurazepam, 30, 110, 204 Fluvoxamine, 13, 204 Fold, 28, 43, 115, 203, 204 Forearm, 183, 204 Fossa, 187, 204 Frontal Lobe, 176, 187, 204, 232 G Galanthamine, 93, 95, 204 Gallbladder, 94, 107, 171, 181, 188, 196, 204, 241 Ganglia, 171, 177, 179, 180, 181, 188, 204, 215, 222, 226, 228, 245 Gap Junctions, 204, 246 Gas, 174, 185, 188, 203, 204, 209, 213, 223, 245, 251 Gasoline, 181, 204 Gastric, 107, 116, 117, 129, 168, 180, 204, 208, 213, 228, 233, 241 Gastric Acid, 107, 116, 117, 204, 228 Gastrin, 93, 107, 204, 208, 228 Gastritis, 107, 204 Gastroenteritis, 128, 204 Gastroenterology, 128, 129, 204 Gastrointestinal, 12, 93, 107, 118, 129, 183, 188, 200, 201, 204, 215, 233, 240, 242, 245 Gastrointestinal tract, 188, 201, 204, 215, 240 Gelatin, 204, 206, 247 Gene Expression, 25, 40, 153, 205 General practitioner, 58, 205 Genetic Code, 205, 224 Genetic Engineering, 182, 189, 205 Genetics, 35, 205 Genital, 189, 205, 251 Genitourinary, 205, 251 Genotype, 205, 228 Geriatric, 5, 10, 11, 133, 134, 141, 205 Germ Cells, 205, 217, 224, 242 Gestation, 35, 205, 230 Giant Cells, 205, 239 Ginkgo biloba, 84, 112, 205 Ginseng, 80, 85, 205 Gland, 114, 172, 205, 216, 226, 227, 230, 233, 239, 244, 247 Glioma, 50, 115, 205 Glomerular, 205, 214, 237 Glomeruli, 34, 205 Glomerulonephritis, 34, 205 Glomerulus, 205, 222 Glossopharyngeal Nerve, 202, 205
262
Benzodiazepines
Glucocorticoid, 111, 112, 206 Glucose, 76, 152, 186, 196, 206, 207, 209, 212, 236 Glucose Intolerance, 196, 206 Glucuronic Acid, 102, 206 Glucuronides, 206 Glutamate, 38, 49, 104, 206 Glutamic Acid, 206, 233 Glycerol, 184, 206, 229 Glycine, 17, 50, 94, 102, 206, 240, 244 Glycogen, 114, 206 Glycoprotein, 203, 205, 206, 213, 247, 250 Glycosidic, 186, 206, 222, 224 Gonadal, 206, 244 Gout, 130, 206 Governing Board, 206, 232 Graft, 206, 209, 211 Grafting, 106, 193, 206 Granule, 26, 195, 206, 238 Granulocytes, 207, 241, 253 Guanosine Diphosphate, 119, 207 Guanosine Triphosphate, 119, 207 H Habituation, 42, 207 Haematemesis, 199, 207 Half-Life, 10, 103, 207 Hallucinogen, 207, 217 Haloperidol, 13, 207 Haptens, 172, 207 Headache, 116, 117, 129, 141, 184, 207, 209, 251 Headache Disorders, 207 Health Services, iv, 14, 15, 41, 150, 207 Heart attack, 185, 207 Heart failure, 105, 114, 192, 207 Heme, 181, 194, 207 Hemodialysis, 140, 196, 207, 214 Hemoglobin, 59, 175, 200, 207, 208 Hemoglobinuria, 152, 208 Hemorrhage, 35, 106, 193, 199, 207, 208, 244 Hemorrhoids, 4, 208 Hemostasis, 208, 240 Hepatic, 27, 49, 59, 61, 114, 173, 194, 208, 216, 219 Hepatic Encephalopathy, 49, 59, 61, 208 Hepatocytes, 80, 208 Hereditary, 188, 206, 208, 220, 238 Heredity, 204, 205, 208 Heterogeneity, 172, 208 Hip Fractures, 41, 49, 54, 138, 202, 208
Hippocampus, 18, 25, 29, 30, 31, 32, 38, 39, 107, 195, 208, 215, 236, 245 Histamine, 32, 175, 177, 181, 196, 208 Histidine, 208 Holidays, 14, 208 Homeostasis, 16, 108, 113, 208, 242 Homologous, 208, 210, 240, 246 Hormonal, 13, 45, 105, 179, 182, 188, 201, 208 Hormonal therapy, 13, 208 Hormone therapy, 208, 209 Host, 35, 180, 190, 209, 210, 211, 215, 252 Hybrid, 35, 42, 209 Hybridization, 19, 209, 211, 224 Hydrogen, 90, 101, 121, 171, 174, 181, 185, 196, 209, 219, 224, 225, 234 Hydrolysis, 57, 90, 179, 186, 209, 222, 229, 231, 234 Hydrophobic, 102, 209 Hydroxamic Acids, 20, 209 Hydroxylysine, 190, 209 Hydroxyproline, 190, 209 Hyperkinesia, 116, 117, 209 Hyperplasia, 107, 209 Hypersecretion, 116, 117, 209 Hypersensitivity, 174, 195, 196, 209, 215, 238, 240 Hypertension, 16, 40, 114, 116, 117, 184, 185, 192, 207, 209, 213, 235, 248, 250 Hypertrophy, 16, 105, 192, 209, 249 Hyperuricemia, 206, 209 Hypnotic, 20, 23, 29, 36, 42, 46, 51, 73, 93, 95, 141, 180, 196, 201, 204, 209, 219, 223, 232 Hypoglycaemia, 194, 209 Hypotension, 177, 209 Hypothalamus, 25, 107, 171, 180, 196, 209, 215, 230, 247 Hypoxia, 183, 187, 194, 209, 247 I Iatrogenic, 129, 210 Ibuprofen, 140, 210 Id, 74, 82, 152, 159, 164, 166, 210 Idiopathic, 129, 210, 235, 239 Illusions, 210, 239 Imidazole, 99, 119, 182, 208, 210 Imipramine, 59, 128, 138, 210 Immersion, 181, 210 Immune function, 34, 210, 211 Immune response, 177, 180, 207, 210, 240, 245, 252
