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

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

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

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

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

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Methylphenidate: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00725-8 1. Methylphenidate-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.

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

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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 methylphenidate. 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 METHYLPHENIDATE ................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Methylphenidate ........................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 68 The National Library of Medicine: PubMed ................................................................................ 69 CHAPTER 2. NUTRITION AND METHYLPHENIDATE ..................................................................... 115 Overview.................................................................................................................................... 115 Finding Nutrition Studies on Methylphenidate ........................................................................ 115 Federal Resources on Nutrition ................................................................................................. 118 Additional Web Resources ......................................................................................................... 118 CHAPTER 3. ALTERNATIVE MEDICINE AND METHYLPHENIDATE ............................................... 119 Overview.................................................................................................................................... 119 National Center for Complementary and Alternative Medicine................................................ 119 Additional Web Resources ......................................................................................................... 125 General References ..................................................................................................................... 126 CHAPTER 4. DISSERTATIONS ON METHYLPHENIDATE ................................................................. 127 Overview.................................................................................................................................... 127 Dissertations on Methylphenidate ............................................................................................. 127 Keeping Current ........................................................................................................................ 129 CHAPTER 5. PATENTS ON METHYLPHENIDATE ............................................................................ 131 Overview.................................................................................................................................... 131 Patents on Methylphenidate ...................................................................................................... 131 Patent Applications on Methylphenidate................................................................................... 139 Keeping Current ........................................................................................................................ 151 CHAPTER 6. BOOKS ON METHYLPHENIDATE ............................................................................... 153 Overview.................................................................................................................................... 153 Book Summaries: Online Booksellers......................................................................................... 153 Chapters on Methylphenidate .................................................................................................... 154 CHAPTER 7. PERIODICALS AND NEWS ON METHYLPHENIDATE .................................................. 157 Overview.................................................................................................................................... 157 News Services and Press Releases.............................................................................................. 157 Academic Periodicals covering Methylphenidate....................................................................... 161 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 163 Overview.................................................................................................................................... 163 U.S. Pharmacopeia..................................................................................................................... 163 Commercial Databases ............................................................................................................... 164 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 167 Overview.................................................................................................................................... 167 NIH Guidelines.......................................................................................................................... 167 NIH Databases........................................................................................................................... 169 Other Commercial Databases..................................................................................................... 171 APPENDIX B. PATIENT RESOURCES ............................................................................................... 173 Overview.................................................................................................................................... 173 Patient Guideline Sources.......................................................................................................... 173 Finding Associations.................................................................................................................. 175 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 177 Overview.................................................................................................................................... 177 Preparation................................................................................................................................. 177 Finding a Local Medical Library................................................................................................ 177

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Medical Libraries in the U.S. and Canada ................................................................................. 177 ONLINE GLOSSARIES................................................................................................................ 183 Online Dictionary Directories ................................................................................................... 183 METHYLPHENIDATE DICTIONARY ..................................................................................... 185 INDEX .............................................................................................................................................. 239

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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 methylphenidate 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 methylphenidate, 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 methylphenidate, 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 methylphenidate. 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 methylphenidate, 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 methylphenidate. 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 METHYLPHENIDATE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on methylphenidate.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and methylphenidate, 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 “methylphenidate” (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: •

Chronic Constipation in Children: Rational Management Source: Consultant. 42(12): 1723-1732. November 2001. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This article reviews a strategy of rational management of chronic constipation in children. The authors note that irregular bowel habits are a common cause of chronic constipation in children; illness and travel are among the disruptions in daily routine that can result in stool withholding. Medical conditions, such as diabetes and Hirschsprung disease, and medications, including methylphenidate, analgesics, and cough syrups, can also cause constipation. Encopresis (fecal incontinence, or involuntary loss of stool), anal outlet bleeding, and rectal pain caused by anal fissures

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are associated with chronic constipation; hemorrhoids rarely develop in children. Barium enemas, survey films, and colonic transit studies can detect and define functional or structural obstruction. Physicians should recommend regular postprandial (after a meal) toilet visits; moderate exercise; and increased fluid and fiber intake, using a 'medicinal' fiber product if necessary. Parents should be discouraged from excessive use of laxatives and cathartics. Options for long term therapy include mineral oil and osmotic laxatives. 3 tables. 69 references.

Federally Funded Research on Methylphenidate The U.S. Government supports a variety of research studies relating to methylphenidate. 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 methylphenidate. 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 methylphenidate. The following is typical of the type of information found when searching the CRISP database for methylphenidate: •

Project Title: ADHD, STIMULANTS, AND D4 KNOCKOUT MICE Principal Investigator & Institution: Glaser, Paul E.; Psychiatry; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Dr. Glaser is a dedicated physician/scientist who is strongly committed to a career as an academic physician. He is currently an Assistant Professor on a tenure-track at the University of Kentucky. His scientific goal is to understand the neurobiology of Attention-Deficit/Hyperactivity Disorder (ADHD) and its treatments. With his joint appointments in Psychiatry and Anatomy & Neurobiology, he will be receiving laboratory and resource support from both departments. During the entire award period Dr. Glaser will be spending 75% of his time with laboratory related activities. In addition to research, he will be spending 15% of his time pursuing clinical activities, primarily in the areas of Child Psychiatry and Pediatrics in the treatment of children and adults with symptoms of ADHD. 10% of his time will be devoted to the teaching of residents and students, as well as educational activities. His sponsor, Dr. Gerhardt, is a leader in the field of neuropsychopharmacology of dopamine modulating medications as well as a recent co-collaborator in the field of ADHD. The neuroscience community at the University of Kentucky will also provide a rich source for collaboration and intellectual support. Additional support will be provided by cosponsor Dr. F. Xavier Castellanos at NYU, a leader in translational ADHD research. The

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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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primary goal of Dr. Glaser's proposal is to investigate physiologically-relevant differences in dopaminergic activity evoked by different isomers of amphetamine found in clinically prescribed medications for ADHD using a novel combination of voltammetric and microdialysis in the mouse striatum and nucleus accumbens. A secondary goal is to investigate the possible contribution that dopamine D4 receptors (D4R) may have to dopaminergic function in the mouse. Dr. Glaser will utilize mice designed by Dr. Grandy at the Oregon Health Sciences University that are missing the D4R (D4R knockout mice) to specifically investigate differences in their baseline behavior and stimulant induced behaviors. The integrated training, mentorship, research, and teaching of Dr. Glaser provided by this award will allow him to develop as an independent investigator dedicated to using basic neuroscience to solve important problems which physicians face everyday in the treatment of children and adults with ADHD and potentially will lead to better understanding and superior treatments for ADHD, thus reducing its burden on today's schools, health systems, and society. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AFFINITY LABELING THE DOPAMINE TRANSPORTER ACTIVE SITE Principal Investigator & Institution: Vaughan, Roxanne A.; Biochem and Molecular Biology; University of North Dakota 264 Centennial Drive Grand Forks, Nd 58202 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): One of the major sites of action for cocaine and amphetamine in the brain is the dopamine transporter (DAT), a neuronal protein responsible for rapid re-uptake of dopamine after synaptic transmission. Cocaine and other psychostimulants act by inhibiting dopamine reuptake, which results in increased levels of synaptic dopamine and enhanced downstream neural activity. Some therapeutic agents such as methylphenidate also act at DAT, and dysfunctions in DAT activity may be related to dopaminergic disorders such as Parkinson s disease, depression, Attention Deficity Hyperactivity Disorder, and schizophrenia. It is currentlynot known if cocaine and other DAT inhibitors bind to the same or different sites on DAT or how they prevent transport. This basic lack of understanding of the molecular basis of the action of these compounds arises in part because so little is known about DAT structure and active sites, and is a major obstacle in the development of DAT-specific drugs that could be useful for treating psychostimulant abuse or other dopaminergic disorders. The goal of this study is to label DAT with irreversible analogs of cocaine and other uptake blockers and use proteolysis, epitope-specific immunoprecipitation, and mass spectrometry to identify the domains of the protein that interact with the ligands. The ligands to be developed will be modifications of previously-analyzed irreversible ligands whose sites of binding are known, and the patterns of incorporation of the new ligands, in conjunction with the previous findings, will lead to better understanding of the three-dimensional structure of DAT and the domains that contribute to antagonist and transport active sites. New ligands with distinct structures will also be examined. The long term objective of this research is to determine how DAT domains are spatially arranged to generate the binding sites for inhibitors, and to use this information to elucidate the molecular mechanisms underlying transport and transport inhibition. This knowledge will aid in the development of improved agents and therapeutic medications for drug abuse and other dopaminergic system disorders, and may be useful for generation of new agents for DAT imaging. The similarity of DAT to the norepinephrine and serotonin transporters presents the potential for these studies to be applicable to these other transporters.

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

Project Title: ALTERING BEHAVIORAL RISK FOR DRUG DEPENDENCE Principal Investigator & Institution: Cherek, Don R.; Professor; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AN FMRI STUDY OF EXECUTIVE FUNCTIONING AFTER TBI Principal Investigator & Institution: Levin, Harvey S.; Professor; Phys Med and Rehabilitation; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant) Executive functions (EFs) are cognitive control processes that include flexibility in problem solving, planning, allocation of attention, maintenance and manipulation of information over time, and self-regulation. EFs, which deploy specific cognitive skills such as declarative memory and other domains such as perceptuomotor skills, are mediated by prefrontal cortex and its circuitry. EFs are frequently impaired after traumatic brain injury (TBI), thus contributing to disability and reduced quality of life. Working memory and inhibition are fundamental processes of EFs which have been associated with prefrontal cortex and its network. Although the prefrontal region is vulnerable to injury by acceleration/deceleration and blunt trauma, structural brain imaging is limited in understanding the neurobiology of EF deficits after TBI. Using functional magnetic resonance imaging (fMRI), the Aims 9 of this 3 center project are to (1) Investigate whether the extent of cortical activation during working memory (N-back for faces) and inhibition (left-right incompatibility of arrows) tasks in adults 3 months following moderate to severe TBI differs from that of adults who have sustained extracranial injury; (2) Examine longitudinal changes in activation of prefrontal and related cortical regions during performance of working memory and inhibition tasks in TBI patients reimaged at I year postinjury; (3) Investigate the relationship between patterns of brain activation during working memory and inhibition tasks at 3 months and 1 year postinjury and performance on laboratory, clinical, and everyday measures of EF; (4) In an ongoing study of a separate cohort of moderate to severe TBI patients, evaluate the effects of methylphenidate (MPH) taken for 1 month on prefrontal activation during performance of working memory and inhibition tasks and the associated changes in performance on EF measures. Moderate to severe TBI patients (total n= 180) and general trauma patients (total n=60) will be recruited from the neurosurgery and surgery services at 3 centers. Aims 1-3 will be addressed by fMRI and EF assessment at 3 months and 1 year postinjury. Aim 4 will involve fMRI and EF assessment of TBI patients with working memory deficit who are treated for 28 days with MPH 15 in- bid beginning between 3 and 12 months postinjury. Patients studied for Aim 4 will undergo fMRI and EF assessment before beginning MPH and 1 hour after their final dose of MPH. Laboratory EF measures include dual task performance, subject ordered pointing, N-back letters task, selective learning, and risk taking; the revised Neurobehavioral Rating Scale provides clinical ratings of EFs; and assessment of EFs in everyday activities will include measures of dysexecutive functioning and planning. Analyses will test TBI-related alterations in brain activation at 3 months postinjury, changes on reimaging at 1 year, relationship to EFs, and MPH effects.

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Project Title: ASSESSING ABUSE POTENTIAL IN HUMAN--CNS STIMULANTS Principal Investigator & Institution: Rush, Craig R.; Associate Professor of Psychiatry; Behavioral Science; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: Methylphenidate (RITALIN), a piperidine derivative, is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Alarmingly, recent data from the Drug Enforcement Agency (DEA) indicate that methylphenidate (METH) abuse is widespread and represents a significant publichealth concern. For example, between 1989 and 1993 emergency-room admissions involving METH increased by as much as 715%. There is accumulating evidence that the symptoms of childhood ADHD persist into adulthood in a significant number of cases, and adulthood ADHD is associated with high rates of psychiatric comorbidity, including cocaine (COC) abuse. Whether COC abusers with ADHD are at risk to abuse METH is unclear, and many clinicians are reluctant to prescribe stimulants to these patients because of their histories of COC abuse. The specific aim of this project is to rigorously characterize the abuse potential of METH, the most commonly prescribed medication for the treatment of childhood and adulthood ADHD. To accomplish this aim, 3 inpatient, laboratory experiments will be conducted with volunteers with histories of COC abuse. Exp. 1 will replicate and extend findings from a previous study conducted in our laboratory that showed the discriminative-stimulus and subjective effects of METH are indistinguishable from those of COC. Exp. 2 will determine the relative reinforcing effects of METH and COC. Exp. 3 will determine the influence of rate of onset on the reinforcing, subjective and physiological effects of drugs by examining the effects of sustained- and immediate- release METH. We have two primary hypotheses. First, METH and COC will produce positive subjective effects and function as reinforcers. METH and COC will differ in terms of potency, but not efficacy. Second, sustained- release METH will have less abuse potential than immediate-release METH. The experiments proposed in the present application have at least 3 basic science and clinical implications. First these experiments will determine the abuse potential of METH in individuals with histories of COC abuse. Second, these experiments will determine whether decreasing the rate of onset of METH's effect reduces its abuse potential. Rate of onset is thought to be an important determinant of a drug's abuse potential. Third, these experiments may identify compounds that have reduced abuse potential (e.g., sustained-release METH) and may guide the pharmacological treatment of COC abusers with ADHD. The proposed experiments will also allow us to assess the effects of participating in non-treatment, inpatient, drug-abuse studies and to conduct retrospective analysis to determine the influence of individual differences (e.g., amount of cocaine use, amount and kind of other drug use, gender, ethnicity, socioeconomic status, as well as scores on a structured mental status exam, the Wender-Utah Rating Scale, the Beck Depression Inventory and several measures of personality function) on the behavioral and physiological responses to stimulants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BEHAVIORAL ECONOMICS IN CLOSED ECONOMIES Principal Investigator & Institution: Madden, Gregory J.; Assistant Professor; Psychology; University of Wisconsin Eau Claire Eau Claire, Wi 54701 Timing: Fiscal Year 2003; Project Start 25-SEP-2003; Project End 24-SEP-2005

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Summary: (provided by applicant): Behavioral economics is the application of microeconomic concepts (e.g., consumer demand) and measures within the experimental analysis of behavior. Recent behavioral-economic research suggests that relative reinforcer efficacy is not a singular construct, but should instead be understood as several different components of consumer demand. According to this model, relative reinforcer efficacy may be completely assessed only by measuring a) demand intensity (e.g., drug consumption when drug access is unconstrained), b) elasticity of demand (sensitivity of consumption to price fluctuations), c) P-max (price at which demand shifts from inelastic to elastic) and d) O-max (peak response rate maintained by the reinforcer). Limited empirical evidence supports this analysis and suggests that these measures may be used to predict other measures of reinforcer efficacy (e.g., breakpoint and preference) even when the latter measures disagree (e.g., higher breakpoints maintained by cocaine than methylphenidate but no preference between the drugs in a choice situation). The proposed research will address a limitation of the extant behavioral-economic literature: Only three experiments have thus far examined the relation between the four demand measures noted above and more traditional measures of relative reinforcer efficacy. One of these studies employed only hypothetical rewards and one failed to demonstrate concordance between all measures. Thus, the evidence for the superiority of the behavioral economic account is presently limited. The proposed experiments will assess relative reinforcer efficacy in a closed economy (access to reinforcers is obtained only during the experimental sessions) using steady-state experimental designs. Experiment 1 will examine preference between two reinforcers across a broad range of prices. Demand curves collected over the last two years with these reinforcers will be used to predict a) preferences across the range of prices, b) peak response rates, and c) progressive-ratio breakpoint. Correct predictions will support the behavioral economic account of relative reinforcer efficacy. Experiment 2 will assess the same predictions using drug (alcohol self-administration) and non-drug reinforcers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BEHAVIORAL EFFECTS OF OPIOIDS IN VOLUNTEERS Principal Investigator & Institution: Zacny, James P.; Associate Anesthesiology; University of Chicago 5801 S Ellis Ave Chicago, Il 60637

Professor;

Timing: Fiscal Year 2002; Project Start 15-MAR-1995; Project End 29-FEB-2004 Summary: Until recently, little attention had been paid to characterizing behavioral effects of opioids in normal volunteers (i.e., volunteers with no history of drug or alcohol dependence) using the rigorous testing methodologies that had been employed in the studies with abusers. For the past three years, we have employed an abuse liability/behavioral toxicology testing methodology to examine the effects of a number of different opioids that are typically given to patients for postoperative pain. This application will have four series of studies that are logical continuations of studies from the previous grant period. In the first series of studies, we will focus on opioids that are typically given to patients who are recovering from outpatient surgery. These patients might be at home or at work, engaging in different activities that may or may not be adversely affected by the opioids. It is vitally important to understand the behavioral toxicology of these opioids, yet rigorous toxicology studies (employing multiple measures of behavior and examining a range of doses that might be used by patients) have not been conducted to date. Therefore, we plan to continue our opioid characterization studies in normal volunteers, focusing on four oral drugs commonly used in outpatient settings: hydrocodone, oxycodone, propoxyphene, and tramadol. In the second series of studies, we will follow up on a study from the previous granting

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period in which some of morphine's subjective effects were attenuated by a painful stimulus. In four studies, we will use a cumulative dosing procedure recently developed in our laboratory to examine the degree to which a painful stimulus modulates the subjective and psychomotor effects of morphine, meperidine, butorphanol and nalbuphine. We will study different opioids at different doses and at different levels of painful stimulation in order to better understand how pain, which frequently accompanies opioid administration in patients, modulates behavioral effects of opioids. In the third series of studies, we will again follow up on a previous study from our laboratory in which we demonstrated that a painful stimulus modulated the reinforcing effects of an opioid, fentanyl. We propose to utilize a patient controlled analgesia (PCA) methodology to examine the degree to which four different opioids- morphine, meperidine, nalbuphine and butorphanol- maintain self-administration, and the degree to which self-administration is modulated by a painful stimulus. In the fourth series of studies, the effects of psychomotor stimulants alone and in combination with an opioid will be examined. Psychomotor stimulants are often given as adjuncts to opioids in patients suffering from chronic malignant pain to offset the sedating and impairing effects of high-dose opioid therapy. We will study buprenorphine in combination with three psychomotor stimulants- d-amphetamine, methylphenidate, and pemoline- to determine the relative pharmacodynamic profiles and which combination(s) produces the most analgesia with the least degree of troublesome side effects (including marked sedation and psychomotor/cognitive impairment). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BLOOD PRESSURE AND STIMULANT MEDICATIONS IN CHILDREN Principal Investigator & Institution: Sorof, Jonathan M.; Assistant Professor; Pediatrics; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2004 Summary: (Provided by Applicant): The primary objective of this proposal is to investigate the cardiovascular and sleep effects of the stimulant medications commonly used in children diagnosed with attention deficit hyperactivity disorder (ADHD). We propose 2 specific aims to test the hypotheses that stimulant medications in children with ADHD: 1) circadian blood pressure patterns and raise blood pressure, and 2) affect overall level of hyperactivity and quality of sleep. Using a double blind, placebocontrolled, random crossover design, 100 children aged 5 to 15; with ADHD by DSM-IV criteria will undergo 24-hour ambulatory blood pressure monitoring (ABPM) and actigraphy while receiving their usual dosing regimen of stimulant medication and while receiving placebo. Each subject will receive their usual stimulant medication (either methylphenidate or amphetamine-salt) for three and an identical placebo for three days in random order. At the end of the 1st 3-day period, subjects undergo 24hour ABPM and then crossover to the other arm of the study. After the 2nd 3-day period, subjects will again undergo 24-hour ABPM. The issue of cardiovascular and other side effects has become increasing important since ADHD is a highly prevalent disorder and prescriptions for psychotropic medications in children with behavioral disorders such as ADHD have risen significantly over the last 5 years. Virtually all studies stimulant medications have found significant dose response elevations in some combination of systolic, diastolic, and mean blood pressure. Chronic blood pressure elevation is one of the leading causes of attacks, stroke and renal failure. Since many children are treated for years with these medications, serious cardiovascular consequences of their chronic usage may result. The studies proposed will provide the

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published data on the effect of both short and long-acting stimulant medications on 24hour blood pressure patterns and the likelihood of inducing sustained hypertension. In so doing, these studies may suggest that long term use of these drugs places children at high risk for cardiovascular disease that may ultimately result in significant morbidity and mortality in adulthood. If so, physicians who prescribe these medications must increased awareness of the need to monitor blood pressure carefully in these children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CBT AND MODAFINIL FOR COCAINE ADDICTION Principal Investigator & Institution: Malcolm, Robert J.; Professor; Psychiatry and Behavioral Scis; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Thus far, an effective pharmacologic treatment for cocaine dependence has not been discovered. The present trial proposes cognitive behavior therapy (CBT) as the psychosocial platform to compare two doses of modafinil with placebo for the treatment of cocaine addiction. Modafinil is a marketed, atypical stimulant which has been approved by the FDA for the treatment of nacrolepsy. Modafinil acts intracellularly in several nuclei in the anterior hypothalamus to promote cortical activation, but does not alter dopamine systems. Controlled trials with modafinil indicate that it decreases hypersomnolence, elevates mood, enhances attention/concentration, and decreases appetite. Several preclinical human trials indicate that abuse potential of modafinil is low. Side effect profile for modafinil is modest and modafinil does not have pharmacokinetic interactions with cocaine, amphetamines, or methylphenidate. In a human laboratory study (n=12) from our group, Modafinil 400 and 800 mg suppressed subjective "high," "drug effect," and "amount willing to pay for high" to both low doses (20 mg) and high doses (40 mg) of IV cocaine. We postulate that modafinil serves as an atypical agonist replacement therapy for cocaine. Modafinil should ameliorate the symptoms of cocaine abstinence, blunt multiple dimensions of the cocaine "high" and enhance benefits of the CBT. To test these hypotheses and the safety of modafinil, we propose a two week screening baseline period followed by an eight week randomized parallel study of modafinil 200 mg, 400 mg and placebo daily. Follow up will occur four and eight weeks after all therapies cease. Outcome measures will include the number of cocaine non-use days and consecutive non-use days as assessed by self-report that will be confirmed by urine assays for quantitative benzoylecgonine three times a week. Secondary assessments will include measures of mood, daytime sleepiness, and subjective aspects of cocaine withdrawal and cocaine "high." Compliance with placebo and study medications will be assessed by quantitative urine riboflavin levels and serum modafinil levels. Safety will be assessed by a combination of self-report and repeated physical examinations, laboratory studies, ECGs, and monitoring by an independent data safety monitoring board. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMICAL/BEHAVIORAL STUDIES ON HALLUCINOGENIC AGENTS Principal Investigator & Institution: Glennon, Richard A.; Professor; Medicinal Chemistry; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 15-APR-1989; Project End 31-MAR-2008