Index 263
Immune system, 157, 180, 198, 210, 211, 215, 216, 221, 251, 252 Immunity, 80, 173, 210 Immunization, 210, 211, 240 Immunoassay, 70, 210 Immunodeficiency, 50, 152, 210 Immunoenzyme Techniques, 210 Immunohistochemistry, 30, 210 Immunologic, 187, 210 Immunology, 172, 210 Immunosuppressive, 34, 206, 210, 211 Immunosuppressive Agents, 34, 211 Immunotherapy, 196, 211 Impairment, 4, 7, 22, 32, 36, 55, 64, 81, 171, 179, 181, 187, 194, 198, 211, 218, 234 Impotence, 16, 211 In situ, 19, 31, 211 In Situ Hybridization, 19, 211 In vitro, 16, 20, 21, 24, 31, 34, 37, 43, 59, 71, 73, 78, 79, 80, 115, 182, 211, 243 In vivo, 16, 18, 21, 28, 34, 37, 79, 108, 115, 182, 211 Incision, 211, 213 Incontinence, 54, 128, 133, 211, 239, 244 Indicative, 123, 211, 227, 251 Induction, 80, 107, 114, 177, 211, 214 Infant, Newborn, 173, 211 Infarction, 106, 177, 183, 187, 193, 211, 218, 221 Infection, 128, 187, 194, 204, 210, 211, 216, 222, 227, 238, 245, 252 Infertility, 109, 211 Infiltration, 205, 211 Inflammatory bowel disease, 116, 117, 212 Informed Consent, 131, 141, 212 Infusion, 21, 192, 212 Inhalation, 44, 96, 109, 110, 131, 172, 175, 212, 231 Initiation, 11, 24, 29, 212 Initiator, 182, 212 Inlay, 212, 237 Inorganic, 91, 212, 220 Inositol, 42, 212, 239 Inotropic, 197, 212 Insight, 18, 40, 49, 212 Insomnia, 4, 6, 14, 21, 29, 46, 50, 51, 53, 63, 66, 77, 83, 103, 120, 130, 138, 141, 212, 225, 249 Insulin, 107, 182, 212, 250 Insulin-dependent diabetes mellitus, 212 Intensive Care, 35, 77, 212 Interindividual, 28, 212
Interleukins, 211, 212 Intermittent, 17, 44, 129, 212, 216 Internal Medicine, 15, 61, 70, 204, 212 Interneurons, 29, 31, 45, 212 Interstitial, 109, 156, 158, 213, 222, 237 Intervention Studies, 48, 213 Intestinal, 27, 185, 188, 200, 213, 217 Intestine, 27, 181, 183, 190, 198, 208, 213, 214, 235, 237, 241, 242 Intoxication, 17, 22, 97, 194, 213, 253 Intracellular, 31, 42, 108, 113, 184, 186, 211, 213, 231, 236, 239, 241 Intracranial Embolism, 187, 213 Intracranial Embolism and Thrombosis, 187, 213 Intracranial Hypertension, 207, 213, 248 Intramuscular, 131, 213, 226 Intravascular, 106, 213 Intravenous, 14, 60, 62, 98, 103, 131, 212, 213, 227 Intrinsic, 18, 31, 45, 76, 119, 172, 213, 228 Intrinsic Factor, 213, 228 Invasive, 35, 109, 128, 210, 213 Involuntary, 109, 128, 181, 188, 192, 201, 213, 221, 242, 243, 244 Ion Channels, 19, 23, 29, 36, 51, 179, 213, 223, 246 Ions, 20, 181, 197, 199, 209, 213, 219, 231, 234, 242 Irritable Bowel Syndrome, 107, 116, 117, 213 Ischemia, 104, 114, 179, 183, 187, 213, 223 Isopropyl, 112, 213 J Jealousy, 213, 226 Jet lag, 116, 117, 213 Joint, 130, 213, 245 K Kainic Acid, 104, 214 Kallidin, 183, 214 Kava, 78, 84, 85, 214 Kb, 148, 214 Ketamine, 127, 159, 214 Kidney Disease, 148, 153, 214 Kidney Failure, 140, 200, 214 Kidney Failure, Acute, 214 Kidney Failure, Chronic, 214 Kinetic, 19, 26, 214 Kynurenic Acid, 38, 214 L Labile, 42, 102, 191, 214 Lag, 116, 117, 213, 214
264
Benzodiazepines
Large Intestine, 190, 196, 213, 214, 237, 242 Latent, 214, 232 Lavage, 168, 215 Legionellosis, 129, 215 Length of Stay, 15, 98, 215 Lesion, 193, 215, 216, 246, 250 Lethal, 35, 180, 215 Leukemia, 152, 215, 234 Leukocytes, 183, 187, 207, 212, 215, 250 Leukotrienes, 178, 215, 216 Levodopa, 72, 197, 215, 240 Library Services, 164, 215 Life cycle, 172, 197, 215 Ligament, 215, 233 Ligands, 17, 18, 37, 38, 39, 43, 49, 50, 51, 57, 76, 80, 105, 115, 124, 215 Limbic, 174, 215, 232 Limbic System, 174, 215, 232 Linkages, 207, 215, 222 Lipid, 184, 206, 212, 215, 219 Lipophilic, 43, 215 Lipopolysaccharide, 49, 215 Lipoxygenase, 21, 178, 215, 216 Lipoxygenase Inhibitors, 21, 216 Lithium, 6, 8, 9, 11, 177, 216 Liver cancer, 173, 216 Liver Cirrhosis, 114, 216 Lobe, 45, 174, 176, 187, 204, 216, 232, 246 Localization, 28, 31, 34, 115, 210, 216 Localized, 29, 39, 130, 171, 183, 195, 203, 211, 216, 219, 230, 250 Locomotion, 30, 216, 230 Long-Term Care, 13, 14, 216 Loop, 19, 50, 216 Lupus, 34, 216 Lymph, 187, 216, 239 Lymph node, 187, 216, 239 Lymphatic, 211, 216, 218, 242, 243 Lymphatic system, 216, 242, 243 Lymphocyte, 177, 216, 217 Lymphoid, 34, 176, 193, 216 Lymphoma, 152, 216 Lysergic acid, 128, 217 Lysergic Acid Diethylamide, 128, 217 M Maintenance therapy, 9, 217 Malabsorption, 152, 217 Malignancy, 115, 217 Malignant, 65, 115, 152, 158, 172, 177, 216, 217, 239 Malnutrition, 173, 179, 217, 220 Mammary, 193, 217
Mania, 217 Manic, 9, 177, 182, 216, 217, 234 Manic-depressive psychosis, 217, 234 Manifest, 133, 217 Mediate, 16, 32, 34, 48, 81, 138, 197, 217 Mediator, 188, 197, 217, 240 Medicament, 73, 217 MEDLINE, 149, 151, 153, 217 Meiosis, 217, 246 Melanin, 217, 229, 250 Melanocytes, 217 Melanoma, 152, 217 Membrane Glycoproteins, 218, 231, 242 Memory, 36, 39, 57, 76, 107, 114, 124, 168, 174, 176, 194, 195, 218 Meninges, 187, 193, 218 Menopause, 6, 218, 231 Menstrual Cycle, 218, 233 Menstruation, 174, 218, 232 Mental deficiency, 203, 218 Mental Disorders, 218, 234 Mental Health, iv, 14, 42, 148, 150, 218, 235 Mescaline, 95, 218 Mesenchymal, 57, 218 Mesolimbic, 177, 218 Meta-Analysis, 49, 218 Metabolic disorder, 206, 218 Metabolite, 38, 63, 218, 232 Metastasis, 98, 218 Metastatic, 115, 218, 239 Methionine, 111, 218, 245 MI, 108, 169, 218 Microbe, 218, 248 Microbiology, 73, 171, 180, 218 Microcirculation, 216, 219 Microorganism, 190, 219, 252 Midazolam, 28, 35, 219 Middle Cerebral Artery, 104, 219 Mitochondria, 35, 73, 113, 116, 219, 225 Mitochondrial Swelling, 219, 221 Mitosis, 178, 219 Modeling, 43, 72, 198, 219 Modification, 6, 20, 29, 72, 158, 205, 219, 236 Modulator, 17, 23, 219, 246 Molecular Structure, 219, 249 Monitor, 97, 219, 223 Monoamine, 174, 177, 196, 219, 240 Monoamine Oxidase, 174, 177, 196, 219, 240 Mononuclear, 220, 250
Index 265
Monotherapy, 110, 220 Mood Disorders, 9, 96, 220 Morale, 94, 220 Morphine, 35, 63, 95, 175, 190, 220, 221, 224 Morphogenesis, 203, 220 Morphological, 173, 199, 217, 220 Motility, 129, 220, 233, 240 Motion Sickness, 220, 221, 239 Motor Activity, 220 Motor nerve, 220 Movement Disorders, 12, 177, 220, 247 Mucociliary, 220, 241 Mucosa, 4, 188, 216, 220, 241 Mucus, 220, 250 Muscle Contraction, 16, 58, 175, 220 Muscle Fibers, 220, 221 Muscle relaxant, 3, 4, 7, 42, 93, 95, 103, 109, 117, 118, 130, 141, 157, 176, 194, 201, 220 Muscle tension, 96, 220 Muscular Atrophy, 152, 220 Muscular Dystrophies, 198, 220 Mutagenesis, 23, 35, 220 Mutagens, 221 Mydriatic, 196, 221, 239 Myocardial infarction, 106, 177, 193, 218, 221 Myocardium, 218, 221 Myoclonus, 12, 221 Myosin, 220, 221 Myotonic Dystrophy, 152, 221 N Naive, 30, 221 Naloxone, 72, 221 Naltrexone, 72, 221 Narcosis, 221 Narcotic, 7, 98, 131, 175, 202, 220, 221, 223, 248 Narcotic Antagonists, 131, 221 Nausea, 44, 116, 118, 128, 177, 178, 204, 221, 226, 250 Neck Muscles, 129, 221 Necrosis, 49, 108, 178, 187, 211, 218, 221, 239, 250 Neonatal, 35, 222 Neoplasia, 152, 222 Neoplastic, 202, 216, 222 Nephritis, 34, 222 Nephropathy, 214, 222 Nerve Fibers, 94, 171, 222