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Summary: (provided by applicant): We have shown that arylalkylamines of abuse can produce one or more of at least three distinct discriminative stimulus effects in rats: a 1(2,5-dimethoxy-4-methylphenyl)-2-aminopropane-like (D(c)M-like) effect typical of classical hallucinogens (H), a (+)amphetamine-like effect typical of stimulants (S), and a third type of effect that has not yet been well defined but is typified by the phenylalkylamine N-methyl-l-(4-methoxyphenyl)-2-aminopropane (PMMA) (P). The model implies three distinct effects, three distinct structure-activity relationships (SARs), and three distinct mechanisms of action. The actions, SARs, and mechanisms of action of phenylalkylamine hallucinogens and stimulants have been relatively well investigated. In contrast, almost nothing is known about the SAR and mechanism of action of PMMAlike agents. Furthermore, certain agents have been demonstrated to produce multiple effects and are best classified as, for example, H/P- or S/P- type agents; these agents likeiy act by composite mechanisms and likely possess composite SARs. The abused phenyiaikylamine MDMA ("Ecstasy') is such an agent. We have classified this agent as belonging to the S/P-category, and what is known about its actions and SAR are consistent with the model. Types of questions now being addressed include: What structural traits did MDMA-iike agents inherit from (+)amphetamine and which were inherited from PMMA? We have been able to antagonize the stimulus effects of MDMA; are the effects of both MDMA isomers inhibited to the same degree or by the same mechanism? Can the PMMA-stimulus be antagonized in a similar manner? Using primarily a drug discrimination paradigm [with groups of animals trained to discriminate either DOM, (+)amphetamine, PMMA, MDMA, (-)MDMA, (+)MDMA from vehicle], we propose to investigate structure-activity relationships for PMMA-like activity, to study the stimulus mechanism of action of PMMA, and to classify various agents as to the type of effect(s) they produce. For example, the actions of numerous controlled (i.e., Schedule 1) substances are poorly understood; various novel street drugs (including their metabolites and synthetic by-products) are even less well understood. Investigation of such agents not only allows their classification, it also adds to the structure-activity data being collected that can ultimately be used to forecast the actions of newer agents. Compounds necessary for the studies are proposed for synthesis. Because stereochemistry plays a key role in the actions of many of the compounds (with enantiomers sometimes producing different effects), most will be examined as individual isomers. Where agents possess two chiral centers, all four isomers will be prepared and examined. Other studies relevant to the above model include examination of the stimulus effects of DOM and MDMA metabolites. The novel classification scheme provides a platform from which mechanism of action (and mixed mechanisms of action) can be investigated and unraveled. This will eventually lead to a better understanding of abuse prevention and treatment modalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHILDHOOD STIMULANT EXPOSURE IMPACT ON LATER DRUG ABUSE Principal Investigator & Institution: Castellanos, Francisco X.; Professor and Director; Psychiatry; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The study addresses major public health concerns regarding the relationships between stimulant treatment in childhood on 1) incidence of SUD in later life, and 2) brain development. Based on developmental animal studies and brain imaging findings in individuals with ADHD, it is hypothesized that 1) age at first stimulant treatment is positively related to later SUD, and 2) there is an inverse

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relationship between age at first treatment and white matter volume, controlling for possible confounds (i.e., initial severity, SES, CD, IQ, etc.). The study capitalizes on a unique, large sample (N=226) of systematically diagnosed children with ADHD first treated with stimulants between ages 6-12 (M, 8y) (probands), and matched comparisons (N=188). We have detailed information on stimulant dose and treatment duration. Subjects have been followed up previously when at mean ages 18 (range: 1623) and 25 (23-30), and have been tracked ever since. We propose: 1. to reevaluate probands and comparisons at mean age 39 (33-45), and spouses, for psychiatric history (SCID), detailed substance use (PRISM), IQ, social, educational, occupational, conjugal functioning, medical history. 2. to obtain high-resolution anatomic MRI and diffusion tensor imaging scans (on a Siemens Allegra 3.0 Tesla research-dedicated scanner). In addition to primary analyses, we will explore the relationship between features of stimulant treatment (duration, cumulative dose) and SUD, interactions between age at first stimulant treatment and MRI findings on SUD, and medical history. The study will also provide important information on adult functioning of children with ADHD. A key goal is to validate the relationship between earlier age at first treatment and lower risk for SUD by examining brain structure; importantly, even if the primary hypotheses are not confirmed, findings generated will have major significance by informing on possible sequelae of exposure to stimulants with regard to brain structure, medical liability, and will be the first to describe fully the functioning of children with ADHD in midadulthood, after age of risk for most disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC DRUG EXPOSURES; SERIAL MRI STUDIES Principal Investigator & Institution: Kaufman, Marc J.; Assistant Professor; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2004; Project Start 15-MAR-2004; Project End 28-FEB-2009 Summary: (provided by applicant): The aim of this program is to provide protected time to allow me to devote more than 75% of my effort to continue work on 3 interrelated projects. I am a newly independent Principal Investigator on a NIDA R01 (DA 14674) using functional MRI (fMRI) to elucidate mechanisms underlying sex differences in cocaine's acute brain effects. I am a co-Principal Investigator on a subcontract to a NIDA R01 (DA11231, PI: M. Pollack) using phosphorus spectroscopy (31p MRS) to study cerebral metabolism in methadone-maintained opiate dependent subjects. I am a Principal Investigator on a private foundation grant combining a nonhuman primate chronic cocaine self-administration model along with magnetic resonance (MR) technology to study brain structural and functional effects of chronic cocaine exposures. I developed expertise in clinical MR imaging during a K01 award by conducting studies of the acute brain effects of cocaine and methylphenidate. I identified sex differences in cerebrovascular reactivity to cocaine that may be bases for sex differences in chronic cocaine's brain effects. That work led directly to my R01 grant. I also collaborated on studies of chronic cocaine, heroin, and polydrug abusers that led to the subcontract noted above and learned first hand about confounds and limitations of human models. This led me to pursue collaborations and develop funding to conduct prospective MRI, MRS, and fMRI studies of controlled chronic drug exposures using non-human primate models. My primary goals in monkey studies are to identify relationships between cumulative self-administered cocaine dose and brain dysfunction severity (as suggested by human studies) and to determine how acute drug effects lead to chronic druginduced brain dysfunction. This work is in collaboration with Dr. Linda Porrino at Wake Forest University. The K02 award will allow me stability and flexibility to continue

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work on these interrelated projects. This stability is particularly important as I apply expertise learned in my Wake Forest collaboration to develop methods and funding to conduct monkey high field MR studies on the McLean Hospital 4.0 Tesla scanner and on a proposed 9.4 Tesla scanner. The protected time offered by the K02 will allow me more time to train and mentor the next generation of scientists interested in conducting these types of interdisciplinary research, and will assist me in making the transition from newly independent to independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLONIDINE IN ADHD Principal Investigator & Institution: Sallee, Floyd R.; Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2002; Project Start 18-AUG-2000; Project End 31-JUL-2006 Summary: Attention Deficit, Hyperactivity disorder (ADHD) is a common mental health disorder of significant morbidity for which approximately 100,000 children yearly are treated with clonidine (CLON) in the US, either as an alternative to psychostimulants, or as combination therapy. Adequate ADHD efficacy and safety data are lacking and CLON is not FDA approved for ADHD. Rationales for combination with methylphenidate (MPH) are that it may be synergistic, may extend the stimulant effect, and/or that CLON may address certain core symptoms not treated by stimulants alone. No data support these rationales, yet the combination is increasingly being prescribed despite reports of serious adverse events linked to combination therapy. CLON has yet to be comprehensively studied in primary ADHD, but an NINDS sponsored evaluation of the safety and efficacy of CLON alone and in combination with MPH is currently being conducted in children with Tourette Syndrome with comorbid ADHD (TACT). TACT subjects however may be predominantly "inattentive" subtype, in contrast to combined type, most commonly seen in primary ADHD. TACT data also cannot be extrapolated to primary ADHD because treatment with CLON in TACT is dually targeted to the treatment of both tics and ADHD such that dosing interval and potentially safety findings (if adverse events are dose related) may not be readily applied to primary ADHD. Efficacy and safety data from TACT therefore may be inadequate for primary ADHD treatment, for which the majority of CLON is prescribed. The clinical trial machinery and expertise of the TACT team however is uniquely positioned to study CLON in primary ADHD. Advantages would be: 1) reduced cost by using TACT existing infrastructure; 2) an opportunity to pool safety data across studies such that low frequency adverse events may be detected; 3) to compare therapeutic outcomes in primary ADHD to ADHD with comorbid Tourette Syndrome to determine if CLON has differential effects in "inattentive subtype" versus "hyperactive/impulsive" or combined subtypes; and 4) to determine if chronic treatment with MPH can contribute to the development of tic disorder. We propose a multicenter, controlled study of CLON, MPH, and CLON plus MPH for children with primary ADHD. The study will A) determine the safety and efficacy of CLON for the treatment of ADHD in children; B) evaluate the safety and efficacy of combined CLON+MPH for treatment of ADHD compared to standard MPH therapy; C) provide a lyr extension for all subjects to follow-up tic development during course of the study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COCAINE-BINDING DOPAMINE TRANSPORTER: MOLECULAR BIOLOGY Principal Investigator & Institution: Bannon, Michael J.; Professor; Psychiatry & Behav Neuroscis; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2003; Project Start 01-APR-1990; Project End 31-JAN-2008 Summary: (provided by applicant): Neurons utilizing dopamine (DA) as a neurotransmitter constitute a rare neurochemical phenotype but nevertheless play an important role in regulating locomotion, motivation, cognition and hormone release. The DA transporter (DAT) is a plasma membrane transport protein that controls the spatio-temporal domains of DA neurotransmission by rapidly reaccumulating DA that has been released into the extracellular space. A wide spectrum of neurological and psychiatric disorders, including drug abuse, Parkinson's disease, schizophrenia, affective disorders, and attention deficit hyperactivity disorder is thought to involve DA systems and the DAT. The DAT is an important target for therapeutic and illicit drugs (e.g. methylphenidate, buproprion, amphetamine, and cocaine), and serves as the point of entry for DA-specific neurotoxins. DAT radioligand binding provides an in vivo measure of DA cell integrity and can be used to monitor the efficacy of therapeutic interventions in neurodegenerative disease. The Aims of this project are to identify the silencing element(s) and cognate transcription factor(s) that repress transcription of the human dopamine transporter gene in non-dopaminergic cells, as well the mechanism by which the transcription factor nurrl activates human dopamine transporter gene transcription in dopamine neurons. It is likely that a greater understanding of the regulation of the DAT expression will impact the diagnosis and treatment of a number of neuropsychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COGNITION AND METHYLPHENIDATE--FMRI STUDY OF ADHD ADULTS Principal Investigator & Institution: Rao, Stephen M.; Professor of Neurology; Neurology; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2004 Summary: (Adapted from applicant's abstract): Attention Deficit Disorder (ADHD) is a common neurodevelopmental disorder that defines a group of individuals with developmentally inappropriate levels of inattention and hyperactivity-impulsivity. Long-term follow-up studies indicate that ADHD persists into adulthood in 30-66 percent of cases. Neuropsychological studies have identified a wide range of cognitive deficits in ADHD, including impairments on measures of response inhibition, sustained attention/working memory, timing perception/reproduction, and conceptual reasoning, prompting the suggesting that ADHD is associated with abnormal functioning of the prefrontal cortex and its subcortical connections. As a result of significant technological advances in human brain imaging, it is now possible to identify functional brain abnormalities that may underlie the cognitive deficits in ADHD. The long-range goal of this project, therefore, is to apply whole-brain fMRI to better understand the brain- mediated neurocognitive deficits in ADHD adults and to elucidate the mechanisms of action of psychostimulants commonly used to treat this disorder. The first hypothesis to be tested is that, relative to healthy individuals, unmedicated ADHD subjects will evidence minimal or no task- induced regional brain activation in frontostriatal circuitry. The second hypothesis is that methylphenidate (M)P will produce increases in task- induced functional activity in frontostriatal circuity

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in both ADHD and normal subjects. Third, the investigator hypothesizes that MP will "normalize" task-induced functional specificity in ADHD individuals relative to normal subjects. Three specific aims will be addressed: 1) to determine the regional changes in functional brain activation in unmedicated ADHD adults in response to performing cognitive tasks involving response inhibition, working memory, timing perception/reproduction, and conceptual reasoning, 2) to determine the effects of MP on task-activated brain activation patterns in normal subjects using a double-blind, placebo-controlled, cross-over design, and 3) to determine the effects of MP on taskactivated brain activation patterns in ADHD subjects using a double-blind, placebocontrolled, crossover design. The proposed fMRI experiments, therefore, should not only enhance our understanding of the brain abnormalities associated with ADHD, but should also provide a general blueprint for evaluating the neurocognitive effects of drugs in normal and abnormal populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SURVIVORS

COGNITIVE

CHANGES

IN

PEDIATRIC

BRAIN

TUMOR

Principal Investigator & Institution: Taylor, Lloyd A.; Health Professions; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2004; Project Start 01-SEP-2004 Summary: (provided by applicant): Pediatric brain tumors comprise approximately 20 percent of all pediatric cancer diagnoses. Treatment is aggressive, involving surgery and/or irradiation/chemotherapy. Numerous studies have documented the deleterious effects of irradiation therapy and chemotherapy on neuropsychological functioning (Brown, Mulhern, & Simonian, 2002; Mulhern, et al., 1999) and findings have demonstrated declines in performance measures of intelligence, attention, and memory. Recent investigations revealed similar cognitive declines among children who undergo surgical intervention alone (Meyer et al., 2000). There have been burgeoning efforts to manage the cognitive late effects associated with the CNS treatment of pediatric cancer among those children who have received irradiation and/or chemotherapy as part of their treatment. Efforts to enhance the cognitive difficulties experienced in children with brain tumors who undergo surgical intervention alone have not routinely occurred. Because these children also evidence declines in cognitive functioning, attention, and memory, research that addresses the management of this population is critical. This application outlines a training program designed to prepare me in research design and methodology related to the implementation of randomized clinical trials aimed at identifying evidence-based treatments to address cognitive difficulties for this subset of children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONSEQUENCES OF DRUG EXPOSURE IN FEMALES Principal Investigator & Institution: Collins, Stephanie L.; Neurology; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 28-FEB-2003; Project End 31-AUG-2005 Summary: (provided by applicant): Most research to date using animal models of drug abuse has focused on the effects of psychostimulants on brain neurochemistry and behavior in adult, prenatal, or preweanling animals. There has been little research focusing on the effects of psychostimulants on adolescent rats even though it is well known that a large number of people who use drugs started as teenagers. Because of

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this, it is of interest to examine the effects of psychostimulants in the adolescent population in order to determine whether there may be a difference in how this class of drugs effects this age cohort. Sex differences in periadolescent and adult rats may be important in determining the behavioral and neurochemical effects of psychostimulants and this should be taken into account when researching the effects of these drugs. Therefore, the effects of cocaine and methylphenidate on behavior and neurochemistry in female periadolescent and adult rats will be examined in this study. An understanding of the differential effects of drugs during periadolescence and adulthood in females may lead to different treatments for males and females in different age groups. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROLLED STUDY OF METHYLPHENIDATE IN ADULTS WITH ADHD Principal Investigator & Institution: Spencer, Thomas J.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-MAY-1998; Project End 28-FEB-2003 Summary: (Applicant's abstract): This is a resubmission of an R29 proposal that has been extensively revised. Despite the increasing recognition that children with attention deficit hyperactivity disorder (ADHD) commonly grow up to be adults with the same disorder, little is known about the treatment of this disorder in adults. There are five unanswered questions regarding the MPH treatment of ADHD adults: 1) what is the efficacy of robust MPH therapy (i.e., doses of up to 1.0 mg/kg/day) in ADHD adults diagnosed using DSM-IV, combined type criteria?, 2) what is the medium-term response of ADHD adults to MPH?, 3) what is the safety and tolerability of MPH treatment over the medium-term 4) can MPH-associated improvements in ADHD symptomatology be sustained without MPH after 6 months of effective treatment in ADHD adults ?, and 5) will MPH-associated improvements in ADHD symptomatology translate into improved functional capacities (neuropsychological, social and occupational) as well as increased quality of life after 6 months of effective treatment 7 To this end, the applicant proposes a double-blind, placebo- controlled, study to evaluate the efficacy and tolerability of MPH using daily doses of up to 1.0 mg/kg/day in the treatment of adults with the DSM-IV diagnosis of ADHD of childhood-onset. Careful diagnostic-assessment methods and clinically meaningful doses will be used and the effects on measures of function will be examined. Specific hypotheses will be examined in each of three phases of a double-blind, placebo-controlled, parallel study design. Phase I of the study will consist of a six week assessment of efficacy. During Phase II; subjects who respond in Phase I will be assessed every four weeks for six months. In Phase III, half of the MPH subjects will have their medication discontinued blindly over a four week period and half will remain on their dose of methylphenidate. The double-blind will be maintained throughout each Phase of the protocol. The study will include 150 subjects with the diagnosis of ADHD assessed using the module on ADHD derived from the KiddieSchedule for Affective Disorders and Schizophrenia and that of comorbid disorders using the Structured Clinical Interview for adult disorders. Diagnostic and symptom specific rating scales based on DSM-IV will also be used. The ADHD Rating Scale and the Clinical Global Impression Scale will be used to assess global severity and improvement of ADHD symptomatology. Psychosocial functioning and Quality of Life also will be assessed. The auditory and visual continuous performance tasks and the Stroop test will be used to further assess treatment efficacy. A larger neuropsychological battery will be used to assess the long term effects of MPH treatment.

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Project Title: COOPERATIVE MULTICENTER TRAUMATIC BRAIN INJURY CLINICAL Principal Investigator & Institution: Zafonte, Ross; Professor and Chair; Physical Medicine and Rehabilitation; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): The University of Pittsburgh Brain Injury System (UPBI) has been established as a clinical care and research center to serve the entire population of western Pennsylvania and portions of northern West Virginia and eastern Ohio. The need for a TBI clinical trials network is evidenced by the conclusions of the 1998 NIH TBI conference. The investigators feel that understanding the mechanisms that impact recovery and interventional efficacy, as well as the establishment of proxy measures that can predict long term outcome is an important role of the TBI clinical trials network. The UPBI spans from injury site to community and from the University's fundamental research labs to the homes of local adults and children with TBI. The UPBI provides state of the art care for and acquires data on over 300 severe and moderately injured adults and children each year. The follow-up rate of over 90% is a testament to the extensive resources that have been committed to this program. The UPBI is cornerstoned by a key group of investigators and consultants with a history of successful collaborative TBI clinical research. Specifically, the TBI research focus includes (1) mechanisms of injury and recovery of dopamine systems, (2) gender related differences in injury, recovery, and response to therapies, and (3) genetic influences on mechanisms of injury, recovery, and pharmacotherapeutic efficacy. Special emphasis has been placed on the study of the effects of methylphenidate on executive functioning and outcome after TBI and the influence of gender and dopamine transporter genotype on therapeutic efficacy of this drug. UPBI participation in the TBI clinical trials network will serve to enhance the UPBI in achieving its aims and goal of providing excellent clinical care, continuing participation in TBI clinical trials, developing methods and measures of objective and meaningful outcome, and evaluating specific pharmacological and therapeutic interventions for improved outcomes with TBI. Through its participation, the UPBI hopes to help fulfill the NIH recognized objective to evaluate, through multiple centers using common protocols, the relationship between acute care practice andrehabilitation strategies to the long-term functional outcome of TBI patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--CYCLOTRON / RADIOCHEMISTRY 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 Cyclotron/Radiochemistry Core provides all of the radionuclides, radioactive precursors, and approved PET radiopharmaceuticals for the research and clinical projects of this Program Grant. This includes production of fluorine-18 and carbon-11 precursors for Project 1, and routine deliveries of d-threo[11C]methylphenidate, [11C]raclopride, (+) [11C]dihydrotetrabenazine, [15O]water and 5- [123i]iodobenzovesacicol for Projects 2-4. PET radionuclide production is done using a dedicated Cyclotron Corp. CS-30 cyclotron, outfitted with 10 cyclotron targets, 8 of which are located on a vertical beam ladder. Primary and secondary production targets

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are available for all radionuclides. All cyclotron targetry, mechanical, electrical and computer systems have been constructed in house; the Core provides all routine and emergency repairs for all of these systems, as well as for the cyclotron itself. Radiochemical research and routine production of PET radiopharmaceuticals is done in a well-equipped radiochemistry laboratory, which has the capability to delivery clinical doses of carbon- 11 radiopharmaceuticals in sequential fashion at less than 1 hour intervals. All syntheses are done remotely using apparatus designed, constructed and maintained by Core staff members. The Core provides established expertise in radiochemistry, radiation safety, quality control (including sterility and pyrogen testing), and documentation for regulatory approvals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: D4 RECEPTOR-MEDIATED EFFECTS OF METHYLPHENIDATE IN MICE Principal Investigator & Institution: Grandy, David K.; Associate Professor; Physiology and Pharmacology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) is a complex behavioral condition characterized, in part, by distractibility, impulsivity, hyperactivity, and abnormal novelty-seeking behavior. ADHD is currently estimated to affect 2.5 million children and adults nationwide. The molecular basis for ADHD is unknown but a wealth of clinical data supports the hypothesis that dysregulation of dopamine (DA) signaling in the central nervous system significantly contributes to its etiology. Although most individuals diagnosed with ADHD benefit from low doses of the psychostimulant Ritalin (r) (methylphenidate, MPD), its exact mode of action and long-term consequences of exposure are unclear. However, since MPD can elevate extracellular DA levels by interfering with DA transporter function, its cIinical benefit may involve an indirect stimulation of DA receptors (DARs). Of the five known DAR subtypes, recent family and twin studies have revealed an association between an allele of the human DA D4R gene (DRD4.7) and ADHD. Anatomically, D4Rs are expressed in brain regions thought to be relevant to ADHD. Furthermore, incipient congenic D4R-/mice display locomotor supersensitivity to the psychostimulants cocaine and methamphetamine in addition to elevated striatal dopamine content and diminished novelty-seeking behavior. Taken together these observations suggested to us the hypothesis: DA D4Rs mediate MPD's effects in mice and humans. Since the selective pharmacological antagonism of D4Rs in vivo has yet to be convincingly demonstrated, we chose to begin testing our hypothesis in D4R-deficient mice and have found that congenic (N10 on C57B1/6J) D4R-/- mice display a dose-dependent locomotor supersensitivity to MPD. Encouraged by these findings we propose the following course of experimentation: In specific aim 1 we describe studies designed to establish whether acute and/or chronic MPD exposure influences novelty-seeking and impulsivity behaviors in juvenile and adolescent mice lacking D4Rs. In aim 2 we address the question: What are the effects of acute and chronic MPD exposure on gene expression in ADHD-relevant brain regions of wild-type and D4R-deficient juvenile and adolescent mice? Finally, in aim 3, we propose to generate three novel strains of knock-in mice that express either the human allele associated with ADHD (DRD4.7), a "normal" human D4R allele (D4.4), or Green Fluorescent Protein-tagged (GFP) murine D4Rs to more reliably localize the receptor protein in mouse brain tissue. It is our expectation that upon the successful completion of these aims, a better understanding of the complex