Nervous System, 3, 8, 11, 16, 19, 20, 25, 50, 91, 93, 101, 104, 112, 113, 114, 126, 130, 152, 157, 171, 172, 173, 174, 180, 181, 184, 187, 188, 189, 196, 204, 206, 207, 215, 217, 220, 221, 222, 223, 224, 225, 228, 239, 240, 242, 245, 246 Networks, 29, 222 Neural, 9, 25, 29, 32, 39, 71, 172, 203, 219, 222, 242 Neuraminidase, 21, 222 Neuroanatomy, 37, 215, 222 Neuroendocrine, 25, 157, 222 Neurogenic, 3, 222 Neuroleptic, 13, 54, 96, 130, 134, 173, 177, 189, 222 Neurologic, 5, 11, 35, 129, 157, 176, 222 Neuromuscular, 4, 129, 156, 171, 194, 222, 250 Neuromuscular Junction, 171, 222 Neuronal, 18, 24, 36, 39, 42, 70, 104, 116, 118, 189, 221, 222 Neuropathy, 4, 222, 228 Neuropeptide, 93, 222 Neurophysiology, 195, 223 Neuroprotective Agents, 91, 223 Neurosis, 93, 223, 229 Neurotic, 176, 223, 251 Neurotoxicity, 50, 214, 223 Neurotransmitters, 16, 104, 202, 223, 242 Niacin, 223, 249 Nicotine, 14, 38, 95, 116, 117, 127, 128, 223 Nifedipine, 28, 223 Nitrazepam, 73, 201, 223 Nitrogen, 173, 174, 203, 214, 223, 249 Nitrous Oxide, 28, 223 Nonmalignant, 158, 223 Norepinephrine, 16, 172, 197, 223 Nuclear, 119, 180, 199, 201, 215, 221, 223, 233, 247 Nuclei, 174, 176, 199, 205, 215, 219, 224, 234, 252 Nucleic acid, 111, 205, 209, 211, 221, 223, 224, 235 Nucleic Acid Hybridization, 209, 224 O Obsession, 191, 224 Odour, 178, 224, 250 Oligosaccharides, 222, 224 Oliguria, 214, 224 Oncogene, 121, 152, 224 Oocytes, 36, 50, 65, 224 Opacity, 195, 224
266
Benzodiazepines
Opium, 220, 224 Opsin, 224, 238 Optic Chiasm, 209, 224 Optic Nerve, 224, 237 Oral Health, 127, 129, 131, 224 Organelles, 113, 194, 217, 224, 227, 230 Orgasm, 198, 225 Orofacial, 7, 202, 225 Orphenadrine, 66, 225 Orthostatic, 177, 225 Osmosis, 225 Osmotic, 21, 173, 219, 225, 241 Osteoporosis, 98, 201, 225 Osteosarcoma, 225, 234 Outpatient, 9, 15, 27, 37, 225 Overdose, 167, 192, 225 Overexpress, 113, 225 Ovum, 193, 205, 215, 225, 233 Oxazepam, 60, 85, 225 Oxidation, 20, 171, 177, 178, 194, 225 Oxidative Phosphorylation, 113, 225 Oxides, 37, 225 Oxygen Consumption, 225, 237 P P53 gene, 225, 233 Paediatric, 57, 225 Palliative, 53, 225, 247 Palsy, 116, 117, 187, 225, 243 Pancreas, 94, 107, 171, 182, 196, 204, 212, 226, 241 Pancreatic, 107, 119, 152, 188, 196, 226 Pancreatic cancer, 152, 226 Pancreatic Juice, 107, 226 Pancreatitis, 107, 226 Panic, 20, 21, 41, 42, 52, 59, 66, 82, 93, 96, 103, 107, 116, 117, 126, 156, 204, 210, 226 Panic Disorder, 20, 21, 42, 52, 59, 66, 96, 103, 107, 116, 117, 156, 204, 210, 226 Paraganglia, Chromaffin, 188, 226 Paralysis, 193, 226, 243 Paramedic, 138, 226 Paranasal Sinuses, 226, 241 Paranoia, 25, 226 Parasitic, 197, 226 Parenchyma, 115, 226 Parenteral, 104, 226 Paresthesias, 156, 226, 227 Parkinsonism, 177, 215, 225, 227 Parotid, 206, 227, 239 Paroxetine, 44, 227 Paroxysmal, 96, 152, 207, 227, 251 Particle, 227, 249
Patch, 17, 24, 31, 36, 45, 72, 227 Patch-Clamp Techniques, 24, 227 Pathogenesis, 4, 16, 227 Pathologic, 4, 18, 178, 182, 192, 193, 209, 227, 251 Pathologic Processes, 178, 227 Pathologies, 16, 227 Pathophysiology, 3, 227 Patient Compliance, 96, 97, 227 Patient Education, 62, 156, 162, 164, 169, 227 Patient Selection, 131, 227 Pediatric Dentistry, 131, 227 Pelvic, 109, 227, 233 Penicillin, 176, 227 Penis, 198, 227 Pentagastrin, 108, 228 Pentylenetetrazole, 21, 228 Pepsin, 228 Peptic, 181, 228 Peptic Ulcer, 181, 228 Peptide, 99, 114, 188, 200, 228, 231, 233, 234, 236, 249 Perception, 59, 79, 118, 180, 195, 228, 239 Percutaneous, 106, 228 Peripheral Nervous