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relationship between MPD exposure, D4R stimulation, gene expression, and rodent behaviors relevant to ADHD will emerge Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEVELOPMENT OF COCAINE ABUSE TREATMENT AGENTS Principal Investigator & Institution: Ojo, Babatunde; Savannah State University Savannah, Ga 31404 Timing: Fiscal Year 2002 Summary: The overall goal of this proposed research is to synthesize and pre- clinically evaluate several new series of reversible and irreversibly binding cocaine antagonists in the methylphenidate class of stimulant agents. Extensive structural modifications involving the piperidine, ester moiety and aromatic ring of methylphenidate will be examined. It is anticipated that these structural modifications will provide therapeutic agents which inhibit cocaine binding, but spare dopamine uptake. The syntheses of desbenzene methylphenidate and a novel class of methylphenidate-like analogs (with piperidine ring replacement) are also proposed. These compounds will be evaluated in rats striatal tissue sin vitro for activity at the cocaine binding site using the [3H]WIN 35, 428 radioreceptor assay and for their ability to block synaptosomal [3H] dopamine transport. The ability to antagonize the behavioral effects of cocaine mediated through central dopaminergic pathways will be assessed utilizing tests which measure locomotor activity, cocaine discrimination and rotation following unilateral nigrostriatal lesions. Compounds which exhibit partial agonist or antagonist activity in the behavioral testings will be further evaluated ex vivo in the [3H]WIN 35, 428 and [3H] dopamine transport assays to obtain a better understanding of their interactions with the dopamine uptake complex in vivo. Computational modeling studies will be initiated to rationalize the biological significance of discrimination ratio (DR). Correlation between potency, dopamine uptake, DR, and the computational chemical analyses will be used to establish new structure activity relationships and hence, identify compounds which may be useful in directing efforts to develop medications for cocaine abuse. Successful completion of this research program will result in drugs with therapeutic potential against the reinforcing and addicting properties of cocaine. Ultimately, this work could serve as a significant contribution to the solution of cocaine addiction problem, a major continuing problem in the United States. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENTAL AFFECTS OF RITALIN ON BRAIN Principal Investigator & Institution: Milner, Teresa A.; Professor; Neurology and Neuroscience; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2005 Summary: (provided by applicant): Ritalin (methylphenidate; MPH) is one of the most commonly prescribed drugs for children with attention deficit hyperactivity disorder (ADHD). Over the past decade, ritalin usage has increased in the United States such that children diagnosed with ADHD often are maintained on the drug throughout late childhood and adolescence. Little is known however, regarding the long term consequences of therapeutic doses of MPH on brain development. Developmental MPH exposure may profoundly affect synaptogenesis, myelination and gliogenesis in several brain regions. Of particular note is the process of synaptogenesis, which occurs postnatally in several regions of the brain that are associated with learning and memory (e.g., hippocampus and cerebral cortex). Thus, the present proposal seeks to generate

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Methylphenidate

data to aid in evaluating the safety of therapeutic maintenance of MPH in children and adolescents. To achieve this goal, two aims are proposed: (1 ) to develop an animal model that reflects the clinical maintenance of MPH in children and (2) to assess the effects of long-term developmental exposure to therapeutic doses of MPH in this model on the adult brain. Initially, this model will utilize the maximum therapeutic dosage and duration of MPH that is used to treat ADHD in children. Long-term exposure to therapeutic doses of MPH then will be assessed in the forebrain of young adult rats at two time-points using sensitive, quantitative immunocytochemical methods. Focus will be on the: (a) dopaminergic system; (b) ascending noradrenergic system; and (c) ascending serotonergic system (especially their innervation of the cerebral cortex and hippocampus), since current experimental evidence indicates that these monoamines are either directly or indirectly affected following MPH administration. Additionally, the basal forebrain cholinergic and cortical glutamatergic systems will be analyzed since both are targeted by monoaminergic afferent systems, play a prominent role in attention and undergo synaptogenesis postnatally. Monoaminergic and cholinergic neurons and their efferent processes will be identified using antibodies to either their synthetic enzymes or transporters (i.e., to label subpopulations that are important in uptake and release), whereas cortical glutamatergic synapses will be identified by antibodies to NMDA receptors. If changes in any of the immunocytochemical markers are seen using these parameters in this model, future experiments would focus on: (1) dosage (e.g., to determine the maximum dose necessary to see these changes); (2) duration (e.g., to determine if the changes diminish with smaller periods of exposure or to identify developmental stages that may be uniquely sensitive to the drug effects); and (3) the age of assessment (e.g., to determine if the changes persist as the brain ages). Determining how therapeutic dosage regimens effect these transmitter systems is critical in understanding the safety of long-term therapeutic doses of MPH administered to children and adolescents with ADHD and other related disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DOPAMINE MECHANISMS IN DEVELOPMENT OF TYPE-2 DIABETES Principal Investigator & Institution: Hajnal, Andras; Neural and Behavioral Science; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): Obesity causes or exacerbates many chronic illnesses, most notably non-insulin-dependent diabetes mellitus (NIDDM). Most obesity is caused by modest, but chronic overeating. Otsuka Long-vans Tokushima fatty (OLETF) rats, which lack the CCK-A receptor, are hyperphagic, obese, and gradually develop NIDDM. In OLETF rats, increased food intake is necessary for the development of obesity, suggesting that the NIDDM is secondary to the prediabetic hyperphagia. Thus, OLETF rats are reasonable model of the most prevalent form of NIDDM in humans. The underlying cause of the chronic hyperphagia in this strain is unknown and cannot be explained entirely by their peripheral satiation deficits. Rather, a dysfunction in central pathways critical to the control of meal size is the most likely contributor. In this project, OLETF rats are used to study the relationship between the hyperphagic behavioral phenotype and dopamine (DA) signaling within the central motivational system during the development of type-2 diabetes. We propose that altered dopaminergic functioning in the mesoaccumbens dopamine (DA) system contributes to the overeating in OLETF rats by increasing preference for the orosensory stimulatory effects of normally preferred foods. Behavioral, neurochemical and histological methods

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will be employed to challenge this hypothesis. The application has four specific aims: 1) to characterize the basic dopaminergic phenotype (basal and stimulated DA release and reuptake) of the OLETF rats at three ages, reflecting the development of diabetes; 2) to characterize hyperphagic behavioral phenotype by investigating nutrient preference functions in prediabetic OLETF rats based on their orosensory and postabsorbtive properties; 3) to assess the relationship between behavior and DA signaling by comparing the effects of sham-feeding of preferred sucrose or fat solutions between prediabetic OLETF and age- and body weight-matched non-mutant control (LETO) rats; 4) to address causality of the relationship by using chronic treatment of the psychostimulant methylphenidate to reverse preference for and intake of sucrose and fat, and to delay onset of diabetes in OLETF rats. These studies will help determine how plasticity in the dopaminergic system affects behavioral and metabolic factors related to hyperphagia and the development of dietary-induced NIDDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNDROME

DOPAMINE

SYNAPTIC

MECHANISMS

IN

TOURETTE'S

Principal Investigator & Institution: Albin, Roger L.; Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: Tourette syndrome (TS) is a common neuropsychiatric disorder with onset in childhood. Some data suggests that TS is part of a spectrum ranging from tics to Obsessive-Compulsive Disorder. The clinical pharmacology of TS implicates abnormalities of dopaminergic neurotransmission, possibly involving the nigrostriatal dopaminergic projection, in the pathophysiology of TS. Our prior data indicates normal density of dorsal striatal dopaminergic innervation. We hypothesize that TS is marked by abnormal regulation of striatal dopamine neurotransmission. We will use PET methods to study striatal dopaminergic function in TS and control subjects to determine the existence of functional abnormalities in TS striatal dopaminergic synapses. We will compare binding of one striatal dopamine terminal marker, [[11C]dihydrotetrabenazine, that is not regulated by alterations in synaptic dopamine flux, with another dopamine terminal marker that is regulated by synaptic dopamine flux, [11C]methylphenidate. We will search for specific alterations in striatal dopamine synaptic physiology by direct measurement of the stimulant releasable pool of striatal dopamine with amphetamine challenge- [11C]raclopride PET and estimates of synaptic striatal dopamine concentrations with [11C]raclopride PET after alpha-methyl-tyrosine depletion of dopamine. Discovery of an alteration in striatal dopamine synaptic physiology would lead to more mechanistic hypotheses regarding the nature of the abnormality in TS. The major alternative hypotheses is a subregional difference in dopaminergic innervation of the ventral striatum. We have preliminary data suggesting the presence of a focal abnormality of ventral striatal dopaminergic innervation in TS. We will collect additional imaging data evaluate the validity of this finding. Failure to uncover abnormalities in striatal dopamine synapse function or subregional difference sin innervation will direct attention away from the striatal dopaminergic synapse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DOPAMINERGIC CHALLENGE IN ADOLESCENT SUBSTANCE ABUSE Principal Investigator & Institution: Upadhaya, Himanshu P.; Assistant Professor; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425

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Methylphenidate

Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 28-FEB-2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUG ABUSE LIABILITY & SENSATION SEEKING Principal Investigator & Institution: Kelly, Thomas H.; Professor; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 27-SEP-2002; Project End 31-AUG-2003 Summary: (provided by applicant) This grant proposes five years of research to continue an ongoing investigation of sensation seeking status as a potential predictor of drug abuse in young adults. Prior epidemiological research has established a link between sensation-seeking (or novelty-seeking) behavior and drug abuse in humans. Research with rat models further suggests that novelty-seeking behavior is predictive of individual differences in dopamine function and in the reinforcing and other behavioral effects of drugs of abuse. Our ongoing studies have confirmed the predictive association between sensation-seeking status and individual differences in the behavioral effects of drugs with abuse liability in young adults. Reliable and substantial group differences on the sensation-seeking factor were insured as a result of the availability of the Lexington Longitudinal Database for recruitment of study participants. Currently, studies of the reinforcing, discriminative and other behavioral effects of d-amphetamine and diazepam are ongoing. We propose to continue these investigations and to extend this work to include other drugs with high abuse liability (marijuana, nicotine, alcohol, methylphenidate). In addition, the potential use of high sensation activities to modulate the behavioral effects of d-amphetamine will be investigated as a potential prevention intervention. Finally, since high- and low-sensation seekers have been shown to differ along a number of clinically important dimensions, we will begin investigations of the interrelationships among these dimensions by evaluating the extent to which predicts individual sensitivity to the behavioral effects of drugs with abuse liability. The wealth of data available in the Lexington Longitudinal Database (e.g., peer associations, school performance, prior drug use, family status, other intrapersonal factors) will also be available to examine individual differences in behavioral response to drugs with abuse liability, in addition to sensation seeking status. These studies will have important implications for understanding individual differences in risk for drug abuse, and may help to guide future prevention interventions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DRUG ABUSE PREVENTION - A LIFECOURSE PERSPECTIVE Principal Investigator & Institution: Bardo, Michael T.; Professor; Center for Prevention Research; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2003; Project Start 30-SEP-1992; Project End 31-AUG-2006 Summary: (provided by applicant) The Center for Prevention Research at the University of Kentucky is distinguished by thematic integration around the construct of novelty/sensation (N/S) seeking. Over the past 12 years, we have evaluated N/S seeking behavior at a number of complementary levels of analysis and have made considerable progress in our understanding of the onset and development of drug abuse, and in applying this information to the development of more focused and effective prevention efforts. Our work has clearly benefited from the strong interdisciplinary collaboration among distinct yet complementary laboratories, both within the Center and with other ongoing projects on the University of Kentucky

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campus. The three specific aims of the Center Core are (1) Scientific: To generate and publish high quality prevention science that is recognized as state-of-the-art research across relevant disciplines; (2) Organizational: To provide an intellectually stimulating, creative, and productive environment in which research questions and issues are examined from a multilevel, interdisciplinary perspective; and (3) Leadership: To serve as a resource, advocate and leader for drug abuse and prevention science, in part by training the next generation of drug abuse prevention researchers. The substantive theme that consistently links scientists and research projects together in our Center is a broad and in-depth focus on N/S seeking behavior in the onset and development of drug abuse, and in applying this information for the development of more focused and effective prevention efforts. The three projects proposed in the current application continue and extend the Center?s on-going evaluations of the effects of N/S seeking on drug use and abuse. (1) Animal Laboratory: Individual Differences in Drug Response: An Animal Model (Mike Bardo, PI). This project will use an animal model to study the relationship between N/S seeking and amphetamine reward; the guiding hypothesis is that novelty, similar to stimulant drugs of abuse, activates the mesolimbic dopamine reward system. (2) Human Laboratory: Drug Abuse Liability and Sensation Seeking Status (Tom Kelly, PI). This project will expand the research team?s prior work on N/S seeking as a moderator of the relationship between drug dose and the discriminative, reinforcing and other behavioral effects and abuse liability of marijuana, nicotine, alcohol and methylphenidate. (3) Community Laboratory: Comprehensive Drug Prevention for Youth (Dick Clayton, PI). This project will continue a long-standing Center tradition of evaluations of school-based, curriculum-driven prevention programs with the evaluation of a comprehensive prevention program featuring both universal and selective high sensation value components. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DRUGS OF ABUSE AND COMPLEX BEHAVIOR Principal Investigator & Institution: Galizio, Joseph Mark.; Professor; Psychology; University of North Carolina Wilmington 601 S College Rd Wilmington, Nc 284035973 Timing: Fiscal Year 2003; Project Start 01-APR-2000; Project End 30-JUN-2006 Summary: (provided by applicant): Drugs of abuse are associated with a variety of cognitive deficits including disruption of learning and memory. This is a particular concern with respect to the so-called "club drugs" such as methylenedioxymethamphetamine (MDMA) and methamphetamine. A major difficulty in characterizing the nature of such impairments is to separate the drug's effect on learning from more general performance decrements. The goal of the proposed research is determine the effects of several of the club drugs on learning using a rat model that brings the methodological sophistication of the repeated acquisitions technique to the study of spatial navigation in the Morris Swim Task, a two-dimensional analogue of the Morris Task, and olfactory discrimination learning. In the repeated acquisitions procedure, drug effects on a well-learned problem can be compared directly with acquisition of a new problem. Experiment 1 will determine the effects of the MDMA, methamphetamine, and methylphenidate on acquisition of spatial navigation (Morris Swim Task) in rats. Experiment 2 will evaluate the effects of the same three drugs using a touch-screen apparatus to study repeated acquisition of visual discrimination learning problems. Experiment 3 will study these drugs using an olfactory discrimination learning procedure. In all three sets of studies, the acute effects of moderate drug doses will be determined and the residual effects of potentially neurotoxic high doses will also be evaluated. Finally, the same procedures will be used to evaluate the effects of NMDA

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Methylphenidate

antagonists phencyclidine, dizocilpine and LY235959 (Experiments 4 & 5). An overarching goal of the project is to continue to develop and evaluate the utility of these new methodologies as tools in the assessment of drug effects on learning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EARLY STRESS, PTSD, AND THE NEUROBIOLOGY OF ADDICTION Principal Investigator & Institution: Teicher, Martin H.; Associate Professor; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2004; Project Start 15-JUN-2004; Project End 30-MAY-2009 Summary: Exposure to repeated stress and trauma during childhood produces a cascade of molecular and cellular events that has the potential to exert enduring effects on brain development. These changes may be responsible for the development of depression, posttraumatic stress disorder (PTSD) and increased vulnerability to substance use and addiction. Study 1 will test the hypotheses that both PTSD and recurrent major depression mediate the association between childhood traumatic stress and increased risk for substance abuse. This study will also test the hypothesis that a functional polymorphism in the MAO-A promoter, which produces low levels of MAO-A activity will be associated with increased vulnerability to the adverse effects of childhood traumatic stress on drug use. These hypotheses will be tested in a sample of 20-25 year olds (n=500) who either have no history of exposure to childhood abuse or who have had a history of exposure to childhood abuse that fulfills the A(1) A(2) criteria for PTSD. Study 2 will test the hypotheses that exposure to chronic childhood traumatic stress effects the morphology, neuronal integrity and paramagnetic properties of the cerebellar vermis, and that cerebellar vermal abnormalities will be associated with enhanced risk for substance abuse. Three groups of subjects (30 per group) will be identified from the first study. Subjects will either have: (1) had no history of exposure to child abuse trauma; (2) childhood traumatic stress, and PTSD; or (3) childhood traumatic stress and recurrent major depression. Subjects in the three groups will be matched for degree of substance use. Morphometric MRI, T2-relaxometry and proton-echo-planarspectroscopic imaging will be used to test these hypotheses. These subjects will also receive a probe dose of methylphenidate and a repeat T2-RT scan to test the hypothesis that exposure to childhood traumatic stress enhances hemodynamic response to stimulant drugs in the striatum and cerebellar vermis. Study 3 will test the hypotheses that exposure to childhood traumatic stress produces an increased and more enduring corticotropic, noradrenergic and vasopressin response, (and decreased or delayed oxytocin response) to stress in the Trier Social Stress Test. Overall, these studies will provide new insight into the neurobiological effects of chronic childhood traumatic stress and new understanding of the potential for PTSD and depression to mediate, and MAO-A levels to moderate, the association between early stress and drug abuse. These studies will also pursue the novel hypotheses that stress induced alterations in the cerebellar vermis and in oxytocin release are related to risk for substance abuse in survivors of chronic childhood traumatic stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECTS TRANSMISSION

OF

METHYLPHENIDATE

ON

CATECHOLAMINE

Principal Investigator & Institution: Devilbiss, David M.; Psychology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006

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Summary: (provided by applicant): Attention-deficit hyperactivity disorder (ADHD) is characterized by inattentiveness and/or hyperactivity and impulsiveness, placing individuals at risk for social, academic, and occupational dysfunction. Pharmacological treatments of ADHD with lowdose administration of amphetamine (AMPH)-Iike stimulants, i.e. methylphenidate, target monoaminergic neurotransmission. Virtually all information regarding actions of AMPH-like stimulants has been obtained using doses that exceed greatly those used clinically. This lack of information concerning the neural actions of therapeutically-relevant doses of methylphenidate and other AMPH-like stimulants represents a substantial lacuna in our understanding of ADHD. The proposed studies are designed to determine the effects of therapeutically-relevant doses of methylphenidate on: 1) Rates of norepinephrine/dopamine efflux; 2) Basal (tonic) and sensory driven (phasic) discharge of locus coeruleus neurons, and; 3) Cortical and subcortical neuronal circuit function. Ultimately, a better understanding of the neurochemical, cellular and network mechanisms of the therapeutic actions of these drugs is necessary for development of pharmacological treatments that do not possess the negative properties of AMPH-like stimulants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVALUATION OF STIMULANT DRUGS Principal Investigator & Institution: Wigal, Sharon B.; Pediatrics; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 11-JAN-2002; Project End 31-DEC-2006 Summary: The applicant is requesting five years of funding through the PatientOriented Research Career Award (K-23) program to enhance her independence as an investigator. The proposed training is in crucial basic methods for research in clinical and psychopharmacology of children with Attention Deficit Hyperactivity Disorder (ADHD). Methylphenidate (Ritalin(R)) is the most frequently prescribed psychostimulant by physicians to treat cases of ADHD. Few studies have been done to evaluate the efficacy of methylphenidate (MPH) in preschoolers with ADHD or to compare the time-response function of this age group with school-aged children. No study has addressed the comparative pharmacokinetics of MPH in these two age groups. The applicant will address these questions. The training will be based at the University of California, Irvine Child Development Canter, which has a well-established program for the treatment of ADHD and is a leading site for studying pharmacokinetics (PK) and pharmacodynamics (PD) of psychoactive stimulants. A unique component is the laboratory school paradigm (LSP) which was developed here. The research plan is designed to evaluate the variability of PD of MPH in preschoolers (3 to 5 year olds) versus school-aged (6 to 8 year olds) children with ADHD. Within-subject PK variability in time-course of serum concentration for each medication will be analyzed, and the time-response characteristics also will be estimated based on PD measures for methylphenidate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATIENTS

EXAMINING

NEUROANATOMICAL

DEFICITS

IN

ADHD

Principal Investigator & Institution: Epstein, Jeff N.; Assistant Professor; Psychiatry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 14-DEC-2001; Project End 30-NOV-2006

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Methylphenidate

Summary: (provided by the applicant): As stated in the NIMH Consensus Development Conference on ADHD, there is a clear need to more basically define ADHD using basic research techniques. Despite technological advances in neuroimaging (e.g., fMRI) which allow for more direct examination of neurobiological bases to clinical disorders, few neuroimaging studies have been conducted with ADHD populations. The paucity of clinical imaging studies likely results from a lack of investigators who are sufficiently trained in both clinical psychology and neuroimaging, thus being able to define and study the population of interest. The primary objective of the proposed activities is to enhance my expertise in neuroimaging and to apply this expertise to my established research with ADHD patients. Using time liberated by the proposed award, I plan to further my career development by participating in coursework, "hands-on" experiences, and mentoring and teaching activities which will enhance both my own and my students/colleagues expertise in state-of-the-art neuroimaging methods and analysis. This plan will accomplish my immediate research and training goals by allowing me to establish myself as a patient-oriented researcher with expertise in clinical neuroimaging. This short-term goal will foster my long-term career interests which center on conducting extensive investigations into the multiple neurobiological correlates (e.g., neuroanatomy, genetics) of ADHD. The study proposed in the research plan will utilize 30 concordantly-affected ADHD parent-child dyads and 15 non-ADHD normal dyads. All dyads will perform a series of neuropsychological tests while generic brain activation is assessed using functional MRI (fMRI). ADHD parent-child dyads will also participate in a repeated measures study examining functional neuroanatomical change in response to stimulant medication. Between-group comparisons will evaluate structural and functional neuroanatomical differences between ADHD and normal parent-child dyads. Within-group analyses will compare ADHD patients functional activation changes across placebo and active medication conditions. In addition, parentchild correspondences in neuropsychological performance, neuroanatomy, and brain activation will be examined within the two groups of dyads. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FETAL ALCOHOL EFFECTS IN MONKEYS: DOPAMINE AND BEHAVIOR Principal Investigator & Institution: Schneider, Mary L.; Professor; Kinesiology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-MAY-2006 Summary: Fetal alcohol syndrome, (FAS) is the leading known cause of mental retardation today and currently represents an enormous problem for our society. The central question addressed by this proposal is whether moderate alcohol exposure constitutes a danger to the developing offspring. To address this issue, we propose to assess the behavior and physiology in 50 monkeys from four conditions: 1) mothers consumed moderate level alcohol daily throughout pregnancy 2) mothers experienced psychological stress; 3) mothers consumed moderate level alcohol and experienced psychological stress; and 4) mothers consumed sucrose (controls) (Schneider et al., 1997). The specific aims are as follows: 1) to characterize dopamine D2 receptor densities in striata of offspring using in vivo PET imaging techniques 2) to characterize dopamine synthesis in these same cohorts, also using PET imaging, and to uncouple presynaptic synthesis of dopamine from postsynaptic receptor binding availability; 3) to evaluate these monkeys with a standard battery of widely accepted tests and measurements, which index cognitive functioning and behavior; and 4) to determine the effects of a dopamine agonist, methylphenidate, on behavior and cognitive performance in this