System, 225, 228, 245 Peripheral Neuropathy, 4, 228 Periventricular Leukomalacia, 35, 228 Pharmaceutical Preparations, 120, 187, 201, 204, 228 Pharmacodynamic, 22, 135, 228 Pharmacokinetic, 44, 135, 159, 228 Pharmacologic, 6, 7, 9, 11, 13, 21, 77, 96, 130, 131, 158, 175, 203, 207, 228, 248 Pharmacotherapy, 6, 8, 13, 63, 72, 77, 228 Phenotype, 32, 34, 105, 228 Phenprocoumon, 73, 228 Phenyl, 90, 91, 98, 101, 102, 103, 107, 229 Phenylalanine, 229, 250 Phobia, 44, 229 Phobic Disorders, 229 Phosphodiesterase, 21, 109, 229 Phosphodiesterase Inhibitors, 21, 109, 229 Phospholipases, 229, 241 Phospholipids, 202, 212, 229 Phosphorus, 184, 229 Phosphorylated, 30, 229 Phosphorylation, 20, 23, 26, 31, 113, 225, 229 Photocoagulation, 189, 229 Phototherapy, 13, 229 Physical Examination, 130, 229
Index 267
Physical Medicine, 7, 229 Physical Therapy, 158, 229 Physiologic, 131, 173, 182, 197, 207, 218, 221, 229, 236, 240, 249 Physiology, 19, 25, 36, 44, 57, 70, 107, 128, 171, 199, 204, 223, 229 Picrotoxin, 37, 230 Pigment, 181, 217, 230 Pilot study, 15, 230 Pituitary Gland, 114, 230 Placebo Effect, 7, 230 Placenta, 230, 232 Plants, 173, 179, 180, 181, 183, 185, 189, 205, 206, 223, 230, 239, 248, 249 Plaque, 175, 230 Plasma cells, 176, 230 Plasma protein, 173, 230, 234, 241 Plasticity, 20, 26, 30, 35, 230 Plastids, 225, 230 Platelet Activation, 230, 241 Platelet Aggregation, 98, 114, 175, 230 Platelets, 62, 106, 178, 182, 230, 240, 247 Platinum, 216, 231 Point Mutation, 48, 231 Poisoning, 194, 200, 204, 213, 221, 230, 231 Polycystic, 153, 231 Polymerase, 79, 231 Polymers, 46, 99, 231, 234, 245 Polymorphic, 195, 231 Polymorphism, 22, 231 Polypeptide, 116, 174, 190, 203, 209, 228, 231, 241, 253 Polyposis, 190, 231 Polysaccharide, 177, 186, 231 Posterior, 114, 175, 179, 187, 188, 197, 206, 221, 226, 231 Postmenopausal, 201, 225, 231 Postnatal, 25, 203, 231, 244 Postoperative, 129, 231 Postsynaptic, 20, 24, 30, 32, 33, 39, 231, 241, 246 Post-synaptic, 31, 231 Post-translational, 31, 231 Post-traumatic, 207, 220, 231 Potassium, 30, 36, 109, 231 Potassium Channels, 36, 231 Potentiate, 14, 232 Potentiating, 28, 38, 182, 232 Potentiation, 188, 232, 241 Practicability, 232, 249 Practice Guidelines, 150, 232 Precipitation, 42, 232
Preclinical, 43, 232 Precursor, 111, 178, 197, 198, 200, 202, 215, 223, 229, 232, 234, 249, 250 Predisposition, 105, 232 Prefrontal Cortex, 54, 232 Pregnanolone, 24, 232 Pregnenolone, 116, 232 Premedication, 232, 239 Premenstrual, 138, 232 Prenatal, 199, 203, 232 Presynaptic, 24, 232, 246 Prevalence, 8, 41, 44, 47, 50, 61, 62, 79, 120, 157, 232 Probe, 29, 232 Prodrug, 93, 232 Progesterone, 40, 196, 232, 244 Proglumide, 107, 233 Progression, 26, 115, 176, 233, 240 Progressive, 8, 18, 26, 116, 117, 186, 188, 195, 198, 201, 207, 214, 220, 221, 230, 233, 237, 250 Projection, 212, 223, 224, 232, 233, 236, 237 Proline, 22, 111, 190, 209, 233 Prone, 46, 81, 233 Prophase, 224, 233, 246 Prospective study, 78, 233 Prostaglandins, 99, 100, 101, 178, 233 Prostaglandins A, 100, 233 Prostaglandins D, 233 Prostate, 152, 233 Protease, 42, 190, 233 Protease Inhibitors, 42, 233 Protective Agents, 184, 233 Protein C, 36, 105, 173, 174, 180, 233, 250 Protein p53, 121, 233 Protein S, 31, 153, 182, 201, 205, 234, 235, 238 Proteolytic, 191, 203, 234 Prothrombin, 234, 247 Protocol, 15, 234 Protons, 209, 234, 236 Proximal, 197, 232, 234 Pruritus, 178, 196, 234, 250 Psychiatric, 5, 9, 10, 12, 20, 25, 37, 44, 45, 60, 63, 96, 130, 218, 234, 242 Psychic, 223, 234, 240 Psychogenic, 129, 234 Psychology, 39, 43, 46, 71, 72, 126, 134, 191, 197, 234 Psychometric testing, 35, 234 Psychomotor, 43, 63, 130, 133, 185, 194, 222, 234
268
Benzodiazepines
Psychopathology, 13, 234 Psychophysiology, 24, 234 Psychosis, 11, 13, 93, 116, 117, 177, 217, 234, 235 Psychotherapy, 12, 190, 235 Psychotomimetic, 174, 196, 218, 235 Psychotropic, 8, 11, 14, 15, 134, 235 Psychotropic Drugs, 14, 134, 235 Puberty, 25, 235 Public Health, 21, 34, 43, 47, 58, 66, 95, 134, 150, 158, 235 Public Policy, 149, 235 Publishing, 8, 48, 130, 235 Pulmonary, 106, 129, 182, 188, 192, 214, 215, 235, 251 Pulmonary Artery, 182, 235, 251 Pulmonary Edema, 188, 214, 235 Pulmonary Embolism, 106, 235 Pulmonary hypertension, 192, 235 Pulse, 29, 219, 235 Purines, 91, 235, 240 Puromycin, 21, 235 Purulent, 235 Pyloric Sphincter, 94, 235 Pylorus, 107, 235 Pyoderma, 116, 117, 235 Pyoderma Gangrenosum, 116, 117, 235 Pyramidal Cells, 30, 31, 195, 236 Q Quality of Life, 32, 44, 61, 134, 157, 236 Quaternary, 236, 239 Quiescent, 17, 131, 236 R Radiation, 180, 197, 200, 236, 253 Radiation therapy, 197, 236 Radioactive, 33, 180, 207, 209, 223, 236 Radiolabeled, 37, 236 Radiological, 228, 236 Randomized, 13, 35, 40, 44, 47, 49, 52, 56, 57, 60, 198, 236 Randomized clinical trial, 47, 236 Ras gene, 119, 236 Reabsorption, 114, 236 Reagent, 100, 120, 188, 236 Reality Testing, 234, 236 Receptors, Serotonin, 236, 240 Recombinant, 20, 33, 36, 38, 237, 251 Rectum, 4, 178, 190, 196, 204, 211, 212, 214, 233, 237, 241 Recurrence, 182, 217, 237 Red Nucleus, 179, 237 Reductase, 109, 237
Refer, 1, 183, 191, 197, 203, 205, 212, 216, 221, 222, 234, 237 Reflux, 107, 156, 237 Refraction, 237, 243 Refractory, 11, 199, 237 Regimen, 16, 135, 198, 227, 228, 230, 237 Relapse, 62, 237 Relaxant, 42, 93, 95, 194, 201, 220, 237 Relaxation Techniques, 129, 237 Remission, 182, 217, 237 Renal failure, 114, 194, 231, 237, 250 Research Design, 15, 237 Respiration, 113, 172, 178, 185, 186, 187, 192, 193, 219, 237 Respiratory distress syndrome, 129, 237 Restless legs, 5, 140, 156, 157, 237 Restoration, 31, 229, 237 Retina, 70, 188, 191, 224, 237, 238, 252 Retinal, 112, 224, 237 Retinoblastoma, 152, 238 Retinoid, 94, 238 Retinol, 237, 238 Rheumatism, 210, 238 Rheumatoid, 130, 140, 238 Rheumatoid arthritis, 130, 140, 238 Ribose, 172, 238 Ribosome, 238, 249 Rigidity, 96, 227, 230, 238 Risk factor, 58, 233, 238 Risk-Taking, 33, 238 Risperidone, 13, 238 Rod, 189, 238 Rotenone, 80, 238 Rubber, 36, 171, 238 S Sabin, 72, 238 Saliva, 238 Salivary, 6, 8, 196, 226, 238 Saphenous, 193, 239 Saphenous Vein, 193, 239 Saponin, 80, 239 Sarcoidosis, 129, 239 Sarcoma, 225, 239, 242 Schizoid, 239, 253 Schizophrenia, 23, 29, 38, 42, 45, 54, 65, 93, 95, 96, 107, 116, 117, 177, 199, 226, 238, 239, 253 Schizotypal Personality Disorder, 195, 239, 253 Sclerosis, 116, 117, 152, 153, 156, 239, 250 Scopolamine, 37, 239
Index 269
Screening, 4, 35, 40, 42, 57, 66, 72, 92, 99, 100, 105, 112, 113, 189, 239 Second Messenger Systems, 223, 239 Secondary tumor, 218, 239 Secretion, 107, 208, 209, 212, 220, 228, 233, 239, 240, 251 Secretory, 188, 239, 246 Secretory Vesicles, 188, 239 Sedatives, Barbiturate, 239 Seizures, 26, 38, 185, 194, 200, 227, 240, 243 Selegiline, 13, 240 Sella, 197, 230, 240 Semen, 198, 233, 240 Semisynthetic, 175, 217, 240 Senile, 83, 116, 117, 177, 225, 240 Sensitization, 81, 118, 240 Sensor, 46, 240 Serine, 22, 94, 200, 240 Serologic, 210, 240 Serotonin Agonists, 240 Serotonin Antagonists, 129, 240 Serous, 197, 240 Sertraline, 13, 240 Serum, 11, 56, 71, 72, 73, 103, 173, 175, 191, 214, 240, 241, 250 Serum Albumin, 73, 241 Sex Characteristics, 235, 241, 246 Sex Determination, 153, 241 Shock, 81, 221, 241, 249 Sigmoid, 4, 241 Sigmoid Colon, 4, 241 Sigmoidoscope, 4, 241 Sigmoidoscopy, 4, 241 