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cohort of monkeys. Our primate model has allowed control of the exact timing and level of alcohol exposure to the fetus and the separation of the effects of alcohol from other life-style factors, such as psychological stress The proposed studies provide a unique and unprecedented opportunity not only to better understand the underlying neurobiology of fetal alcohol effects, but also to discover potential in vivo diagnostic markers for detecting fetal alcohol- induced brain damage. Increasing our understanding of the association between behavior, cognition, and molecular mechanisms of neuronal function in fetal alcohol-exposed primates could aid in early identification and appropriate treatment of children with prenatal alcohol exposure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FMRI CINGULATE DISSECTION IN CINGULOTOMY PATIENTS & ADHD Principal Investigator & Institution: Bush, Allan George.; Director; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUL-1998; Project End 30-JUN-2003 Summary: (Adapted from applicant's abstract): This is an application for an NIMH Scientist Development Award for New Minority Faculty (K01 special use) titled, "fMRI Cingulate Dissection in Cingulotomy Patients & ADHD". The candidate is primarily interested in elucidating the functions of anterior cingulate (AC) subregions and examining their potential role(s) in the pathobiology of psychiatric disorders, especially Attention-Deficit Hyperactivity Disorder (ADHD). Convergent evidence supports AC subregion delineation into a dorsal cognitive/motor division (AC-CMD), and a rostral affective division (AC-AD). A battery of cognitive-motor and emotional tasks will be refined and used off-line and during fMRI to study these AC subregions. Aim I concentrates on refining the battery of tasks and establishing test-retest reliability. The task battery will be used to resolve questions about AC-CMD mechanisms (i.e., to discern if AC-CMD acts by influencing stimulus selection and/or response selection), and with high-resolution cortical flat mapping to resolve AC topography. Aim II takes advantage of a unique opportunity to study subjects pre- and post-cingulotomy (which specifically targets AC-CMD) with tasks designed to contrast AC-CMD/AC-AD functions. In Aim III, AC-CMD function in ADHD is tested in two ways: a) ADHD patients are compared to matched controls (in an attempt to confirm the hypothesis implicating AC-CMD dysfunction in ADHD pathophysiology), and b) within ADHD patients pre- and post-methylphenidate, to see if AC-CMD response normalizes with treatment. By this proposal, the candidate seeks training in: 1) the basic neurobiology of AC subregions, 2) cognitive neuroscience and cognitive psychology methodology, 3) advanced fMRI physics and techniques (i.e., cortical flat mapping, single-trial format, and high field MRI), and 4) specialized statistics relevant to functional neuroimaging. The rigorous training plan, integrating strong didactics and multidisciplinary expertise, will teach the candidate how to synthesize information from diverse fields in studying normal AC function and psychiatric disease. This integrated program of training and research will advance our knowledge of AC functions, generate new data on ADHD pathobiology, yield new tools for studying AC in health and psychiatric disease, and give the candidate the skills needed to achieve independence in a highly complex field. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Methylphenidate

Project Title: FUNCTIONAL MRI OF HUMAN DRUG ABUSE Principal Investigator & Institution: Risinger, Robert C.; Assistant Professor; Psychiatry and Behavioral Med; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 30-SEP-1994; Project End 31-MAR-2005 Summary: Cocaine and nicotine abuse remain serious problems in society, with high recidivism rates. When self administered by humans, abused drugs exert powerful, direct pharmacological actions within localized brain regions and circuits, while also interacting with specific cognitive systems. The overall goals of this project are to employ fMRI to define those neuronal systems in the human CNS mediating the actions of these two very addictive agents and to determine how cocaine and nicotine interact with specific cognitive and affective processes. The interplay between where cocaine acts in the human brain and how these circuits overlap with nicotine and other abused agents is poorly understood. Additionally, almost nothing is known regarding their neural pharmacokinetic and pharmacodynamic properties and neurochemical sites and mechanisms of action in humans. Specific Aim I of this proposal addresses these pharmacological issues. However, human drug abuse is not simply explained by where a drug acts in the brain. While the powerful reinforcing and, in the case of cocaine, euphorigenic properties of these drugs are important in drug-seeking and drug-taking behavior, drug administration also engages a complex, poorly understood sequence of behavioral alterations that, taken together, perpetuate drug taking behavior. Specific Aim 2 addresses the effects of cocaine and nicotine on cognitive and affective processes. Since cocaine addicts report selective recall of the high over the crash and exhibit considerable difficulty controlling impulses to use and appropriately weighing risks of use. Therefore, it is hypothesized that acute cocaine will enhance sustained attention and recall for events occurring under the influence of the drug and that corresponding alterations in fMRI activation in attentional networks (frontal, parietal, thalamic) and in memory circuits (hippocampus) will be seen. It is further hypothesized that acute cocaine will impair inhibitory control, concept formation and attention switching with corresponding alterations in specific frontal lobe activation. Finally, we will examine the interaction between acute cocaine administration and affective state to test the hypothesis that the reinforcing properties of the drug are enhanced during times of negative affect and cocaine craving. A better understanding of these processes may lead to better behavioral and/or pharmacological therapeutic interventions for cocaine abuse and recidivism and identify a likely cognitive profile resulting from prolonged abuse to help identify those most at risk for dependence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FAMILIES

FUNCTIONAL

NEUROANATOMICAL

DEFICITS

IN

ADHD

Principal Investigator & Institution: Hinshaw, Stephen P.; Professor; Institute of Human Development; University of California Berkeley Berkeley, Ca 947205940 Timing: Fiscal Year 2002; Project Start 11-MAY-2002; Project End 30-APR-2004 Summary: (provided by applicant): Despite a plethora of neuropsychological and family-based research suggesting that Attention Deficit Hyperactivity Disorder (ADHD) is a neurobiologically-based disorder, studies attempting to define the neurobiological nature of ADHD have been few. As stated in the NIMH Consensus Development Conference on ADHD, there is a clear need to more basically define ADHD using basic research techniques. The proposed study will utilize the Multimodal Treatment Study of

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ADHD children (MTA) sample to recruit 30 ADHD parent-child dyads. ADHD dyads will consist of ADHD children and their concordantly-affected ADHD parents. Fifteen normal dyads will also be recruited who do not meet ADHD diagnostic criteria. Volumetric images using Magnetic Resonance Imaging (MRI) will be acquired on all dyads. In addition, all dyads will perform a series of neuropsychological tests while generic brain activation is assessed using functional MRI (fMRI). ADHD parent-child dyads will also participate in a repeated measures study examining functional neuroanatomical change in response to stimulant medication. Brain activation volumes and magnitudes in pre-specified regions of interest will be assessed. Between-group comparisons will evaluate structural and functional neuroanatomical differences between ADHD and normal parent-child dyads. Within-group analyses will compare ADHD patients' functional activation changes across placebo and active medication conditions. In addition, parent-child correspondences in neuropsychological performance, neuroanatomy, and brain activation will be examined within the two groups of dyads. This application is a collaborative R01 that will involve five sites. Participants will be recruited from three MTA sites: University Medical Center (DUMC), New York State Psychiatric Institute, and UC Berkeley. Imaging will be performed at corresponding imaging sites at DUMC, Weill Medical College of Cornell University, and Stanford University respectively. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FAMILIES

FUNCTIONAL

NEUROANATOMICAL

DEFICITS

IN

ADHD

Principal Investigator & Institution: Casey, Betty J.; Professor; Psychiatry; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 11-MAY-2002; Project End 30-APR-2004 Summary: Despite a plethora of neuropsychological and family- based research suggesting that Attention Deficit Hyperactivity Disorder (ADHD) is a neurobiologicallybased disorder, studies attempting to define the neurobiological nature of ADHD have been few. As stated in the NIMH Consensus Development Conference on ADHD, there is a clear need to more basically define ADHD using basic research techniques. The proposed study will utilize the Multimodal Treatment Study of ADHD children (MTA) sample to recruit 30 ADHD parent-child dyads. ADHD dyads will consist of ADHD children and their concordantly-affected ADHD parents. Fifteen normal dyads will also be recruited who do not meet ADHD diagnostic criteria. Volumetric images using Magnetic Resonance Imaging (MRI) will be acquired on all dyads. In addition, all dyads will perform a series of neuropsychological tests while generic brain activation is assessed using functional MRI (fMRI). ADHD parent-child dyads will also participate in a repeated measures study examining functional neuroanatomical change in response to stimulant medication. Brain activation volumes and magnitudes in pre-specified regions of interest will be assessed. Between-group comparisons will evaluate structural and functional neuroanatomical differences between ADHD and normal parent-child dyads. Within-group analyses will compare ADHD patients' functional activation changes across placebo and active medication conditions. In addition, parent-child correspondences in neuropsychological performance, neuroanatomy, and brain activation will be examined within the two groups of dyads. This application is a collaborative R01 that will involve five sites. Participants will be recruited from three MTA sites: Duke University Medical Center (DUMC), New York State Psychiatric Institute, and UC Berkeley. Imaging will be performed at corresponding imaging sites at

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DUMC, Weill Medical College of Cornell University, and Stanford University respectively. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENDER DIFFERENCES IN DOPAMINE FUNCTION AFTER TBI Principal Investigator & Institution: Wagner, Amy K.; Assistant Professor; Physical Medicine and Rehabilitation; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 06-FEB-2002; Project End 31-JAN-2004 Summary: (provided by applicant): Traumatic brain injury (TBI) is an epidemic in the United States with survivors often having many decades of productive life loss. An estimated 5.3 million Americans currently live with disabilities resulting from TBI. Despite the fact that about 25% of the population with TBI are women, the large majority of clinical and animal research on TBI to date has been with males. Evidence shows that females have more difficulties with post-concussive symptoms and poorer outcome after TBI compared to males. It is suspected that dopamine I (DA) plays a crucial role in working memory and other aspects of executive functioning, and decreases in DA system function after TBI are thought to affect cognitive recovery. Estrogen is well known to play a significant role in dopaminergic functioning, and estrogen has been shown to have a neuroprotective effect acutely after TBI. However, no one has evaluated the effect of estrogen on DA functioning and cognitive recovery from TBI. The goal of this proposal is to evaluate the effects of estrogen on DA pathways in female rodents compared to male rodents after TBI. The effects of methylphenidate on cognitive performance and DA function in females and male rodents after experimental TBI will also be studied. The long-term goal is to delineate the role of estrogen on DA system mediated cognitive deficits in order to develop and optimize new and existing therapies that specifically target and enhance recovery of both males and females after TBI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE DISCOVERY IN A PUTATIVE MOUSE MODEL OF ADHD Principal Investigator & Institution: Mcdonald, Michael P.; Assistant Professor; Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Abnormal thyroid levels during gestation can have devastating effects on brain development and cognition. Resistance to thyroid (RTH) syndrome is a heritable condition caused by mutations in the TRbeta gene that typically result in elevated thyroid hormones, short stature, and tachycardia. More than half of RTH patients have attention deficit hyperactivity disorder (ADHD), with the incidence about 50% higher among males. Although the etiology of ADHD is unknown, considerable evidence implicates deficiencies in the dopaminergic and noradrenergic neurotransmitter systems. A normally functioning thyroid system is critical for proper development of the catecholaminergic systems, and thyroid abnormalities can result in behavioral and neurochemical features consistent with ADHD. We have recently found that a TRbeta transgenic mouse bearing a human mutant thyroid beta1 receptor reproduces all of the key symptoms of ADHD, such as juvenile hyperactivity, deficits in sustained and selective attention, impulsivity, and reduced catecholamine levels. Interestingly, the TRbeta transgenic mice have normal levels of thyroid hormones, thyroid stimulating hormone (TSH), and suppression of TSH. This is intriguing because

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it raises the possibility that modest developmental thyroid dysfunction may contribute to a larger proportion of ADHD cases than previously thought. In addition to the core symptoms of the disorder, mice demonstrate many of the more subtle features of ADHD, e.g., the hyperactivity dissipates in adulthood, the penetrance is greater among males than among females, and the deficit in sustained attention is attenuated with greater reinforcement levels. Another interesting feature of the TRbeta transgenic mice is that the hyperactivity phenotype depends on the maternal genotype, independent of the mouse's own genotype. This suggests a possible biological or behavioral basis for maternal or environmental effects on ADHD subtypes. This high degree of analogy between complex human behavioral disorders in an animal model is unparalleled for a complex, multigenic behavioral disorder. We propose to use microarray technology to examine differential gene expression in wild-types vs. transgenics, males vs. females, and offspring of transgenic dams vs. offspring of wild-type dams, in pups, adolescents, and adults. The TRbeta transgenic mouse model provides us with a rare opportunity to discover genes downstream of TRbeta activity that are able to produce all of the core symptoms and many adjunct features of ADHD-genes that may be differentially expressed in a large number of children with ADHD. In addition, we have an unprecedented opportunity to discover how the relationship between gene expression and behavior differs according to diagnostic subtype, gender, treatment refractoriness, and environmental (e.g., maternal) conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIGH FIELD MRI OF STIMULANTS IN ADOLESCENTS AT RISK Principal Investigator & Institution: Anderson, Carl M.; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 29-SEP-2004 Summary: (provided by applicant): This application is in response to (PAR-02-058) Imaging - Science Track Award for Research Transition (I/START) for the study of neurobehavioral and neurobiological factors that may contribute to the initiation of substance use disorders (SUD). The first objective is to obtain preliminary fMRI measurements at 4T of individual functional differences in stimulant response coupled with objective behavioral measures of hyperactivity and structural MRI in a subgroup of male adolescents at risk for SUD, thus, replicating published findings at 1.5 T. The second is to develop preliminary data for an application targeting both male and female adolescents with conduct disorder (CD) under the auspices of a NIDA sponsored Mentored Research Scientist Development Award. Conduct disorder with behavioral hyperactivity (BH) and impulsivity is a known precursor to SUD, particularly with a positive family history of SUD. Behavioral hyperactivity, and its individual variation, is often cited as a critical link between CD and progression to SUD. We have measured, using optical tracking of movement, individual variations in BH, and have reported correlated blood flow abnormalities in dopamine transporter (DAT) rich subregions of the basal ganglia and cerebellum that were reduced, dose-dependently, by methylphenidate (MPH). Hyperactivity and stimulant response-rate appear to mirror disproportionate blood flow among DAT-rich subregions of the basal ganglia-cerebellar system. We hypothesize, those functional and/or structural defects in the basal gangliacerebellar system link BH with risk for SUD. To test functional and structural hypotheses about BH, responsiveness to MPH and volumes of DAT-rich subregions, we will examine, using phased-array MRI at 4T, four groups (n=10 each) of adolescent males (14-17 yrs). Two cohorts with (DSM-IV+) ADHD and comorbid oppositional defiant disorder ODD, having a first degree relative with SUD (SUD+), will be carefully

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screened with optical tracking for either presence (BH+/ SUD+) or absence of hyperactivity (BH-/SUD+) prior to scanning pro- and post-MPH, and compared with matched, (DSM-IV-) comparison groups, with (BH-/SUD+) and without (BH-/SUD-) a family history of SUD. Thus, imaging BH+/BH- individuals with ADHD/ODD will allow a prospective focus on antecedent neurobehavioral and neurobiological factors, in a population at high risk for SUD, without the confounds of developed CD or prior substance abuse on brain development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMAGING THE NEURAL CORRELATES OF GENETIC RISK FOR ADHD Principal Investigator & Institution: Kilts, Clinton D.; Professor and Vice-Chair of Research; Psychiatry and Behavioral Scis; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-APR-2006 Summary: (provided by applicant): A 40-bp variable number (3-13) of tandem repeats (VNTR) polymorphism exists in the 3' untranslated region (UTR) of the dopamine transporter (DAT) gene (dat1). The 10-repeat VNTR (hDAT10), has been associated with attention deficit hyperactivity disorder (ADHD) and nonresponse of ADHD to methylphenidate (MPH). The mechanisms underlying these genotype-phenotype correlations are unknown. This exploratory R21 proposal seeks to use in vitro molecular genetic studies to guide in vivo positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) approaches to clarifying the role of this genetic polymorphism in the pathophysiology and pharmacotherapy of ADHD. Specifically, in vitro gene transfection/expression experiments would define the influence of dat1 VNTR genotype (hDATI0, hDAT9, hDAT0 and hDAT) on DAT binding and function, and pharmacological regulation by MPH. In vivo [18F]FECNT PET studies would compare brain regional DAT binding potential and MPH dose-dependent DAT occupancy in sib pairs discordant for ADHD and dat1 VNTR genotype. Finally, in vivo fMRI studies would define the effect of hDAT10 on the neural correlates of the effect of MPH administration on cognitive impairments associated with ADHD. These studies would test the following specific hypotheses: that the 10- repeat VNTR of dat1 is associated with (1) increases in DAT number and/or function, and attenuated MPH inhibition of DAT in in vitro model cell systems; with (2) increases in the in vivo regional brain DAT binding potential and diminished MPH dose-dependent occupancy of human brain DAT; and, with (3) a blunted effect of MPH administration on the cognitive task-related activation of a prefrontal-parietal cortical circuit. This exploratory proposal would novelly use in vivo imaging approaches to explore genotype-phenotype correlations and partner in vitro and in vivo approaches, and is thus well suited to the goals of the R21 mechanism to foster the exploration of the use of approaches new to a area. By uniquely defining the impact of the dat1 VNTR polymorphism on DAT, these findings will generate knowledge of how genes confer vulnerability to ADHD and medication nonresponse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTEGRATING BRAIN IMAGING AND GENETIC ANALYSIS OF ADHD Principal Investigator & Institution: Vaidya, Chandan J.; Assistant Professor; Psychology; Georgetown University Washington, Dc 20057

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Timing: Fiscal Year 2003; Project Start 09-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The proposal aims to examine functional and structural neuropathology underlying deficits of executive control (indexed by inhibitory control, working memory, and attential set switching, in Attention Deficit Hyperactivity Disorder (ADHD) using whole-brain structural and functional magnetic resonance imaging (fMRI). It is hypothesized that prefontal-striatal-cerebellar circuitry underlying executive control is dysfunctional in ADHD due to abnormal dopaminergic function. We will test two predictions of this hypothesis - (1) fMRI will reveal that the functional activation in prefrontal-striatal-cerebellar regions during inhibitory control (Exp 2), working memory (Exp 3), and attentional set switching (Exp 4) will be abnormal in ADHD children (relative to control children) and will be normalized by the administration of methylphenidate in ADHD children. Sample for Experiments 2-4 will include 48 9-11 year old Combined type ADHD children (24 girls and 24 boys) and 48 age, gender, and IQ-matched healthy children. (2) Functional response to methylphenidate in prefrontal-striatal regions underlying inhibitory control in ADHD will be influenced by dopamine transporter genotype (DAT1) (Exp 1). Sample for Experiment 1 will include 36 Combined-type ADHD children (12 carriers of 480bp10/10, 480bp-10/9, 440bp-9/9, each). These ADHD subjects were participants in an ongoing pharmacogenetic study at CNMC that found superior clinical efficacy of methylphenidate in carriers of 480bp than 440 bp. We have the unique opportunity to examine the functional brain response to methylphenidate during inhibitory control in those same ADHD children. In all experiments, fMRI will be performed on ADHD children with administration of methylphenidate and placebo; control children (in Experiments 2-4) will be imaged without methylphenidate. Further, high resolution structural imaging will be used to examine whether regions activated during fMRI differ in gray matter volume between ADHD subgroups and controls. Novel features of our proposal include: 1) examination of structural and functional brain differences in the same ADHD and control children and ii) examination of the functional brain response to methylphenidate in ADHD children in whom clinical efficacy of methylphenidate varied by DAT1 genotype. Examination of such genotype-phenotype relationships will elucidate potential etiological factors and neuropathophysiology of ADHD that will be useful in diagnosis, early intervention, and treatment planning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERVENTION CLINICAL TRIAL FOR GERIATRIC DEPRESSION Principal Investigator & Institution: Lavretsky, Helen; Psychiatry & Biobehav Sciences; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 05-APR-2001; Project End 31-MAR-2006 Summary: (provided by applicant): The application describes the five-year Mentored Patient-Oriented Research Career Development program (K-23) of Helen Lavretsky, M.D., devoted to the development of necessary research skills to conduct intervention studies of geriatric depression, as well as to study underlying mechanisms of variable treatment response. During the award period, the candidate proposes to engage in an organized program of interdisciplinary training and supervised research under the sponsorship of Dr. Anand Kumar enabling her to conduct methodologically sound intervention studies in depressed geriatric patients and become an independent clinical scientist. The existing evidence indicates that an antidepressant response may be less favorable in patients age 70 and older than in younger patients. Accelerated treatment may be particularly beneficial in this group of patients, which are prone to increased

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frailty and suicide. Chronic medical conditions frequently co-occur with depression in the elderly and may alter disease course and treatment response. Different treatment strategies of depression in these patients may be warranted. There is presently a lack of prospective controlled augmentation antidepressant trials in patients at least 70 years old. The main goal of the proposed project, a randomized, double-blind, placebocontrolled clinical trial of a low-dose methylphenidate (MPH) augmentation of citalopram is to determine whether the addition of MPH to citalopram would increase efficacy and decrease the time to antidepressant response in depressed elderly outpatients age 70 and older. The characteristics of treatment response (speed, completeness, and durability) will be assessed. The PI will also investigate the role of medical burden, cerebrovascular disease, and cognitive impairment documented on magnetic resonance imaging (MRI) in the mechanisms of variability of treatment response. The significance of MRI signal hyperintensities for treatment response will be explored as well. The proposed project will serve as a methodological template for future studies of geriatric depression. Dr. Lavretsky will also improve her skills in the MRI methodology, image analysis, and neuropsychological assessment of geriatric depressed patients. She will spend time in training at the NIMH-sponsored Late-Life Mood Disorders Intervention Center learning the methodology of conducting clinical trials (University of Pittsburgh). Additional coursework and supervision will include reviewing clinical psychopharmacology and experimental therapeutics, biostatistics, clinical trials research design and conduct, bioethics of the responsible conduct of research with the emphasis on clinical trials. With the additional skills and experience acquired during the Award period, Dr. Lavretsky will be well prepared to undertake independent investigations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERVENTION FOR ADHD PLUS DYSLEXIA: DEVELOPMENT PROJECT Principal Investigator & Institution: Tannock, Rosemary; Senior Scientist; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, On Timing: Fiscal Year 2003; Project Start 25-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): Attention-Deficit/Hyperactivity Disorder (ADHD) and Reading Disorder (RD) are the two most prevalent neurocognitive disorders diagnosed in childhood, and they frequently co-occur in the same individual. Despite advances in the development of effective treatments for the two separate disorders, few well-controlled studies have been undertaken to address the question of what constitutes effective treatment for these disorders in combination. Children with ADHD+RD are at risk for being treated ineffectively, even by the best available treatments for the separate conditions of ADHD and RD. which are typically provided independently by health and education agencies, respectively. This is because the best treatment approaches for ADHD do not have any direct beneficial effects on the core cognitive deficits underlying RD. and the best intervention programs for RD do not have any impact on the cognitive and behavioral deficits underlying ADHD. The broad objectives of the proposed project are to develop effective treatments for children with comorbid ADHD+RD by refining and integrating promising intervention approaches for ADHD, RD. and ADHD+RD that are currently being evaluated independently at the University of California (Irvine) and The Hospital for Sick Children (Toronto). These interventions are unique in that they target specific cognitive deficits in ADHD+RD. Specific aims are to: 1) standardize two novel intensive remediation programs that teach specific reading strategies (PHAST') or arithmetic and metacognitive strategies (SCORE)