Signal Transduction, 16, 49, 212, 241 Signs and Symptoms, 97, 237, 241, 250 Sincalide, 196, 241 Sinusitis, 129, 241 Skeletal, 117, 118, 188, 189, 193, 194, 220, 241, 243 Skeleton, 171, 202, 213, 241 Skull, 193, 241, 246 Sleep apnea, 129, 242, 244 Sleep Deprivation, 12, 242 Small intestine, 181, 198, 208, 213, 235, 242 Smooth muscle, 16, 109, 114, 174, 175, 184, 208, 220, 242, 243, 245 Sneezing, 242, 244 Social Behavior, 114, 133, 242 Social Environment, 16, 236, 242 Social Support, 87, 242, 244 Sodium, 12, 128, 157, 158, 206, 236, 242, 251
Sodium Channels, 242, 251 Soft tissue, 121, 130, 183, 241, 242 Soft tissue sarcoma, 121, 242 Solid tumor, 115, 175, 242 Solitary Nucleus, 180, 242 Solvent, 36, 43, 102, 103, 181, 201, 206, 225, 242 Soma, 141, 236, 242 Somatic, 193, 205, 215, 217, 219, 226, 228, 232, 242, 251 Somnolence, 12, 44, 243 Soporific, 32, 243 Spasm, 109, 129, 178, 193, 225, 243 Spastic, 116, 117, 213, 243 Spasticity, 180, 194, 243 Spatial disorientation, 197, 243 Specialist, 159, 196, 243 Specificity, 29, 37, 38, 48, 172, 178, 200, 243 Spectrum, 7, 96, 118, 176, 183, 214, 243 Sphincter, 94, 128, 235, 243 Spinal cord, 171, 179, 180, 183, 187, 188, 192, 218, 222, 223, 228, 243, 245 Spleen, 71, 216, 239, 243 Splint, 66, 243 Sporadic, 238, 243 Sprue, 116, 117, 243 Stabilization, 17, 243 Status Epilepticus, 26, 61, 62, 138, 243 Stavudine, 21, 243 Steady state, 10, 26, 38, 243 Steel, 189, 243 Stem Cells, 57, 244 Sterility, 211, 244 Steroid, 51, 92, 115, 193, 206, 232, 244 Stimulant, 174, 184, 196, 208, 214, 228, 230, 244 Stimulus, 14, 18, 23, 30, 47, 118, 198, 199, 201, 213, 214, 227, 229, 244, 247, 248 Stool, 211, 213, 214, 244 Strand, 231, 244 Stress, 3, 20, 24, 35, 47, 81, 83, 114, 128, 140, 157, 180, 186, 188, 193, 204, 213, 221, 232, 238, 244 Stress incontinence, 128, 244 Stress management, 47, 244 Stroke, 70, 104, 106, 114, 116, 117, 139, 148, 185, 223, 244 Stroke Volume, 185, 244 Stroma, 226, 244 Structure-Activity Relationship, 64, 244 Strychnine, 17, 244 Stupor, 168, 221, 244
270
Benzodiazepines
Styrene, 238, 245 Subacute, 211, 241, 245 Subarachnoid, 207, 245 Subclinical, 211, 240, 245 Subcutaneous, 198, 226, 245 Subiculum, 208, 245 Subspecies, 243, 245 Substance P, 200, 218, 239, 245 Substrate, 28, 216, 222, 245 Subtrochanteric, 208, 245 Suction, 227, 245 Sulfur, 218, 245 Superoxide, 49, 109, 245 Support group, 157, 158, 245 Suppression, 45, 245 Supraspinal, 180, 245 Sympathetic Nervous System, 16, 180, 188, 245 Sympathomimetic, 174, 196, 197, 200, 223, 245 Symphysis, 233, 245 Symptomatic, 5, 11, 12, 47, 176, 226, 245 Synapses, 24, 31, 37, 188, 223, 245, 246 Synapsis, 246 Synaptic, 20, 24, 26, 29, 30, 31, 38, 39, 42, 45, 223, 231, 241, 246 Synaptic Transmission, 38, 223, 246 Synaptic Vesicles, 246 Systemic, 4, 8, 34, 128, 129, 144, 178, 182, 183, 194, 200, 211, 213, 236, 239, 246, 249, 251 Systolic, 209, 246 T Tardive, 54, 107, 116, 117, 177, 189, 246 Taurine, 94, 246 Telangiectasia, 153, 246 Temazepam, 53, 246 Temporal, 29, 45, 174, 207, 208, 246 Temporal Lobe, 45, 174, 246 Tendinitis, 130, 246 Tenosynovitis, 130, 246 Testosterone, 25, 109, 175, 237, 246 Tetrahydrocannabinol, 184, 246 Thalamic, 179, 247 Thalamic Diseases, 179, 247 Thalamus, 196, 215, 232, 247 Therapeutics, 21, 30, 31, 38, 54, 61, 70, 78, 127, 144, 220, 247 Third Ventricle, 209, 247 Threonine, 240, 247 Threshold, 21, 201, 209, 247 Thrombin, 106, 203, 230, 233, 234, 247