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that differentially target specific cognitive deficits in ADHD+RD; 2) standardize the medication protocols for once-daily dosing (OROS-MPH) or twice-daily dosing with methylphenidate; 3) standardize teacher-consultation protocol to promote transfer of specific reading strategies or generalized metacognitive strategies to the regular classroom; 4) estimate intervention parameters (effect size, response rate, attrition rate) from a preliminary evaluation of the relative efficacy of PHAST and MAST in combination with teacher consultation and either OROS-MPH or IR-MPH for improving reading and core ADHD symptoms in children with ADHD+RD; and 5) develop and standardize procedures for implementing and evaluating the intervention in a crossnational multi-site controlled outcome study, including web site development for resource support, video-conferencing, treatment fidelity monitoring, and on-line collection of data. The anticipated outcome is a protocol which is ethically, scientifically sound, and ready to be implemented in a large-scale multi-site randomized controlled trial to investigate the relative effects of these specific intervention approaches on the core cognitive and behavioral deficits in children with ADHD+RD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRASYNAPTIC DOPAMINE RELEASE IN CSHIZOPHRENIA Principal Investigator & Institution: Wong, Dean F.; Professor of Radiology and Radiology Vic; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002 Summary: Using [11C]raclopride, a radioligand already demonstrated to be affected by dopamine (DA) release from methylphenidate and ampetamine (AMP) studies, this study will observe a decrease in Bmax measures with AMP challenge in both schizophrenic (SCZ) patients and normal controls. Through the appropriate PET imaging protocol it is expected that the magnitude of the decrease in Bmax to be greater in SCZ patients than in the controls. It is also expected that there will be no significant change in NMSP binding with AMP challenge in either. Each subject will first have Bmax measurement (2 PET scans) with raclopride or NMSP (saline), followed by a repeat of the same Bmax measurement (2 PET scans) but with AMP rather than saline. No patients will be taken off of medication for research purposes alone. Patients will be carefully selected who have either voluntarily or for purposes of clinical care been taken off medication. Normal will be recruited through the Nuclear medicine pool and will have to pass drug screening as well as tests done in the physical. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LEARNING IMPAIRMENTS AMONG SURVIVORS OF CHILDHOOD CANCER Principal Investigator & Institution: Mulhern, Raymond K.; Director of the Department of Behavioral; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 12-JUL-1999; Project End 30-APR-2004 Summary: (adapted from investigator's abstract): Children surviving some types of cancer, particularly acute lymphoblastic leukemia (ALL) and brain tumors, have an increased incidence of learning impairments compared to their healthy peers in the general population. These impairments, for which there is no known effective treatment, are of sufficient severity to inhibit normal academic achievement, vocational attainment, and quality of life. Previous investigations have suggested a model in which treatmentinduced lesions of the brain, especially in the white matter, are an underlying cause of learning difficulties that are frequently manifested as deficits in the ability to sustain

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attention. The goal of this research proposal is to test the validity of this model by defining the neuroanatomic substrates of problems with attention and learning and by assessing the behavioral response of these problems to pharmacological intervention. To accomplish this goal, quantitative magnetic resonance imaging (qMRI) of the brain and neuropsychological testing will be conducted on 625 participating children treated for ALL or malignant brain tumors at 3 pediatric cancer centers. It is hypothesized that volumes of normal white matter in patients will be: a) significantly reduced compared to healthy peers, b) directly associated with the intensity of their central nervous system treatment, and c) positively correlated with their performance on measures of sustained attention and learning. A second study hypothesis is that methylphenidate will be effective in reducing their problems with attention and learning. This hypothesis will be tested with 200 children selected from the larger screened sample on the basis of objective problems with sustained attention and learning with regard to: (a) immediate (1-1/2 hr) behavioral benefits in our laboratory and (b) short-term (3 week) benefits at home and school in randomized, placebo-controlled, crossover designs, and then (c) long-term (12 month) maintenance benefits at home and school. The results of these studies will have a potentially important impact on childhood cancer by reducing the cognitive morbidities of cancer and cancer treatment and by furthering our knowledge of their biological basis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEVODOPA PHARMACOKINETCA AND PHARMACODYNAMICS Principal Investigator & Institution: Nutt, John G.; Professor; Neurology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-JUL-1984; Project End 31-JUL-2004 Summary: Parkinson's disease (PD) is a common disorder, occuring in 1-2 percent of people over the age of 55. The efficacy of levodopa, our best symptomatic therapy, is limited by the development of motor fluctuations and dyskinesia. Understanding the mechanisms underlying emergence of these motor complications is essential to developing methods to prevent or treat them. The goal of this proposal is to assess the contribution of the remaining striatal monoaminergic terminals to the clinical response to levodopa and its evolution during long-term levodopa therapy. There are three aims. 1) Determine the importance of reuptake of dopamine into residual dompamine terminals by examining the effects of inhibition of the dopamine transporter (DAT) using the DAT inhibitor, methylphenidate. The effects of methylphenidate alone and in combination with levodopa will be examined to determine if dopamine reuptake influences the off drug severity of PD and whether it alters the response to a 2 hour levodopa infusion, specifically, makes it appear more like that observed in advanced PD patients. 2) Determine if serotonin terminals and the serotonin transporter (SERT) assume a role in reuptake and storage of dopamine in advanced PD when the serotonergic terminals become a large portion of the residual stiatal monoaminergic terminals. The effects of paroxetine, a selective SERT inhibitor, on response to a 2 hour levodopa infusions will be examined. 3) Determine if autoreceptors on residual dopamine terminals influence PD severity by examining the response to a step wise infusion with apomorphine, a D-1, D-2 receptor agonist capable of inhibiting motor behavior at low doses in animals. These studies assess the importance of the remaining monoaminergic terminals on the response to levodopa, determine how loss of reuptake contributes to the development of motor complications and suggest whether the remaining terminals might be pharmacologically manipulated to therapeutic advantage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LICIT & ILLICIT ABUSED STIMULANT DRUGS 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-JUL-1984; Project End 30-JUN-2004 Summary: A series of studies is proposed in subjects with histories of drug abuse and in normal human volunteers to investigate several effects that caffeine shares with classic stimulant drugs of abuse. A series of eleven studies will focus on the comparative clinical pharmacology of caffeine, nicotine and cocaine administered intravenously to stimulant drug abusers on a residential research laboratory. A set of four studies will evaluate the comparative intravenous reinforcing effects of caffeine, nicotine and cocaine. A second set of sour studies will examine interactions between acutely and chronically administered caffeine, nicotine and cocaine. Finally, a set of three studies will examine the effects of a selective dopaminergic blocker on the effects of intravenous caffeine, nicotine and cocaine. Concurrent with the residential studies, a series of nonresidential studies in normal volunteers will investigate caffeine physical dependence and reinforcement. One study will explore the use of cerebral blood flow velocity and quantitative EEG as sensitive physiological measures of caffeine withdrawal. Two studies will explore pharmacological mechanisms in caffeine withdrawal by evaluating the effects of an adenosine-mediate challenge drug on caffeine withdrawal and by comparing the effects of caffeine, theophylline and methylphenidate on caffeine withdrawal. Another study will investigate graded dose reduction as a procedure for reducing severity of caffeine withdrawal. Finally, two studies will use choice procedures to compare the reinforcing effects of oral caffeine and d-amphetamine, explore correlates of individual differences in caffeine and d-amphetamine choice, and investigate whether acquisition of a caffeine discrimination enhances subsequent choice of caffeine. Given the widespread elicit use of physical dependence and reinforcement of the general population and in developing caffeine-use reduction or cessation programs as well as programs for minimizing caffeine-associated health risks. This research with caffeine and other classic psychomotor stimulants should also advance our understanding of pharmacological and behavioral mechanisms underlying stimulant drug abuse as well as provide novel information about interactions among commonly used and abused stimulants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MANAGEMENT OF SICKLE CELL VASO-0CCLUSIVE EPISODES Principal Investigator & Institution: Kalinyak, Karen; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2002 Summary: Vaso-occlusive (VOC) episodes represent the major source of morbidity and impairment for patients with sickle cell disease (SCD), and the management of pain is a continued challenge to patients, families, and health care providers. There is little consensus among medical care providers about the optimal pharmacological and nonpharmacological approaches to SCD pain management. In addition, VOC episodes and its medical management can produce physiological and pharmacological sequelae which can be detrimental to the patients. Conversely, optimal management of the VOC episodes is likely to have short-term as well as long term benefits of the patient. This program consists of three integrated clinical research studies which address the optimal management of VOC episodes from psychological, pharmacological and physiological perspectives. The three specific aims of this project are: 1) to conduct a randomized

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clinical trial to test the efficacy of a family-based pain management program designed to teach pediatric patients with SCD and their primary caregivers how to optimally control pain by using a combination of pharmacological and non-pharmacological strategies; 2) to conduct a double-blind randomized clinical trial to determine the benefits and risks of adjuvant use of methylphenidate in the treatment of severe VOC pain in hospitalized patients; and 3) to conduct a randomized trail of the outpatient use of the incentive spirometer during vaso-occlusive episodes to determine if its use this setting will prevent the development of the acute chest syndrome (ACS). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF ANTI HYPERACTIVITY MEDICATIONS Principal Investigator & Institution: Madras, Bertha K.; Professor; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: The use of stimulant medications for attention deficit hyperactivity, which is diagnosed in 2 - 6% of children in North America, has almost tripled since 1990 The increased usage presumably stems from wider recognition of this disorder, as well as the expanding knowledge that such stimulant medication continues to be effective over years, well into adulthood, without known production of adverse side effects There is yet no consensus on the mechanisms of the commonly used anti-hyperactivity medications, amphetamine and methylphenidate Both drugs promote psychomotor slowing of hyperactive children and adults, yet both raise extracellular dopamine levels Paradoxically, elevation of dopamine enhances motor activity, and forms the basis of medications for Parkinson's disease This apparent paradox is the focus of the pilot study The objective of the research is to investigate a novel hypothesis, that a the normal pulsatile supply of dopamine, with a broad range of c oncen trations, results in a different pattern of receptor availability and trafficking than a constant and high supply of the neurotransmitter, which may result with anti-hyperactivity medications To pursue this research, we are cloning the monkey D1 and D2 dopamine receptors and will investigate this hypothesis with the receptor expressed in vitro and in vivo with imaging PUBLICATION Seeman P and Madras BK Anti-hyperactivity medication methylphenidate and amphetamine Mol Psychiatry 3 386-396, 1998 Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MEDICATED & UNMEDICATED ADHD BOYS AT MIDLIFE (35 TO 45) Principal Investigator & Institution: Loney, Jan; Professor; Pediatrics; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 16-FEB-2001; Project End 31-JAN-2006 Summary: This is the midlife follow-up phase of the earliest, largest, and most comprehensive pre-DSM-III U.S. study of boys with the constellation of behavior problems that includes what is currently called Attention-Deficit/Hyperactivity Disorder (ADHD). This phase will involve 364 subjects in four groups: (1) 164 probands who were medicated as children with a central nervous system stimulant such as methylphenidate for an average of 3 years (the MED group), (2) 50 probands who were never medicated (UNMED), (3) 75 unreferred and never medicated full brothers of these 214 probands (BRO), and (4) 75 normal boys drawn from middle school classrooms of the probands during an adolescent follow-up (CLASS). The probands have been followed by the current research team since their referral for diagnostic evaluation and

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treatment to the University of Iowa outpatient child psychiatry clinic between 1967 and 1978. Their data were used to derive and validate Loney and colleagues' two-factor model for (1) assessing inattention-overactivity (10) and aggression-defiance (AG) in boys with behavior problems, (2) placing such boys into symptomatically homogeneous diagnostic subgroups (10, AG, IO+AG, and neither), and (3) predicting their adolescent and young adult outcomes. All subjects will be comprehensively evaluated between ages 35 and 45 in psychiatric, psychological, cognitive, neuropsychological, and psychosocial domains to describe their midlife functioning and to answer questions about selected adult psychiatric outcomes: adult/residual ADHD, personality disorders (e.g., antisocial, paranoid, schizotypal, and avoidant), adult bipolar spectrum disorders (mania, hypomania, and cyclothymia), depression, and alcohol and drug use, abuse, and dependence. Diagnostic information will also be obtained from 433 parents. As children, probands were assigned to medication conditions essentially randomly. Therefore, the investigators will be able to compare the midlife outcomes of (1) MED and UNMED groups to determine the long-term impact of childhood stimulant medication and (2) UNMED ADHD and CLASS groups to determine the impact of ADHD, thus separating the effects of the disorder from the effects of its most common and controversial treatment. Analyses within the MED group will identify which aspects of medication (initial response, maintenance dosage, treatment duration) predict midlife outcomes. The investigators will also examine the external validity of the two-factor JO and AG dimensions and the DSM-IV ADHD inattentive, hyperactive-impulsive, and combined subtypes. Additional information will be available to determine the associations of the probands' childhood and adult disorders with the childhood symptoms of their sons and daughters. This study will provide valuable information about the diagnosis, midlife prognosis, and generational transmission of ADHD and related disorders and about the long-term effects of stimulant medication. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHYLPHENIDATE & GENE EXPRESSION IN THE RAT BRAIN. Principal Investigator & Institution: Baizer, Joan S.; Physiology and Biophysics; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The long-term objectives of this research are to understand the changes in neuronal structure and function that may be caused by longterm use of ethylphenidate. ADHD/ADD is a common disorder affecting as many as 6% of schoolchildren. The ADHD/ADD population is at risk for school failure, difficulties with interpersonal relationships, and later substance abuse. ADHD/ADD is best treated by a combination of medication and behavior management. The most commonly prescribed drug used to treat ADHD/ADD is methylphenidate, Ritalin. Methylphenidate is a highly effective drug for treating impulsivity, hyperactivity, and inattention, the symptoms of ADHD, and seems to be safe. Abuse, tolerance and sensitivity are not major clinical concerns in its use. At present, we do not understand all of the mechanisms by which methylphenidate exerts its beneficial effects, nor do we know what neuronal changes may result from its use. There is concern about the potential effects on the brain and behavior of its long-term use, and especially over whether its use can affect the likelihood of later substance abuse. One reason for this concern is that Ritalin binds to the dopamine transporter and increases dopamine levels in the brain. Other psychostimulant drugs, amphetamine and cocaine, also increase dopamine levels, and these drugs are major drugs of abuse. A single dose of those drugs cause short-tem changes in expression of the Immediate Early Genes. Chronic use

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results in a complex pattern of changes in the expression of the IEG's and other genes. These changes in gene expression are thought to mediate the changes in behavior underlying addiction. We have found that a single dose of Ritalin results in expression of the Immediate Early Gene c-fos in the rat brain. We wish now to analyze the effects of chronic Ritalin use on gene expression, using the techniques of immunohistochemistry and DNA Microarray technology. Knowledge of the effects on gene expression will allow a more direct comparison of the effects of Ritalin on the brain with the effects of amphetamine and cocaine, provide more information about its mechanisms of action and allow more informed predictions about the long-term consequences of its use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHYLPHENIDATE COCAINE ABUSE

ANALOGS

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Principal Investigator & Institution: Davies, Huw M.; Professor; Chemistry; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 28-FEB-2003 Summary: (provided by applicant): The central goal of this project is to synthesize novel methylphenidate analogs and evaluate their potential as medications for the treatment of cocaine addiction and as precursors to novel neuroimaging agents. Even though a reasonably wide range of methylphenidate analogs have been explored in the past, a major shortcoming with the previous studies in this area was the limitations associated with the traditional method used for the synthesis of these analogs. Having developed a very powerful two-step asymmetric synthesis of threo-methylphenidate, this enabling technology will be used for the synthesis of a wide array of methylphenidate analogs. The specific synthetic targets of the project are the following: naphthyl analogs of threoand erythro-methylphenidate, heterocyclic analogs of threo-methylphenidate, oxa and carba analogs of threo-methylphenidate, piperidine ring-modified analogs, and polycyclic derivatives. All compounds will be initially screened for their binding to the dopamine, serotonin and norepinephrine transporters. Classes of compounds that display interesting biological properties will be extended into a more extensive series. Further in vitro and in vivo evaluation of promising compounds will be conducted. Initial studies will also be carried out to determine if useful PET radioligands can be made from any potent and selective analogs that are discovered during these studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHYLPHENIDATE PRESCHOOLERS

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ADHD

Principal Investigator & Institution: Kollins, Scott H.; Assistant Professor; Psychiatry; Duke University Durham, Nc 27710 Timing: Fiscal Year 2003; Project Start 22-SEP-2000; Project End 30-NOV-2004 Summary: This six-site parallel proposal requests ending for a three year study of the efficacy and safety of methylphenidate (MPH) in preschool children with AttentionDeficit / Hyperactivity Disorder (ADHD). Although MPH=s use in all age groups is increasing, its package insert prohibits its use in preschool children. Previous MPH preschool treatment studies have few subjects, and their results can not be combined to yield needed safety information. The proposed study will address these concerns by mounting a six-site, controlled trial of 44 ADHD children per site, or 264 children total. It will be based at the New York State Psychiatric Institute (NYSPI), Duke University, Johns Hopkins University (JHU), New York University (NYU), University of California

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at Los Angeles (UCLA), and University of California at Irvine (UCI). Each site=s subjects (N=44) will include: Group I, ADHD preschoolers (n=33), ages 3-5 years, 6 months; and Group 2, (n=l1), a contrast ADHD group, ages 6-8. After assessment, all children will enter a four-part study. Phase 1 will be a 3 week, open- label safety titration trial of MPH, 2.5 - 10 mg/dose, given 3 times daily (t.i.d.). Those without impairing side effects will enter Phase 2, a five week double-blind, placebo controlled, titration trial, with random assignments (weekly) to either placebo or to one of 4 doses of MPH (2.5, 5, 7.5, and 10 mg/dose) and monitored once in a laboratory (analog) classroom. Phase 3 will be an open-label, one year extension, and Phase 4 will be a double-blind, placebo discontinuation trial. Aim 1 is to determine the safety and efficacy of MPH in preschoolers with ADHD. Aim 2 is to test for differences between Groups 1 and 2 in dose-response to MPH. Aim 3 is to examine if two putative risk loci, the dopamine D4 receptor gene (DRD4) or the dopamine transporter gene (DAT1), are associated with ADHD in a family-based association study of parent to child allele transmission, and whether dose response to MPH is related to genetic variability at these two loci. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHYLPHENIDATE PRESCHOOLERS

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ADHD

Principal Investigator & Institution: Abikoff, Howard B.; Professor; Psychiatry; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2003; Project Start 22-SEP-2000; Project End 30-NOV-2004 Summary: (Adapted from Applicant's Abstract): This six-site parallel RO1 application requests funding for a three year study of the efficacy and safety of methylphenidate (MPH) in preschool children with Attention-Deficit/ Hyperactivity Disorder (ADHD). Although MPH's use in all age groups is increasing, its package insert prohibits its use in preschool children. Previous MPH preschool treatment studies have few subjects, and their results cannot be combined to yield needed safety information. The proposed study will address these concerns by mounting a six-site, controlled trial of 44 ADHD children per site, or 264 children total. It will be based at the New York State Psychiatric Institute (NYSPI), Duke University, Johns Hopkins University (JHU), New York University (NYU), University of California at Los Angeles (UCLA), and University of California at Irvine (UCI). Each site's subjects (N=44) will include: Group 1, ADHD preschoolers (n=33), ages 3-5 years, 6 months; and Group 2 (n=11), a contrast ADHD group, ages 6-8. After assessment, all children will enter a four-part study. Phase l will be a 3 week, open-label safety titration trial of MPH, 2.5 - 10 mg/dose, given 3 times daily (t.i.d.). Those without impairing side effects will enter Phase 2, a five week doubleblind, placebo controlled, titration trial, with random assignments (weekly) to either placebo or to one of 4 doses of MPH (2.5, 5, 7.5, and 10 mg/dose) and monitored once in a laboratory (analog) classroom. Phase III will be an open-label, one-year extension, and Phase IV will be a double-blind, placebo discontinuation trial. Aim I is to determine the safety and efficacy of MPH in preschoolers with ADHD. Aim 2 is to test for differences between Groups 1 and 2 in dose-response to MPH. Aim 3 is to examine if two putative risk loci, the dopamine D4 receptor gene (DRD4) or the dopamine transporter gene (DATI), are associated with ADHD in a family-based association study of parent to child allele transmission, and whether dose response to MPH is related to generic variability at these two loci. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METHYLPHENIDATE STUDY IN YOUNG CHILDREN WITH PDD Principal Investigator & Institution: Ghuman, Jaswinder K.; Associate Professor; Kennedy Krieger Research Institute, Inc. Baltimore, Md 21205 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-MAR-2003 Description (provided by applicant): This application describes an integrated 5-year training program to develop the candidate into an independent investigator in the area of treatment intervention in young children with psychiatric and developmental disorders. Primary mentorship will be provided by Mark Riddle, M.D., an accomplished researcher in the field of pediatric psychopharmacology who has extensive experience training young investigators. Additional mentorship and consultation will be provided by experts, most of whom work in a collaborative environment with the candidate and her primary mentor; each will provide training in a specialized area of expertise critical to the candidate's development. A focused didactic program of formal course work, training, guided study, structured mentored relationship, empirical research, and other career development activities is proposed in several areas relevant to the candidate's short-and long-term goals. The majority of the formal coursework and training will occur at the Johns Hopkins School of Hygiene and Public Health and School of Medicine. The following objectives will be achieved: 1) develop conceptual and methodological understanding of clinical interventions research; 2) design and implement a methylphenidate (MPH) outcome study for the treatment of symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in young children with PDD (Autistic Disorder, Asperger's Disorder and Pervasive Developmental Disorder Not Otherwise Specified); 3) evaluate, analyze, integrate, and interpret data from this study; 4) disseminate results from this research; and 5) develop R01 treatment intervention research application. The primary research vehicle for achieving these objectives involves a research project to study short-term safety and efficacy of MPH in young children with PDD along with symptoms of ADHD. The specific aim of the study is to test the hypothesis that MPH is an effective and safe treatment for the symptoms of ADHD in young children with PDD. A secondary aim of the study is to examine feasibility and treatment-sensitivity of neuropsychological measures for the implicated domains of executive function in ADHD. The proposed study is the beginning of a larger investigation aimed at identifying and developing safe, effective and better treatments for young children with psychiatric and developmental disorders. The proposed training program will allow the candidate to acquire sufficient expertise to carry out future treatment intervention studies in a very specialized area. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METHYLPHENIDATE TREATMENT AND PRENATAL ALCOHOL EXPOSURE Principal Investigator & Institution: Mattson, Sarah N.; Assistant Professor; Psychology; San Diego State University 5250 Campanile Dr San Diego, Ca 92182 Timing: Fiscal Year 2002; Project Start 27-SEP-1999; Project End 30-JUN-2004 Summary: The cognitive and behavioral effects of heavy prenatal alcohol exposure are devastating to the individual, their families, educators, and society. However, treatment of these effects remains understudied and many questions remain unanswered. Three decades of research have clearly documented that prenatal alcohol exposure causes cognitive dysfunction. In contrast, little empirical evidence exists on treatment efficacy in this population. Among the most significant of the cognitive effects in these children are those involving attention deficits. Attentional problems are known to respond to

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treatment in other populations, as in children with attention deficit-hyperactivity disorder (ADHD). About 65 percent of children with ADHD respond to stimulant treatment. Stimulant medication is used with children with histories of prenatal alcohol exposure, but its effectiveness has not been studied empirically. We will evaluate how many children with heavy prenatal alcohol exposure show a positive response to treatment with methylphenidate, a stimulant commonly used in the treatment of ADHD. Effectiveness will be measured using a paired-associate learning paradigm and parent and teacher rating scales. Second, anecdotal evidence suggests that a sizeable minority of alcohol-exposed children will not respond favorably to methylphenidate. At this point, it is not known whether an individual child will be a positive or adverse responder and the pharmacological treatment of these children is often done on a trialand-error basis. We will assess the ability of neuropsychologic, neuroanatomic, and psychiatric variables to predict either positive or adverse response to methylphenidate in children with heavy prenatal alcohol exposure. Measures of attention/executive function and other neuropsychologic variables, psychiatric diagnosis, family adversity status, and size measures of brain structures affected by heavy prenatal alcohol exposure will be included. Knowledge gained from this research will help to provide a more rational basis for the treatment of the well-documented attentional problems in these children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHYLPHENIDATE TREATMENT FOR COCAINE ABUSE AND ADHD Principal Investigator & Institution: Levin, Frances R.; Q. J. Kennedy Associate Professor of Cli; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 100321098 Timing: Fiscal Year 2002; Project Start 20-APR-1998; Project End 31-MAR-2004 Summary: (Applicant's Abstract) Studies targeting subgroups of cocaine abusers are needed because poor treatment outcome may, in part, be the result of comorbid psychiatric disorders. One subgroup that may benefit from targeted pharmacologic treatment is cocaine abusers who have adult attention-deficit hyperactivity disorder (ADHD). The prevalence of this disorder is substantially higher in treatment-seeking cocaine abusers (11%) than in the general population (1-3%). Given the comorbidity of ADHD and cocaine abuse, pharmacotherapies aimed at treating both disorders may be particularly effective. Methylphenidate (MPH), currently one of the most effective and safe treatments for childhood and adult ADHD, is a promising candidate. Individuals may be using cocaine to self-medicate their ADHD symptoms, due to an underlying dopamine deficit. Treating the underlying psychiatric disorder (ADHD) with MPH, may result in a reduction in cocaine use, as well as a reduction in ADHD symptoms. In the human laboratory we have shown that sustained-release MPH does not produce clinically significant cardiovascular changes, even during repeated dosing of cocaine. Further, a high maintenance dose of sustained-releaser MPH, unlike a low dose of sustained-release MPH, is more likely to reduce cocaine craving during repeated cocaine administration. Within the clinic setting, we have also shown that MPH is welltolerated, not abused, and may be an effective treatment for cocaine abuse in adults with ADHD. Taken together, these findings suggest that double-blind, placebo-controlled trial to evaluate the effectiveness of sustained-release methylphenidate (MPH) is warranted. Specific Aims: 1) To determine if sustained-release MPH is more effective than placebo in reducing cocaine and other drug use in cocaine abusers with adult ADHD. 2) To determine if sustained-release MPH is more effective than placebo in

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reducing ADHD symptoms in cocaine abusers with adult ADHD. 3) To determine if improvement in ADHD symptoms precedes a reduction in cocaine use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHYLPHENIDATE TREATMENT OF ADHD IN CHILDREN WITH TS Principal Investigator & Institution: Gadow, Kenneth D.; Psychiatry and Behavioral Scis; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2002; Project Start 01-FEB-1991; Project End 31-DEC-2004 Summary: (Adapted from the Applicant's Abstract): Research clearly indicates that attention-deficit hyperactivity disorder (ADHD) is a common behavioral concomitant of Tourette's syndrome (TS) and chronic tic disorder in child patients. Unfortunately, the most safe, effective, and widely used pharmacological treatment for ADHD, namely methylphenidate, has generally been thought to exacerbate tics and therefore to be contraindicated in such patients. Because (a) the pharmacological alternatives to methylphenidate are often associated with increased risk of adverse drug reactions or are less efficacious for ADHD behaviors, and (b) there is very little controlled research on the long-term use of stimulants in children with tic disorder, there is a compelling need to examine the safety and efficacy of methylphenidate for ADHD in children with tic disorder (ADHD/+tics) and to develop drug evaluation procedures for clinical application. The primary objectives of the proposed study are to (1) assess short- and long-term effects of stimulant drug therapy for children with ADHD/tics+, and (2) describe developmental changes in tics, ADHD and antisocial behaviors, and mood and anxiety symptoms. The proposed study is a continuation of a long-term follow-up study of 82 children between 6 and 12 years of age who have ADHD/+tics and who will (or have) participate (d) in an 8-week, placebo-controlled, double-blind methylphenidate evaluation. Drug response for both ADHD and tic disorder symptoms is assessed using direct observation procedures in a simulated clinic classroom and with physician, teacher, and parent rating scales. Systematic assessment of symptom status is conducted at 6-month intervals for a minimum of 2 years and then at 12-month intervals for an additional 3 years (i.e., minimum of 5 years). To evaluate the impact of tic severity and comorbid internalizing and externalizing symptoms on clinical outcome, children with ADHD/+tics will be compared with an additional sample of children with ADHD/-tics at ages 11 and 16 years. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: METHYLPHENIDATE-ETHANOL INTERACTION IN ADHD AND COABUSE Principal Investigator & Institution: Patrick, Kennerly S.; Pharmaceutical Sciences; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Appropriate drug therapy for attention-deficit hyperactivity disorder (ADHD) requires special consideration of lifestyle and life span comorbidity. (1) dI-Methylphenidate (MPH) is a drug of choice for ADHD; (2) Substance/alcohol abuse and dependence is over-represented in adolescent and adult ADHD, especially in women; (3) A pilot study revealed a novel MPH-ethanol metabolic drug interaction, wherein ethanol combines with MPH to form ethylphenidate (ETPH); and (4) the ethanol also appeared to inhibit MPH metabolism (especially in the female subjects; women have been reported to exhibit reduced first-pass metabolism of

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ethanol). Given these considerations, the potential therapeutic and toxicological significance of the MPH-ethanol interaction is proposed for investigation. SPECIFIC AIM 1 is to test the hypothesis that the enantiomers of the metabolite ETPH contribute to the neuropharmacology of concomitant MPH-ethanol. Monoamine transporter inhibition and mouse behavioral screens will be used for this assessment. SPECIFIC AIM 2 will test the hypothesis that ETPH will be formed enantioselectively. Enantiospecific gas chromatography-mass spectrometry (GC-MS)-negative ion chemical ionization will be used to simultaneously quantitate d-MPH, I-MPH, d-ETPH and IETPH from serial plasma samples. Healthy human volunteers-eight men and eight women--will participate in these pharmacokinetic studies. SPECIFIC AIM 3 (a) will ask what extent the MPH-ethanol interaction increases MPH blood concentrations in men vs. women; (b) will test the prediction that ethanol will not only elevate total plasma MPH levels, but also reduce the plasma d-MPH/I-MPH ratio; and (c) will test the hypothesis that the order of administration of ethanol relative to MPH influences the extent of this drug interaction (in the same order-dependent manner that has been reported for the cocaine-ethanol interaction which forms cocaethylene and can inhibit cocaine metabolism). The findings will serve to broaden our understanding of the toxicological consequences of MPH-ethanol coabuse and contribute to the rational emergency management of this common concomitant drug overdose. Further, the results will be used to support recommendations for optimal drug individualization in the treatment of ADHD, e.g., dextroamphetamine vs. MPH; dI-MPH vs. d-MPH; immediate-release MPH vs. extended-release MPH; or adjustment of MPH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METHYLPHENIDATE-INDUCED GENE EXPRESSION IN THE CORTEX Principal Investigator & Institution: Yano, Motoyo; Cellular & Molecular Pharm; Rosalind Franklin Univ of Medicine & Sci North Chicago, Il 60064 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 30-JUN-2007 Summary: (provided by applicant): Interactions between the basal ganglia and cortex are critical for normal goal-directed behavior. Dopamine in the striatum regulates these interactions. Deficiencies in striatal dopamine function are associated with neuropathologies such as schizophrenia, Parkinson's Disease, and drug addiction. Psychostimulants, including methylphenidate, are widely used in the treatment of Attention Deficit Hyperactivity Disorder, but are also increasingly abused for recreational purposes. Methylphenidate increases extracellular levels of dopamine in the striatum, an effect implicated in its abuse liability. Recent studies have demonstrated that methylphenidate treatment alters gene expression in striatal output neurons in a manner similar to the psychostimulant cocaine. Such molecular changes seem to preferentially occur in the D1 dopamine receptor-regulated "direct" striatal output pathway. Our preliminary experiments show that methylphenidate treatment affects striatal and cortical immediate-early gene (lEG) expression. The proposed research will test the hypothesis that stimulation of striatal D1 receptors contributes to methylphenidate-induced lEG expression in the cortex. This hypothesis will be tested by using intrastriatal infusion of a D1 receptor antagonist. These studies will further our understanding of methylphenidate effects on gene regulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR GENETIC EPIDEMIOLOGY STUDY OF ADHD/DRD4 Principal Investigator & Institution: Moyzis, Robert K.; Professor; Biological Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 20-JUL-2000; Project End 30-JUN-2004 Summary: Utilizing the vast number of marker loci being identified by the Human Genome Project, association studies are being applied to data on many complex disorders. Once an association is identified the issue for investigators is to determine what the association tells us about the disease process. When confirmed by numerous studies, the possibility of he association being a statistical artifact is remote. We are then left with two explanations: the associated allele plays a causative role in the disorder or the allele is in linkage disequilibrium with another locus(polymorphism) which does play a role. In order to truly understand the disorder we will have to distinguish between these, but how? This project is designed to capitalize on our ability to rapidly and accurately sequence DNA for a locus over a large number of individuals ascertained within a rigorous research design, and apply that information to determine the reason for he association. We have chosen to examine Attention Deficit Hyperactivity Disorder (ADHD) and the dopamine receptor gene DRD4. We first reported the association of ADHD with the D4.7 allele of this gene, which has now been confirmed by us and five other studies. ADHD affects about 3-5% of the school-aged population and is considered the most prevalent psychiatric disorder of childhood. Family, twin, and adoption studies have established a strong genetic basis for ADHD. Initial molecular genetic investigations of candidate genes focused on the neurotransmitter dopamine because most patients are responsive to methylphenidate. The DRD4 locus is a highly variable locus where the 7- repeat form of a 48 bp segment occurs in many allelic forms. Other polymorphisms have been identified in DRD4, some of which have known functional significance, but none of which have been evaluated in ADHD studies. Probands will be ascertained through clinical trials at the Child Development Center, UCI when they meet rigorous diagnostic criteria for ADHD. Probands, their parents, and siblings will be studied and their DNA sequenced for DRD4. Other dopamine pathway loci will be genotyped. Within those families who carry D4.7 we will determine the haplotype(s) present in affected individuals for all of the polymorphisms present in the DRD4 gene. For the non-D4.7 families we will test or tight linkage with the DRD4 region. If D4.7 is merely a marker in linkage disequilibrium with a causative polymorphism, then this latter subset of families should also show evidence for linkage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR GENETICS OF NEUROTRANSMITTER TRANSPORT Principal Investigator & Institution: Blakely, Randy D.; Associate Professor; Vanderbilt University Med Ctr Nasville, Tn Timing: Fiscal Year 2002 Summary: Presynaptic dopamine (DA) transporters (DATs) constitute the primary mechanism for inactivation of DA in the brain. DAT proteins are high- affinity targets for important addictive and therapeutic drugs including cocaine, amphetamines and methylphenidate (Ritalin/TM). Little is known regarding how DAT proteins form a selective permeation pathway for DA and how different antagonist impact activity. Recent studies reveal DATs to be acutely regulated by coordinated mechanisms involving kinase activation, transporter phosphorylation and altered membrane trafficking/stabilization, though as yet genes responsible for this regulation remain to be identified. In rodents and man, DATs also constitute the portal through which

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exogenous neurotoxins (e.g. 6- OHDA, methamphetamine and MPP+) enter these neurons and affect lesions reminiscent of the selective pathology of Parkinson's disease. Controversy exits as to whether these toxic insults trigger cell death in vivo via necrotic or apoptotic pathways. We have cloned the product of the C. elegans gene T23G5.5 and demonstrated in its function as a DA transporter (CeDAT), opening the door to genetic strategies for the definition of critical DAT residues, the identification of CeDAT regulators and an understanding of molecular contributors to dopaminergic neuron sensitivity to environmental toxins. In our proposal, we seek to 1) validate the molecular and cellular specificity of CeDAT- targeted drugs and toxins, evaluate the properties of 6-OHDA-induced DA neuron degeneration in the work and determine whether CeDAT is both necessary and sufficient for toxin sensitivity, 2) to establish the cellular specificity, developmental expression and subcellular localization of CeDAT protein CeDAT mutants and CeDAT regulators using novel gain-of-function screens involving suppression of sensitivity to 6-OHDA. Together, these efforts provide important opportunities to identify and characterize regulators of transporter expression, localization and function and may provide clues to molecular determinants of dopamine- dependent psychiatric and neurodegenerative syndromes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MONOAMINE TRANSPORTERS COCAINE USE Principal Investigator & Institution: Kimmel, Heather L.; Division of Neuroscience; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): To date, there is no effective medication for treating cocaine addiction. A better understanding of the manner by which cocaine exerts its effects on the brain will focus medication development efforts. Although cocaine blocks the reuptake of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine, the reinforcing effects of cocaine have been primarily attributed to its effects at the dopamine transporter (DAT). However, not all DAT inhibitors are equally reinforcing. Examining the pharmacokinetics, more specifically, the onset and duration of action, of cocaine and related compounds is important in determining which of these properties are involved in the reinforcing effects of these compounds. In the present research proposal, the reinforcing effectiveness of several monoamine transporter inhibitors (DAT-selective and mixed-action) will be assessed in nonhuman primates. The stimulant effects of these compounds will be assessed by administering them systemically to squirrel monkeys trained on a stimulus termination task. The reinforcing effects will be assessed in separate groups of squirrel monkeys and rhesus monkeys that have been trained to self-administer cocaine. These data will allow us to determine the relative stimulant and reinforcing efficacy and potency of each combination. To determine drug effects on brain dopamine function, squirrel monkeys will undergo in vivo microdialysis procedures following drug administration, allowing us to determine how dopamine levels are altered by the administration of these drug combinations. PET imaging of DAT occupancy will be conducted in rhesus monkeys, allowing us to correlate DAT occupancy with the observed behavior and neurochemistry. Ex vivo binding assays will be conducted in rodents to determine the rate that these compounds bind to DAT. These data will further characterize the role of pharmacokinetics in the addictive properties of cocaine and provide critical information for the development of effective pharmacotherapies that are not, themselves, addictive. This research proposal will extend the candidate's research training in rodent behavioral pharmacology and neurochemistry to nonhuman primate behavioral pharmacology and neurochemistry. In

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addition, this research plan represents a new research direction for the applicant. The training experiences described will provide for the candidate's transition from a mentored scientist to an independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROBIOLOGY OF PERSONALITY AND EMOTION Principal Investigator & Institution: Depue, Richard A.; Professor; Human Development; Cornell University Ithaca Office of Sponsored Programs Ithaca, Ny 14853 Timing: Fiscal Year 2002; Project Start 01-MAR-1997; Project End 31-OCT-2003 Summary: Dopamine facilitation of incentive motivation lays the very foundation of normal goal-oriented behavior, and is suspected of being involved directly or indirectly in an array of abnormal behavioral conditions. Incentive-motivated behavior is facilitated by corticolimbic glutamatergic afferents that carry the salient context predictive of reward to DA neurons in the ventral tegmental area (VTA) and to spiny neurons in the nucleus accumbens (NAS). Much animal work demonstrates that individual differences in VTA DA and NAS DA functioning modulate the extent to which salient incentive contexts a) are bound to VTA and NAS neurons, and hence b) facilitate the behavioral expression of incentive motivational processes in the NAS. We demonstrated (Depue & Collins, 1999) that the foundation of the major personality trait of extraversion is positive incentive motivation, and that variation in both of these is associated with individual differences in DA functioning. Therefore, it can be hypothesized that variation in extraverted affect and behavior is associated with variation in the strength to which salient context comes to facilitate incentive motivational processes. The proposed studies specifically test this hypothesis through four experimental studies that assess a) the extent to which context is paired with a methylphenidate-facilitated incentive motivational state, b) dose dependence of these effects, and the extent to which the effects are modified by c) latent inhibition and d) extinction processes. Significance of the work derives from its development of new methodology, performance measures, and pharmacological designs to study contextmotivational associations in humans. Also, these studies are designed to provide information that may enlighten several psychiatric problems that may involve a contribution of DA to, and contextual facilitation of, disordered behavior. Recent research raises the possibility that determination of DA-behavior relations could have benefit in understanding, and perhaps in treating, pathological forms of personality disorders, some forms of affective disorders, and schizophrenic positive symptoms. Furthermore, the proposed studies may have direct implications for understanding and modeling the genetic-experiential interactive liabilities to alcohol and psychostimulant substance abuse that may depend on the sensitivity of DA receptor systems in interaction with environmental context. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEUROCHEMICAL CONSEQUENCES OF DRUGS IN ADOLESCENT RATS Principal Investigator & Institution: Izenwasser, Sari; Research Professor; Psychiatry and Behavioral Scis; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 30-APR-2008 Summary: (provided by applicant): Most research to date using animal models of drug abuse has focused on the effects of psychostimulants on brain neurochemistry and behavior in adult, prenatal, or preweanling animals. There has been little research

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focusing on the effects of psychostimulants on adolescent rats. However, it is well known that a large number of people who use drugs started as teenagers. Because of this, it is of interest to examine the effects of psychostimulants in this adolescent population in order to determine whether there may be a difference in how this class of drugs effects this age cohort, and on how drug use at this age affects adult susceptibility to addiction. The specific hypothesis of this proposal is that psychostimulants have different effects on the behavior of periadolescent rats than of adult rats, and that exposure to drugs during this critical phase may alter the neurochemical underpinnings of stimulant abuse as an adult. A number of studies have examined the effects of preexposure to drugs on later response to cocaine. In all of these studies, both the pre- and post-exposure phases were conducted after the animal had reached adulthood. These studies have shown that pre-exposure to a number of different drugs can influence both the neurochemical and behavioral effects of subsequently administered psychostimulants. Repeated exposure to direct or indirect dopamine agonists in adult rats produces sensitization to the behavioral effects of psychostimulants. Our preliminary data show that, in adult rats, sensitization is evident both during a seven day treatment period, and 10 days after the treatment ends. In contrast, no sensitization is apparent in periadolescent rats treated under the same drug regimen. The aim of these experiments is to compare the effects of several drugs during the periadolescent phase to during the adult phase. Rats will be treated daily for one week with either cocaine, methylphenidate (ritalin), MDMA (ecstasy) or the appropriate vehicle during the periadolescent or adult phase. Locomotor activity will be tested for one hour daily during this period. Immediately subsequent to this period, or one month later, markers of dopamine and serotonin neurochemistry will be measured. In addition, one month later, the response to cocaine will be tested again on locomotor activity. An understanding of the differential effects of drugs during the periadolescent phase and of how this use impacts drug effects in adults may lead to different treatments for different age groups, as well as a better understanding of how drug use in adolescence may lead to psychostimulant abuse in adulthood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROCHEMISTRY METHYLPHENIDATE

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NEUROPHYSIOLOGY

OF

Principal Investigator & Institution: Waterhouse, Barry D.; Neurobiology and Anatomy; Drexel University College of Medicine 245 N 15Th St Philadelphia, Pa 19102 Timing: Fiscal Year 2002; Project Start 10-JAN-2002; Project End 31-DEC-2004 Summary: (provided by applicant): Attention deficit, hyperactive disorder (ADHD) is a childhood cognitive disorder characterized by inattentiveness and/or hyperactivity and impulsiveness. The most effective treatment for ADHD is chronic low dose administration of amphetamine (AMPH)-like stimulants such as methylphenidate. All of these agents have prominent effects on monoaminergic neurotransmission yet little is known regarding the specific mechanism(s) through which they exert their therapeutic action in ADHD. Almost all of our information concerning AMPH-like stimulants derives from drug abuse studies which employ doses far in excess of those used clinically. Furthermore, there are profound dose and drug-specific differences in AMPH-like stimulant actions on monoaminergic neurotransmission. The central tenet of the proposal is that it is inappropriate to postulate therapeutic mechanisms of action for AMPH-like stimulants on the basis of animal studies of drug abuse. Moreover, a better understanding of the therapeutic actions of these drugs is needed in order to develop pharmacological treatments that do not possess the negative properties of AMPH-like