Thrombocytes, 231, 247 Thrombomodulin, 233, 247 Thrombosis, 106, 114, 187, 193, 213, 218, 221, 234, 244, 247 Thrombus, 106, 193, 211, 230, 247 Thyroid, 247, 250 Thyroxine, 173, 229, 247 Time Management, 244, 247 Tin, 110, 140, 228, 231, 247 Tinnitus, 8, 53, 58, 247, 252 Tissue, 19, 28, 33, 79, 93, 94, 115, 116, 118, 121, 173, 175, 177, 178, 179, 181, 182, 183, 184, 187, 189, 190, 192, 198, 199, 202, 203, 204, 206, 209, 210, 211, 213, 214, 215, 216, 217, 218, 220, 221, 222, 226, 227, 228, 230, 231, 237, 238, 239, 241, 242, 244, 248, 250, 252 Tolerance, 7, 17, 20, 21, 29, 30, 31, 39, 42, 45, 46, 49, 80, 81, 125, 171, 198, 206, 248 Tomography, 37, 38, 248 Tonic, 17, 38, 192, 248 Tonicity, 198, 248 Topical, 6, 201, 248 Torsion, 211, 248 Torticollis, 129, 248 Toxic, iv, 100, 103, 119, 180, 181, 193, 200, 201, 210, 222, 223, 245, 248 Toxicity, 4, 7, 50, 55, 58, 96, 176, 198, 248 Toxicology, 55, 63, 66, 150, 248 Toxins, 177, 206, 211, 248 Trace element, 203, 247, 248 Traction, 189, 248 Tramadol, 58, 158, 248 Tranquilizing Agents, 235, 248 Transcriptase, 171, 243, 248 Transcutaneous, 158, 248 Transcutaneous Electric Nerve Stimulation, 158, 248 Transduction, 16, 49, 212, 241, 248 Transfection, 182, 249 Transgenes, 33, 249 Translation, 20, 50, 201, 249 Translational, 31, 231, 249 Translocation, 201, 249 Transmitter, 171, 179, 197, 202, 213, 217, 223, 246, 249 Trauma, 16, 25, 53, 181, 193, 194, 201, 207, 221, 223, 226, 247, 248, 249 Treatment Outcome, 12, 59, 249 Trees, 238, 249 Tremor, 97, 152, 201, 227, 249 Triazolam, 18, 22, 28, 37, 73, 86, 103, 249
Index 271
Tricuspid Atresia, 192, 249 Tricyclic, 3, 6, 7, 9, 12, 117, 157, 158, 177, 189, 210, 249 Trifluoroacetic Acid, 119, 249 Trigeminal, 202, 249 Trigger zone, 177, 249 Tryptophan, 38, 111, 190, 240, 249 Tuberculosis, 129, 192, 216, 249 Tuberous Sclerosis, 153, 250 Tubocurarine, 204, 250 Tumor Necrosis Factor, 49, 250 Tumour, 178, 250 Type 2 diabetes, 6, 250 Tyrosine, 111, 197, 250 U Ulcer, 107, 198, 228, 250 Ulcerative colitis, 116, 117, 212, 235, 250 Unconscious, 169, 175, 210, 250 Uraemia, 226, 250 Urea, 5, 214, 250 Uremia, 5, 214, 237, 250 Ureters, 250 Urethra, 228, 233, 250, 251 Uric, 206, 209, 235, 250 Urinary, 54, 57, 72, 109, 128, 184, 188, 194, 205, 211, 224, 239, 250, 251 Urinary tract, 109, 250 Urine, 72, 102, 103, 126, 128, 177, 178, 182, 197, 206, 208, 211, 214, 224, 232, 244, 250, 251 Urogenital, 109, 205, 251 Uterus, 187, 193, 218, 233, 251 V Vaccine, 234, 251 Vacuoles, 225, 251 Vagal, 94, 251 Vagina, 109, 195, 218, 251 Vagus Nerve, 242, 251 Valerian, 77, 86, 251 Valproic Acid, 13, 251 Vascular, 106, 114, 174, 181, 184, 187, 188, 207, 211, 216, 219, 230, 247, 251 Vascular Headaches, 181, 251 Vascular Resistance, 114, 251 Vasculitis, 187, 226, 251
Vasoconstriction, 116, 117, 200, 251 Vasodilator, 175, 181, 183, 197, 208, 223, 251 Vasomotor, 201, 251 Vector, 249, 251 Vein, 106, 179, 193, 213, 223, 227, 239, 251 Venous, 179, 187, 208, 213, 234, 249, 251 Venous blood, 187, 251 Ventricle, 174, 179, 192, 208, 209, 235, 246, 247, 249, 251, 252 Ventricular, 105, 192, 249, 252 Venules, 183, 184, 219, 252 Veratridine, 70, 252 Vestibulocochlear Nerve, 248, 252 Vestibulocochlear Nerve Diseases, 248, 252 Veterinary Medicine, 149, 252 Viral, 128, 129, 205, 248, 252 Virulence, 182, 248, 252 Virus, 33, 50, 180, 187, 200, 205, 230, 249, 252 Visceral, 180, 193, 205, 215, 251, 252 Visceral Afferents, 180, 205, 251, 252 Vitamin A, 158, 212, 238, 252 Vitreous Body, 237, 252 Vitro, 16, 20, 21, 24, 31, 35, 37, 43, 50, 59, 71, 73, 78, 79, 80, 116, 182, 211, 243, 252 Vivo, 16, 18, 21, 28, 35, 37, 79, 108, 115, 182, 211, 252 Volition, 213, 252 Vomica, 244, 252 W Wakefulness, 32, 194, 252 War, 15, 252 Weight Gain, 8, 35, 252 White blood cell, 176, 215, 216, 220, 230, 252 X Xenograft, 176, 253 X-ray, 223, 236, 253 Y Yeasts, 228, 253 Z Zymogen, 233, 253
272
Benzodiazepines