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stimulants (e.g. unwanted behavioral side effects, long term toxicities, abuse potential). The goal of the proposed study is to develop methodologies for evaluating the effects of therapeutically-relevant doses of methylphenidate on: 1) catecholaminergic neurotrasmission, 2) the impact of acute and chronic low dose stimulants on sensory processing, sensory detection and attention, 3) the receptor mechanism involved in stimulant-induced alterations in sensory processing, sensory detection and attention, and 4) the long-term consequences of low dose stimulants on a variety of physiological and behavioral processes in developing animals. The major techniques to be employed here include gas chromotography for determining plasma levels of methylphenidate, microdialysis for determining plasma levels of methylphenidate, microdialysis for determining catecholamine levels in specified brain regions, EEG and EMG for identifying behavioral states of arousal, multi-channel many neuron recording in cerebral cortex, thalamus and locus coeruleus for characterizing patterns of neural discharge in awake behaving rats, and computer based analysis of many neuron spike train data. These studies will fill a significant gap in our understanding of therapeutic actions of AMPH-like stimulants in ADHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROIMAGING OF INHIBITION & STIMULANT RESPONSE IN ADHD Principal Investigator & Institution: Pliszka, Steven R.; Associate Professor and Chief; Psychiatry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2005 Summary: (provided by applicant) The overall objective of this project is to develop a system-level model of brain-behavior relationships in ADHD. This proposal builds on previous findings of the P1 and CoPIs using a combination of event-related potentials (ERP), behavioral tasks, anatomical magnetic resonance imaging (MRI) and neuropsychology assessments in ADHD children. In the proposed project, we will use a within-subject, multi-methodological approach to clarify the relationship between anatomical and functional imaging abnormalities in ADHD. We will obtain ERP, eventrelated functional MRI (ER-fMRI), and anatomical MRI at baseline in four cohorts of subjects: ADHD subjects with no history of psychopharmacological treatment, ADHD subjects who have been chronically treated with stimulant medication, subjects with Reading Disorders (RD) who have no history of ADHD or psychopharmacological treatment, and control subjects. Subjects will perform both the ERP and the Stroop task during the ERP and ER-fMRI studies. After baseline studies, ADHD subjects will undergo a 5-week double blind placebo controlled trial of methylphenidate to establish if a child is a responder or non-responder to methyiphenidate and to determine, for the responders, which is the optimal dose. Subjects with ADHD will then undergo ERP and er-fMRI twice more, once on placebo and once on the best dose of stimulant, again performing the Stroop and Stop Signal Task. Our hypotheses are: 1) Relative to controls and RD subjects, ADHD children will show decreased right frontal and anterior cingulate volume as well as decreased caudate volume. 2) On ERP, ADHD subjects will show decreased N200 and P3a responses to the stop signal on ERP and decreased anterior medial negativity to Incongruent vs. Congruent stimuli on the Stroop. 3) On erfMRI, they will show decreased activity in the anterior cingulate during the Stroop task, and decreased right inferior prefrontal cortex (PFC) activity in response to the stop signal. 4) ERP and er-fMRI differences in ADHD children will be attenuated on methyiphenidate relative to placebo. The magnitude of these changes will correlate with

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clinical response of ADHD symptoms to methylphenidate. 5) We will control for effects of gender and age, in particular girls with ADHD may not show the same neurobiological mechanisms as boys. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROPHYSIOLOGIC CORRELATES OF ATTENTION DEFICITS Principal Investigator & Institution: Whyte, John; Director; Moss Rehabilitation Hospital 1200 W Tabor Rd Philadelphia, Pa 19141 Timing: Fiscal Year 2003 Summary: Attention deficits are widespread and disabling after significant traumatic brain injury (TBI). Controversy remains about how to measure attention deficits in this population, as well as their appropriate treatment. Prior research suggest that prefrontal dysfunction, related to focal injury and denervation resulting from diffuse axonal injury, is central to the attention deficits seen in this population. Much of this prefrontal pathology is "invisible" to studies of brain structure. The proposed research intends to use functional imaging to explore the role of prefrontal cortex in the attention deficits seen after TBI, and to examine changes in prefrontal function resulting from drug treatment, as they relate to drug-related changes in behavioral performance. Subjects with TBI will be recruited for a previously-funded study of drug treatments of attention deficits. In that study, subjects will receive methylphenidate and placebo in a crossover design, while extensive data are collected on many different aspects of attentional functions in both drug conditions. Subsequently, 20 of the subjects with TBI and 20 control subjects will be recruited to participate in this proposed study. Subjects will receive 2 fMRI scans (one on methylphenidate and one on placebo, blinded and in counterbalanced order). In each scanning session, several measures will be taken, including: resting cerebral blood flow to prefrontal cortical regions; cerebral blood flow in these same regions during a sustained attention tasks; and BOLD activation measures within the context of a distraction paradigm. Resting blood flow measures will be used to predict severity of attention deficits. Changes in blood flow and activation (off drug) in response to the 2 probe tasks will be used to predict behavioral performance in those tasks. Finally, drug effects on blood flow and activation will be correlated with drug effects on performance to examine the mechanism of action of the drug. Collectively, these results will advance the theoretical understanding of the nature of TBI-associated attention deficits and the possible mechanism of action of therapeutically useful drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL PHARMACOTHERAPIES FOR TREATMENT OF ADHD Principal Investigator & Institution: Tarazi, Frank I.; Assistant Professor; Biostream Therapeutics, Inc. 160 2Nd St Cambridge, Ma 02142 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-JUL-2004 Summary: (provided by applicant): Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition characterized by hyperactivity, inattention and impulsivity, typically in school-aged boys. Psychostimulants, including methylphenidate and amphetamines, are commonly used to alleviate symptoms of ADHD. However, these medications are typically associated with undesirable side effects, prompting the search for novel non-psycho stimulant treatments for ADHD. Salient features of clinical ADHD are commonly modeled in juvenile rats following neonatal lesioning with 6-hydroxy-dopamine (6-OHDA). Such rats exhibit several characteristics resembling symptoms of ADHD, most notably, motor hyperactivity that

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occurs selectively during the periadolescent period, and can be dose-dependently antagonized by psychostimulants. A major recent discovery from our laboratory is that the locomotor hyperactivity associated with neonatal dopamine (DA) lesioning was reversed in dose-dependent manner by a highly selective DA D4 receptor antagonist (CP-293,019), and worsened by a D4 agonist (CP-226,269). These findings accord with a repeatedly reported genetic association of D4 receptor alleles and ADHD, and implicate D4 receptors as attractive targets for innovative treatments for ADHD. This project includes further chemical, pharmacological and behavioral characterization of the neonatal 6-OHDA-lesion-hyperactivity model. Several novel D4 compounds will be chemically synthesized using our proprietary N-benzyl-4- phenylpiperidines to optimize their D4 antagonist activity. This will be accomplished by modifying the piperidine pharmacophore, the N-benzyl substituent, or the phenyl substituent to exploit the rich structure-activity relationships available for increased potency and/or selectivity for the D4 receptor subtype. The pharmacological profile of these compounds will be characterized by determining their affinity to D4 receptors and other DA and serotonin receptor subtypes, as well as their molecular functionality at D4 receptors. The behavioral effects of novel selected compounds that display full D4 antagonistic properties will be assessed in juvenile hyperactive rats and their sham-control littermates to determine their efficacy in reversing locomotor hyperactivity. Expected findings should evolve new principles and lead to novel compounds that can be used as much-needed innovative treatments for ADHD and other major neuropsychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PERIADOLESCENT METHYLPHENIDATE EXPOSURE: BRAIN FUNCTION Principal Investigator & Institution: Dow-Edwards, Diana L.; Professor; Physiology and Pharmacology; Suny Downstate Medical Center 450 Clarkson Ave New York, Ny 11203 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Widespread administration of psychoactive drugs to children, often without documented pathology, occurs in most of the United States today. New trends toward prescribing medications for Attention Deficit Hyperactivity Disorder (ADHD) to children without parental/family physician approval will surely increase the exposure of our population to drugs containing methylphenidate. Adequate knowledge about the long-term effects of chronic exposure of healthy children does not exist. These studies will utilize a rat model to address the following: Specific Aim 1 will determine the behavioral consequences of repeated methylphenidate (MPD) administration during periadolescence. Methylphenidate will be administered orally throughout the periadolescent period. A. Behavioral activation: Behavioral responses to MPD will be determined in photobeam boxes initially and after every thirteen days of dosing. The goal will be to find doses that activate behavior without producing sensitization. B. Spatial Learning: Effects of methylphenidate on performance in the radial arm maze (RAM) will be used as a measure of spatial learning. Rats will be trained on the 8-arm RAM daily following MPD dosing to determine whether MPD at doses which activate behavior facilitates learning. It is expected that MPD will enhance acquisition of spatial learning in the radial arm maze task. Specific Aim 2 will determine the neurofunctional consequences of periadolescent methylphenidate exposure. Brain metabolism using the deoxyglucose method will be determined in rats trained on RAM (Aim 1B) after the last dose on day 60 and shifted to the 12-arm RAM. Brain sections will be analyzed for molecular markers of dopamine

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function using in situ hybridization histochemistry (ISHH). Correlations of brain function and behavior on the 12-arm RAM (assessed simultaneously) and between brain function within specific neuronal circuits will be determined. It is expected that repeated exposure to MPD will alter brain metabolism in two ways: increasing metabolism in components of the mesolimbic and nigrostriatal dopamine circuits and by increasing functional coupling (correlations) among components of the hippocampus. Specific Aim 3 will determine the long-term behavioral and neurofunctional consequences of periadolescent methylphenidate exposure. It is expected that basal levels of brain metabolic function will also be altered 1 month after periadolescent exposure to MPD. Correlations between spontaneous behavior and metabolism as well as among metabolic rates in structures within identified neuronal circuits will be determined. Animals generated in Aim 1A will be used. Specific Aim 4 will determine the plasma levels of methylphenidate which produce behavioral activation. Plasma drug levels will be determined at those doses which were found to produce behavioral alterations. This will facilitate comparison with human studies reporting therapeutic plasma drug levels. These studies will determine the immediate and long-term consequences of administration of methylphenidate in rats during childhood and adolescence. The overall hypothesis to be tested is that chronic administration of methylphenidate to periadolescent rats will alter learning as assessed in the radial arm maze, activate behavior, and produce immediate and long-term alterations in function of critical neural circuits. The functional relationships between components of the hippocampus and spatial cognition will be established and the effects of MPD on these relationships explored. Through these studies, a comprehensive pre-clinical evaluation of the effects of chronic methylphenidate on learning, behavior, brain function and molecular patterns will be completed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: P-GLYCOPROTEIN AND DISPOSITION OF PSYCHOSTIMULANTS Principal Investigator & Institution: Markowitz, John S.; Associate Professor; Pharmaceutical Sciences; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 30-JUN-2006 Summary: (provided by applicant): Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurobehavioral disorder diagnosed in childhood and adolescence and one of the most prevalent chronic health problems afflicting school-age children in the US. One of the cornerstone treatments of the disorder is pharmacotherapy with formulations of the psychostimulants (STIMs) methylphenidate (MPH) or amphetamine (AMP) which represent by far the most common treatments in developing children and adolescents. The use of STIMs has accelerated rapidly in the past decade with prescriptive use of these agents at an all time high. Significant limitation exist regarding long-term use of these agents, including non-response or intolerable side effects in up to 30 percent of patients and the dsk of drug-drug interactions as part of increasingly complex drug regimens. Additionally, unlike many pediatric therapeutic agents, weight-based dosing recommendations have not proven clinically useful and therapeutic drug monitoring is not predictive of response. As with many CNS drugs, significant interindividual variability in the disposition of STIMs, therapeutic response, and side effects is common. In this R21 application, animal studies are proposed to support a long-range goal to improve the outcome of the treatment of ADHD with STIMs by identifying pharmacogenetic biomarkers. This application involves translational research addressing in part, the specific needs outlined in the program

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announcement, PA-03-113 (Developmental Psychopharmacology). Although the STIM agents have been in clinical use for over half of a century, and their metabolism and disposition are reasonably well defined, essentially no data exist on the role of drug transporters in their disposition and clinical effects. The most prominent gene of the ABC cassette family of transporters, ABCB1 (also known as MDR1), is highly polymorphic and encodes for P-glycoprotein (PGP). PGP, as an effiux transporter, provides a protective role for major organs by limitingcellular uptake of its substrates by excreting them into bile, urine, the intestinal lumen, and limiting their accumulation in brain. We hypothesize that PGP is an important determinant of brain access and pharmacologic effects of STIM medications. Futhermore, inhibitionor induction of PGP in the endothelial cells at the blood brain barrier by specific therapeutic agents should increase or decrease, respectively, the brain access and effects of STIMs-possibly in a stereoselective manner, and without altering their systemic exposure significantly. The specific aims are (i) to conduct stereospecific studies assessing whether MPH or AMP are PGP substrates using transgenic mice; (ii) to determine the effects of PGP inhibition on plasma and tissue concentrations of STIMs; (iii) to obtain pharmacodynamic correlates (e.g. locomotor behavior) of differential brain penetration of STIMs. The proposed data could support future human trials to improve ADHD therapy by genotyping patients to determine PGP status prior to drug selection and dosage, predicting and avoiding deleterious drug-drug interactions, and to explore the use of PGP modulation to influence brain penetration of STIMs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHARMACOKINETICS REINFORCEMENT

OF

PSYCHOSTIMULANTS

AND

Principal Investigator & Institution: Volkow, Nora D.; Chairman; Brookhaven Science Assoc-Brookhaven Lab Brookhaven National Lab Upton, Ny 11973 Timing: Fiscal Year 2002; Project Start 30-SEP-1994; Project End 31-MAY-2003 Summary: APPLICANT'S ABSTRACT: Cocaine and methylphenidate (MP) are both psychostimulant drugs. Yet cocaine is considered one of the most reinforcing and addictive drugs of abuse, while MP is widely used to treat attention deficit disorder in children. MP has a similar affinity for the dopamine transporter (DAT) as cocaine. Preliminary work from our laboratory using PET and [11C]cocaine and [11C]methylphenidate showed a striking similarity for the pattern of distribution of these two drugs in the human brain with competition for the same binding sites. However, they differ in their pharmacokinetics.MP's clearance from brain is significantly slower than that of cocaine. We hypothesize that the slow clearance of MP in brain will interfere with the magnitude of the response to a subsequent dose of MP, or cocaine, thus decreasing the likelihood of "bingeing" behavior. We propose to test these hypotheses by investigating the relation between the pharmacokinetics of MP in brain, its inhibition of the DATs and its behavioral effects after single and repeated administration.We will also investigate the effects of MP administration on the binding of cocaine in brain. We propose to use PET in conjunction with: [11C]methylphenidate to measure brain pharmacokinetics of MP, d-threo-[11C]methylphenidate to measure DAT occupancy after single and repeated iv MP administration and [11C]cocaine to evaluate binding inhibition by pharmacological doses of MP. For this last experiment we have chosen to use oral administration rather than iv because of the potential usefulness of a "slow release" form of MP in the treatment of cocaine addict. In parallel we will also evaluate the effects of oral MP on the behavioral response to a pharmacological dose of iv MP. Our working hypotheses are as follows: (1) The initial uptake of MP, as well as

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the fast inhibition of the DAT by MP, will be associated with the "high", but the continuous inhibition of the DAT will not. When a second dose is administered while the DATs are still inhibited, the "high" will be significantly decreased despite equivalent or even a larger percent of DAT inhibition. (2) Oral MP administration, will inhibit binding of [11C]cocaine and [11C]MP to a comparable extent and will decrease the magnitude of the iv MP-induced "high". Understanding the relation between MP's pharmacokinetics in brain, its length of occupation of the DAT and its psychoactive effects is important not only in understanding the addictive potential of MP and other psychostimulant drugs but also for the development of therapeutic strategies to treat cocaine addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHARMACOLOGICAL STIMULANT ADDICTION

REPLACEMENT

STRATEGIES

FOR

Principal Investigator & Institution: Spealman, Roger D.; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: The overall objective of this program is to identify candidate medications that may function as pharmacological replacements for abused stimulants Synthetic efforts, conducted by H M Deutsch, Ph D , Georgia Institute of Technology, focus on derivitization of two indirect dopamine agonists, methylphenidate and the novel bicyclooctane LR-5182 The aim is to modify the structures of these compounds to generate potent, long-lasting drugs that substitute for cocaine and may thus prevent craving and withdrawal symptoms induced by drug abstinence (analogous to methadone for the treatment of heroin abuse) During the last project period we evaluated several structural derivatives of methylphenidate for their capacity of mimic the discriminative stimulus effects of cocaine in a manner predictive of cocaine-like subjective effects Monkeys were trained to discriminate a behaviorally active dose of cocaine (0 3 mg/kg, i m ) from vehicle using a two-choice drug discrimin ation pro cedure Under test conditions, cocaine, methylphenidate and a number of N-substituted and aromatic ring-substituted derivatives of methylphenidate induced dose-related increases in drug-appropriate responding reaching r 90% responses on the cocaineassociated lever Of these compounds dichloromethylphenidate, dichlororitalinol and dichlororitalinol methyl ester were more potent and had slower onsets and longer durations of action compared either cocaine or methylphenidate, suggesting that they may be suitable candidates for further evaluation in drug self-administration studies scheduled for the forthcoming year Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHASE III TRIAL OF OROS METHYLPHENIDATE Principal Investigator & Institution: Mcburnett, Keith; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PRECLINICAL DEVELOPMENT OF DRUGS FOR STIMULANT ABUSE Principal Investigator & Institution: Deutsch, Howard M.; Principal Research Scientist; Chemistry & Biochemistry; Georgia Institute of Technology 505 10Th St Nw Atlanta, Ga 303320420 Timing: Fiscal Year 2002; Project Start 20-JAN-1999; Project End 30-NOV-2003 Summary: The purpose of this work is to synthesize and test compounds which will be useful therapeutic agents in the treatment of stimulant abuse. Synthetic efforts will center around the derivatization of two indirect acting dopamine agonists, methylphenidate and LR-5182 (a bicyclooctane). The aim is to alter their basic structures in such a manner as to generate either (1) potent, long-lasting agonists which will substitute for the abused (analagous to methadone in the treatment of heroin addiction), (2) partial agonists or mixed agonist-antagonists which will lessen the subjective effects of the abused stimulant, but exhibit a mild stimulant effect of their own; or (3) antagonists, which will block the subjective effect of the abused stimulant, but have no intrinsic stimulant activity. The compounds will be evaluated using a multi-tiered battery of tests. The first level will consist of the in vitro determination of potency to block dopamine uptake and [3H]WIN 35,428 binding, selectivity for the dopamine transporter, and right-shift of the cocaine inhibition curve against dopamine uptake Based on the outcome, some compounds will progress to the second level of testing, where their ability to substitute for and/or antagonize cocaine in drug discrimination and conditioned place preference tests in rats will be assessed. Compounds judged to have therapeutic potential at this point will then advance to testing in primate selfadministration and drug- discrimination paradigms. Although the aim is to develop agents for the treatment of stimulant abuse, the findings may also have application in other disorders involving dopaminergic pathways, including attention deficit disorder, Parkinson's disease, Tourette's syndrome, and schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PSYCHOSTIMULANTS AND MONOAMINE TRANSPORTERS Principal Investigator & Institution: Fleckenstein, Annette.; Professor; Pharmacology and Toxicology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2003; Project Start 01-FEB-1998; Project End 31-DEC-2007 Summary: (provided by applicant): Methylphenidate (MPD) and amphetamine (AMPH) are stimulants of abuse that are used by millions for the treatment of attention deficit hyperactivity disorder. Our laboratory recently identified previously unreported effects of these agents. Specifically, MPD rapidly and reversibly increases vesicular dopamine (DA) uptake in a vesicle-enriched subcellular fraction prepared from treated rats. In contrast, AMPH analogs decrease vesicular DA uptake in the same fraction. These effects occur concurrent with increases and decreases in vesicular monoamine transporter-2 (VMAT-2) immunoreactivity after MPD and AMPH analog treatment, respectively, and appear to reflect trafficking of VMAT-2 protein and/or vesicles within nerve terminals. Accordingly, this proposal will test the hypothesis that MPD affects vesicular DA transport and the intraneuronal localization of VMAT-2 in a manner distinct from AMPH. This will be accomplished by: A. demonstrating the unique features of MPD on VMAT-2 localization, and comparing these properties with those of AMPH. Specifically, we will: i) identify the vesicles associated with the redistribution of VMAT- 2, and the subcellular compartments among which VMAT-2 are trafficking; ii) determine the regional selectivity of the MPD-induced redistribution of VMAT-2, and if

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this change is unique to DA neurons; and iii) determine the impact of age and chronic treatment on the MPD-induced redistribution of VMAT-2. B. elucidating mechanisms whereby MPD alters VMAT-2 localization. This will be accomplished by investigating: i) the role of D1 and D2 receptors in redistributing VMAT-2; ii) the acute effect of MPD on D2 receptor localization; and iii) the role of synapsin in the MPD-induced changes in VMAT-2 distribution. C. demonstrating functional consequences of the effect of MPD on vesicular trafficking. Specifically, we will investigate if: i) MPD alters vesicular DA sequestration; and ii) MPD-induced alterations in VMAT-2 distribution are neuroprotective against the long-term monoaminergic damage caused by high-dose methamphetamine administration. Completion of these studies will advance our understanding of the therapeutic effects of MPD and AMPH, as well as their abuse and dissimilar neurotoxic liabilities. These data will also provide insight into mechanisms underlying the regulation of vesicular DA uptake and sequestration. Finally, these studies will advance our understanding of a wide array of processes including those underlying addiction and those contributing to the development of DA neurodegenerative diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PSYCHOSTIMULANTS FOR FATIGUE IN AMBULATORY MEN WITH PC Principal Investigator & Institution: Roth, Andrew J.; Associate Attending Psychiatrist; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 01-MAR-2001; Project End 28-FEB-2004 Summary: (Adapted from investigator's abstract) Fatigue is perhaps the most highly prevalent and debilitating symptom of advanced cancer. Recent reports estimate that fatigue is a distressing symptom in at least 75-100 percent of patients with advanced cancer. Patients with advanced prostate cancer are amongst those most at risk for developing fatigue because they are likely to have widespread bony metastases, anemia and are likely to continue to receive chemotherapy, hormonal therapy or radiation therapy during very late stages of illness. Studies of the prevalence of fatigue in ambulatory prostate cancer patients suggest a rate of up to 67 percent. Interventions for cancer-related fatigue, particularly in patients with advanced disease, have not been studied, and no controlled trials have been published. These interventions include strategies aimed at reversing the etiology of fatigue (e.g., treating anemia), and at strategies aimed at treating fatigue directly through pharmacological (e.g., corticosteroids, psychostimulants) and non-pharmacological interventions (e.g., energy conservation and exercise). The few controlled pharmacologic interventions for fatigue with psychostimulant medications (e.g., amphetamine, methylphenidate and pemoline) have been studied to a limited degree in patients with cancer, AIDS and multiple sclerosis. Thus the potential of psychostimulants as effective tools in the management of fatigue is of interest to oncology and health care practitioners. Fatigue in cancer and AIDS patients has been significantly associated with psychological distress, depression, hopelessness and overall psychological distress. This project's overall aim is to study the efficacy of psychostimulant drugs in the treatment of fatigue in ambulatory prostate cancer patients with advanced disease. The investigators propose to compare the frequency and severity of treatment emergent severity, neuropsychological test performance, and overall quality of life. Specifically, they propose to conduct a randomized, double blind, placebo-controlled, parallel design trial, evaluating the relative benefits and risks of 2 psychostimulant medications (methylphenidate, pemoline), in the treatment of fatigue in advanced prostate cancer patients. This study

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will be the first controlled evaluation of a pharmacologic intervention for fatigue in cancer patients, utilizing novel psychotropic agents (psycho stimulants). Outcomes will be assessed with validated measures of fatigue, side-effects, psychological distress, depression and overall quality of life. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESPONSE VARIABILITY IN STIMULANT TREATMENT OF ADHD Principal Investigator & Institution: Mcgough, James John.; Psychiatry & Biobehav Sciences; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: The proposed Mentored Patient-Oriented Research Career Development Award outlines a program of career development and research in clinical pediatric psychopharmacology. A focus of this program will be a clinical trial with methylphenidate in 160 children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD). Although stimulant medications are regarded as first-line treatments for ADHD, individual children show tremendous differences in response to drug, and there is no method to determine a priori the particular stimulant or dose likely to provide optimal benefit. The Specific Aims of the study will address possible underlying mechanisms for this variability in response to stimulant treatment. Implications of this award may be enhanced understanding of factors contributing to individual differences in response to medication and optimization of pharmacological response to ADHD and other psychiatric disorders. The candidate is an accomplished clinician and educator. The educational and research plan is designed to facilitate a change in career emphasis from clinician and clinical teacher to clinical investigator. The proposed research is specifically intended to provide mentored research experience in the application of emerging concepts from basic sciences to clinical investigations in child mental health. The five-year career development plan includes didactic instruction in neurosciences and clinical research at the UCLA Neuropsychiatric Institute and biomathematics at the UCLA School of Medicine. The proposed educational plan includes courses in clinical research methodologies, pharmacokinetics, neurophysiology, statistical analysis, neurochemistry, neuropharmacology, and human genetics. Additional time will be devoted to supervised individual courses of study in molecular psychiatry, laboratory methods, clinical pharmacology, and medical research ethics. In addition to funding the candidate's transition to independent research the proposed study would also contribute to our knowledge of the basis of individual response to medication in psychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SENSITIZATION PSYCHOSTIMULANTS

&

CROSS-SENSITIZATION

TO

Principal Investigator & Institution: Yang, Pamela B.; Neurobiology and Anatomy; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2002; Project Start 01-JUL-2002 Summary: (Provided by Applicant): Repeated treatment with methylphenidate (MPD; Ritalin) and other psychomotor stimulants, such as amphetamine and cocaine, has been shown to cause behavioral sensitization in rats and humans. Behavioral sensitization is characterized by an increase in locomotor and/or stereotypic behavior. It is not known, however, whether the behavioral sensitization produced by MPD involves the same

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neuronal mechanisms as amphetamine and cocaine. More importantly, chronic administration of MPD may also result in cross-sensitization with other psychostimulants. Methylphenidate is widely used to treat attention deficit/hyperactivity disorder (ADHD). The objectives of this study are to determine whether early exposure to MPD in juvenile rats increases their sensitivity to the drug when they are adult rats and whether treatment with MPD in juvenile and adult rats produces cross-sensitization to amphetamine. The study will consist of (1) monitoring the locomotor activity of two strains of rats (a model of ADHD and its control) before and after acute and repeated MPD administration when the rats are young and as adults followed by an amphetamine treatment and (2) evaluating sensory evoked potentials before and after drug treatment in freely moving rats with electrodes implanted in brain regions believed to be involved with ADHD, behavioral sensitization, and crosssensitization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SENSORY GATING AND HABITUATION IN SCHIZOPHRENIA Principal Investigator & Institution: Braff, David L.; Professor; Psychiatry; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-JAN-1987; Project End 16-APR-2003 Summary: Attentional and information processing deficits have frequently been implicated in the psychopathology of schizophrenia. In recent years, the hypothesis of dopamine (DA) overactivity has also assumed significance in understanding schizophrenia. This proposal specifically outlines studies with humans and related animal models that will extend our knowledge of how DA overactivity relates to the sensory gating and habituation deficits that may underlie the cognitive fragmentation and thought disorder characteristic of schizophrenia. In animal experiments, we will further explore dopaminergic, noradrenergic, and specific anatomical pathways involved in the observed sensory gating deficits. To accomplish these goals, we propose to utilize the prepulse inhibition (PPI) and habituation of the startle reaction in humans and rats using the very similar paradigms, stimulus parameters, dependent measures, and statistical analyses that we have developed in our previous work. In humans, we will use electromyographic monitoring of the blink reflex component of the startle reaction (SR). In rats, we will use measures of whole body startle. Sensory gating will be accomplished by weak prestimulation and habituation using 121-trial tests in both humans and animals. Schizophrenic and control patients will be tested longitudinally and through various phases of their illness, while their clinical, symptomatic, neuropsychological, homovanillic acid levels, radioreceptor assay levels, and other measures are obtained. As an animal model of DA overactivity, rats having 6hydroxydopamine-induced depletions of nucleus accumbens DA will be tested in the PPI paradigm following systemic treatments with apomorphine, noradrenergic agonists, and/or various dopaminergic antagonists. Liquid chromatography will be used to confirm the DA depletions. Our objectives are to clarify the neurochemical and anatomical pathways that underlie sensory gating and habituation deficits in schizophrenia and to explore the functional importance of dopamine overactivity in schizophrenia. We intend to further our understanding of how DA overactivity and its underlying neuroanatomic correlates may relate to the specific cognitive dysfunction, symptoms, and outcome of the schizophrenic disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SEROTONIN STRUCTURE/FUNCTION

AND

GABA

TRANSPORTERS--

Principal Investigator & Institution: Mager, Sela; Mount Sinai School of Medicine of Cuny New York, Ny 10029 Timing: Fiscal Year 2002 Summary: The principal objective of this proposal is to understand the molecular mechanism of serotonin uptake by the mammalian serotonin transporter. The serotonin transporter utilizes the Na+ electrochemical potential to transpor6t neurotransmitters into the cell against their concentration gradient, so that a low extracellular neurotransmitter concentration can be maintained. The molecular mechanism that underlies this process is not known. The proposed set of experiments will help to establish an integrated picture of transporter function and identify structural domains that participate in specific steps of the transport cycle. According to this study's working hypothesis, the transporter protein contains a channel-like lumen flanked by extracellular and intracellular gates. The opening and closing of these gates is governed by the binding of organic substrate and ions in the lumen. The energetic coupling between neurotransmitter transport and the electrochemical potential of ions is a result of the sequential opening and closing of the gates as well as the dependance of neurotransmitter binding on the binding of co-transporting ions. The proposed research will utilize electrophysiology and other functional measurements in order to characterize mutated transporters, and to identify and study functional domains that contribute to specific aspects of the transport process. We will investigate domains in the protein that (1) participate in transporter gating, (2) form the transporter lumen, and (3) form and are actively involved with ion and serotonin binding sites. Studies have shown that an alterations in the activity of the human serotonin transporter is associated with several mental disorders and possibly with alcohol and cocaine abuse. The transporter is also a major target for therapeutic drugs such as fluoxetine, methylphenidate, and amphetamine. Understanding the roles of the serotonin transporter in normal brain function, mental disorders, and drug abuse requires more insight into the biophysical and molecular mechanisms of transporter function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SLEEPINESS METHYLPHENIDATE

AND

THE

REINFORCING

EFFECT

OF

Principal Investigator & Institution: Roehrs, Timothy A.; Director of Research and Academic Appoin; Psychiatry; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 10-JUN-1998; Project End 31-MAY-2004 Summary: (Adapted from applicant's abstract): Stimulant abuse remains a social problem. Studies of the reinforcing and subjective effects of stimulants, specifically amphetamine and cocaine, report variations in subjective and reinforcing effects among individuals and within individuals as a function of time-of-day. The variations may be due, in part, to differences in daytime sleepiness-alertness. Daytime sleepiness-alertness can be reliably and validly measured using standard electrophysiological methods and it varies within and among healthy individuals as a function of time-of-day and the prior amount of sleep. To further understand the conditions leading to stimulant use and abuse, this project will explore how sleepiness-alertness influences the reinforcing and subjective effects of methylphenidate in healthy adults without drug abuse histories. Methylphenidate will be studied because it is the most often prescribed

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stimulant and primarily to a population known to be sleepy due to sleep loss. Thus, the working hypothesis of this project is that one way stimulants, and specifically methylphenidate, may gain reinforcing effects is by enhancing behavioral function and alertness in "sleepy" people. The project will combine established methods of assessing the reinforcing and subjective effects of drugs with standard sleep laboratory methology and performance testing to document levels of sleepiness and the alerting and behaviorally enhancing effects of methylphenidate. Four experiments exploring the modulating role of sleepiness-alertness for the reinforcing and subjective effects of methylphenidate are proposed for the five year grant period. Over the first two years a parametric analysis will be done of the interaction of time-in-bed (TIB) and its consequent sleepiness-alertness with doses of methylphenidate. During the third year the investigator will determine whether the level of sleepiness-alertness during one's initial experience with methylphenidate is important to its subsequent reinforcing and subjective effects. In year four, rather than exploring state differences in sleepinessalertness, trait-like differences in sleepiness-alertness will be the study focus. And finally during year five the interaction of behavioral demand placed on subjects and different levels of sleepiness-alertness will be the focus. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STEPPED PHARMACOTHERAPY FOR AGGRESSIVE YOUTH WITH ADHD Principal Investigator & Institution: Blader, Joseph C.; Long Island Jewish Medical Center 270-05 76Th Ave New Hyde Park, Ny 11040 Timing: Fiscal Year 2002; Project Start 19-SEP-2002; Project End 31-JUL-2003 Summary: (provided by applicant): The goal of this Mentored Patient-Oriented Research Career Development Award is to promote the candidate's progress toward an independent scientific career focused on treatment strategies for youth with severe disruptive disorders. Didactics and apprenticeship in interventions research skills in Year 1 will prepare the candidate to initiate a study of stepped pharmacotherapy for aggressive youth with attention-deficit/hyperactivity disorder (ADHD). This study, conducted in Years 2, 3 and part of 4, will a) provide the candidate with supervised experience in controlled treatment research, and b) address the critical need for rigorous trials to examine if combined medication approaches improve outcomes over monotherapy in this patient group. Childhood aggressive behavior most often develops alongside other disruptive disorder symptoms, which are highly comorbid with ADHD. Stimulant medication is first-line treatment for ADHD. Yet, for many children receiving stimulant treatment, aggressive behavior and affective instability remain significant impairments, leading clinicians to layer additional medications in efforts to diminish aggressive dyscontrol. However, the lack of evidence to support any medication combination strategy for these children is a great concern. The proposed study will first optimize open stimulant treatment for aggressive children 6- 12 years old with ADHD and a comorbid disruptive disorder. Children whose ADHD symptoms benefit from stimulant treatment but whose aggression persists will be randomly assigned to the mood stabilizer divalproex sodium or placebo during an 8-week double-blind trial while their stimulant treatment continues. All families will receive structured psychosocial treatment. The study will furnish preliminary data to enable a full-scale efficacy study, supported through an R01 to be submitted in Year 4. Further training activities throughout the award period will equip the candidate with research skills and provide experience in the areas of: a) intervention trial design and statistics, b) development and adoption in clinical settings of treatment strategies, including

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combined medication and psychosocial treatment, and c) assessment, including observational and laboratory approaches to outcome and mediator measurement. Mentors (N. Schooler, P. Jensen, V. Kafantaris) and consultants (including H. Abikoff, P. Frick, C. Grillon, J. Halperin, J. Kane, D. Kolko, S. Pliszka) will provide expert training and supervision. The proposed program will therefore culminate in the awardee's competence as a well-rounded clinical scientist focused on the complex treatment needs of youth with severe behavior disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STIMULANT DRUG TREATMENT OF ADHD, INATTENTIVE TYPE Principal Investigator & Institution: Solanto, Mary V.; Associate Professor; Psychiatry; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2003 Summary: (Applicant's abstract): The Inattentive subtype (IN) of AftentionDeficit/Hyperactivity Disorder was newly defined in DSM-IV (1994). Recent epidemiological studies suggest that IN is at least as common and as impairing academically and socially as the more commonly recognized Combined type (CB). However, little is known about the etiology, course and outcome, or treatment of the IN type. Notably, although stimulant drugs are commonly used clinically to treat the disorder, there have been no systematic studies of its efficacy in the IN subtype. Differences between the IN and CB subtypes in behavioral phenotype, as well as in gender ratio, age of onset, and comorbidity suggest there may be critical differences in neurobiology, which may have relevance for response to drug treatments. The lack of data concerning stimulant drug efficacy in the IN type thus constitutes an important issue from the perspective of public health and quality of care. The proposed research is responsive to the current RFA in that it will study the efficacy of an established treatment (stimulants) in a new patient population (the IN subtype). The proposed project will assess and compare the response of the IN and CB subtypes to placebo and low, medium, and high doses of immediate-release methylphenidate in a double-blind crossover trial with one week of exposure to each condition. Order of conditions will be counterbalanced. Twenty-four male and female children between the ages of 7 and 12 will be enrolled in each group. Outcome measures will include weekly ratings by parents and teachers on wellnormed measures of ADHD symptoms and functional impairment previously shown to be drug-sensitive (Conners and SKAMP scales). In addition, children will be examined and rated weekly by a child psychiatrist on a measure of Clinical Global Improvement. A second specific aim is to test a hypothesis, emerging from a review of the literature, of divergence between dose-response curves for effects on activity and attention. We predict that the dose that optimizes performance on ratings of hyperactivity-impulsivity will be lower than that which optimizes performance on ratings of attention. We will similarly examine whether differences in dose-response curves for specific functions extend to differences between subtypes in optimal dose. The final aim of the current study is to compare the IN and CB subtypes with respect to selected measures of neurocognitive function on placebo and in response to drug treatment. We predict that the IN subtype will perform more poorly on measures of spatial orienting and stimulus encoding, whereas the CB subtype will show greater deficits on measures of cognitive inhibitory control, and that both types of cognitive deficit will respond to drug treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SUBSTITUTED AMPHETAMINES: NO-DEPENDENT MECHANISMS Principal Investigator & Institution: Itzhak, Yossef; Professor; Biochem and Molecular Biology; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 15-MAR-2001; Project End 28-FEB-2006 Summary: Substituted amphetamines such as methamphetamine (METH) and 3,4methylenedioxymethamphetamine (MDMA; 'ecstasy') are synthetic drugs which are widely abused as psychostimulants. In recent years, there is a growing epidemic of METH and MDMA abuse not only in urban areas, but also in many rural parts of the US that were previously unexposed to psychostimulant abuse. Repeated use of METH and MDMA causes the development of severe addiction, aggression, violent and psychotic behavior, memory loss, and potential dopaminergic and serotonergic neurotoxicity. Currently, there are no pharmacotherapies against substituted amphetamines addiction and neurotoxicity. The long term goal of this project is to identify potential pharmacotherapies against amphetamines addiction. Our recent studies suggest that besides the role of dopamine in the action of psychostimulants, nitric oxide (NO) may play a pivotal role in mediating the effects of these drugs. In brain, NO is produced by the neuronal, inducible and endothelial nitric oxide synthase isoforms (nNOS, iNOS, eNOS) and has been implicated in neural transmission, plasticity and neurotoxicity. We hypothesize that nNOS has a major role in 1) the psychomotor stimulating effects, 2) the reinforcing properties and 3) the dopaminergic neurotoxicity produced by substituted amphetamines. Accordingly, the specific goals of this proposal are: 1) To investigate the effects of selective NOS inhibitors on the development of behavioral sensitization to substituted amphetamines, and the effects of the latter on nNOS and iNOS knockout (KO) mice. Potential alteration in the expression of the NOS protein levels in correlation with behavioral sensitization will be investigated. 2) To examine the role of NOS isoforms in the rewarding effects of amphetamines. The effect of NOS inhibitors on amphetamines-induced conditioned place preference (CPP) will be investigated, and the effects of the amphetamines on the acquisition of reward in NOS KO mice will be determined. 3) To investigate the role of nNOS and iNOS in dopaminergic and serotonergic neurotoxicity elicited by various amphetamine analogs, and whether alteration in the expression of NOS proteins is associated with neurotoxicity. The proposed studies will utilize pharmacologic, genetic, and molecular techniques to investigate the role of NO in amphetamine-induced behavioral sensitization, reward, and neurotoxicity. The combined behavioral, neurochemical and molecular approaches designed will lead to better understanding of the mechanisms underlying the effects of substituted amphetamines and the development of new therapeutics for the management of amphetamine addiction and toxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE NEURAL BASIS OF HYPERACTIVE WHEEL RUNNING IN MICE Principal Investigator & Institution: Rhodes, Justin S.; Zoology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-JUN-2002 Summary: The major goal of the proposed project is to investigate the neural basis of hyperactivity in a novel mouse model. Through artificial selection we have produced lines of mice that are internally motivated to run faster on running wheels than randombred controls, resulting in a 26-fold increase in wheel revolutions in a 24 hour period. Wheel-running in the hyperactive animals is composed of short bursts of activity separated by frequent short rests. High wheel-running mice are also more active in their

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home cages when deprived of wheels. The high-running mice may, therefore, be a good animal model for attention deficit hyperactivity disorder (ADHD). An association between deficiencies in dopamine transmission and ADHD has been suggested, and preliminary neuropharmacological results are consistent with the hypothesis that the hyperactive wheel running is caused by diminished dopaminergic function. To further explore the neural basis of genetic hyperactivity, I propose to examine whether: 1) apomorphine, and Ritalin(TM) attenuate wheel-running behavior in the high-running mice, 2) dopamine metabolism is slower in the high-running mice compared to controls at a given speed of running, and 3) the high-running mice contain fewer or smaller dopamine neurons in the ventral tegmental area. Together the proposed studies will help clarify the underlying neurochemistry and neuroanatomy of genetic hyperactivity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF NOREPINEPHRINE IN HYPERACTIVITY DISORDERS Principal Investigator & Institution: Bruno, Kristy J.; Neuroscience and Anatomy; Pennsylvania State Univ Hershey Med Ctr 500 University Drive Hershey, Pa 170332390 Timing: Fiscal Year 2002; Project Start 15-AUG-2002 Summary: (provided by applicant): Hyperactivity is associated with several human neurological disorders, such as attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS). The coloboma mouse represents a model of spontaneous hyperactivity. Coloboma mice have a heterozygous, semidominant deletion mutation on mouse chromosome 2 that spans the Snap gene and causes a 50% reduction in SNAP-25 (synaptosomal-associated protein). SNAP-25 is a presynaptic docking protein that regulates exocytotic neurotransmitter release. Therefore, it is likely that presynaptic mechanisms are responsible for the hyperactivity of coloboma mice. In fact, presynaptic dopamine (DA) regulation is thought to play a major role in hyperactivity disorders. Dopaminergic abnormalities in patients who have such disorders have been studied intensively for several decades. However, it is becoming increasingly clear that norepinephrine (NE) also plays a role. The majority of drugs efficacious in the treatment of ADHD modify both DA and NE neurotransmission. Indeed, administration of clonidine, an a2-adrenergic receptor agonist that inhibits NE release, ameliorates symptoms in some ADHD and TS patients. Studies of coloboma mice also implicate NE in hyperactive behavior. Coloboma mice have high levels of NE in the striatum and nucleus accumbens, brain regions implicated in movement and attention, respectively. Destruction of noradrenergic terminals with neurotoxin DSP-4 decreases locomotor activity of coloboma mice. Thus, coloboma mice may be extremely useful for determining the role of NE in the regulation of hyperactivity. We hypothesize that aberrant neurotransmission of NE contributes to the hyperactivity of these mice. The specific aims of this proposal are 1) to determine if noradrenergic challenge will ameliorate the coloboma phenotype, and 2) to determine the effect of drug challenge on neurotransmitter release. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: TRAFFICKING TRANSPORTERS

AND

REGULATION

OF

MONOAMINE

Principal Investigator & Institution: Melikian, Haley E.; Assistant Professor; Psychiatry; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2007

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Summary: (provided by applicant): Monoamine reuptake is a major mechanism for regulating extraneuronal monoamine levels and terminating synaptic transmission. Reuptake is mediated by plasma membrane transporters that are the primary targets for psychostimulants such as cocaine, methamphetamine and MDMA ("Ecstasy"), as well as for therapeutic drugs such as fluoxetine (Prozac), sibutramine (Meridia), bupropion (Wellbutrin) and methylphenidate (Ritalin). These agents block reuptake, resulting in elevated extraneuronal monoamine levels and enhanced postsynaptic responses. Recent evidence demonstrates that transporters are subject to acute regulation by cellular signaling pathways. Transporter regulation is coupled to dynamic changes in transporter cell-surface presentation, suggesting that membrane trafficking is fundamental to transporter homeostasis and regulation. However, the cellular and molecular mechanisms governing transporter regulation and trafficking are not yet defined. Given the pronounced effect pharmacological transporter blockade exerts on synaptic transmission, it is highly likely that transporter sequestration also has significant downstream effects on neuronal signaling. Moreover, modulation of transporter availability is certain to have significant impact on the efficacy of psychoactive drugs. The major goals of this project are to elucidate the cellular and molecular mechanisms mediating acute transporter regulation and trafficking. This investigative line will be pursued by testing the following hypotheses: (1) Transporters undergo constitutive internalization and recycling, and (2) transporter regulation is achieved by altering transporter trafficking kinetics. These hypotheses are based on strong preliminary data that the dopamine transporter (DAT) undergoes constitutive endosomal trafficking and that protein kinase C (PKC) activation directly alters DAT trafficking. The proposed hypotheses will be tested by directly analyzing basal and regulated transporter trafficking kinetics in cell lines. Intrinsic domains mediating basal and PKC-regulated DAT trafficking will be identified using molecular truncation and mutagenesis approaches. It is expected that these approaches will provide a clear and comprehensive picture of the mechanisms underlying acute transporter modulation. Such results are expected to have a significant impact on future therapeutic strategies aimed at monoamine-related drug abuse and mental illnesses. Moreover, the outcomes will greatly improve our understanding of the factors contributing to monoamine availability and signaling in the brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSCRIPTOMIC ANALYSIS OF THERAPEUTICS IN BRAIN TRAUMA Principal Investigator & Institution: Dixon, C Edward.; Associate Professor; Neurological Surgery; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): Recovery of cognitive function after traumatic brain injury (TBD is a dynamic process that likely revolves multiple neural systems. Several studies by our laboratory and others indicate that cognitive recovery can be enhanced by post injury activation of dopaminergic systems or exposure to an enriched environment. The effectors of such therapeutic activation are likely to involve simultaneous gene expression changes m numerous neural systems. The recent development of DNA microarrays has allowed scientists for the first time the ability to observe thousands of gene expression changes in parallel. While there are limitations, DNA microarrays provide a new systemic view to study brain injury and the treatments that stimulate and enhance recovery of function. Recently, we have evaluated a number

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of DA agonists that are clinically used off label, for their ability to enhance recovery of cognitive function in our experimental model of TBI, and found three to be beneficial: amantadine hydroehloride, bromoeriptine, and methylphenidate. While all are putative dopaminergic agonists, they have varying degrees of specificity to DA systems. We have also observed that bromoeriptine treatment, when initiated 24 hours after TBI, can attenuate hippocampal cell death. This suggests that DA agonists may have mechanisms of action beyond just being DA replacement therapies (e.g. cell survival effects). In support of this concept, we have new pilot microarray data indicating that, relative to a vehicle treatment, the DA agonist methylphenidate treatment can enhance the gene expression of DA receptors, alter injury-induced inflammatory responses, and apoptosis related gene expression. DNA microarrays are well suited to investigate the effects of DA agonists on multiple pathways. The overall goal of the project is to determine common genes that are changed by these therapies and whether these gene expression changes can be further enhanced by the addition of enriched environment therapy. Tiffs exploratory R21 application (in response to RFA#HD-02-023) will obtain the preliminary information needed for a larger-scale R01 study to increase the number of cases, refine and increase the number of genes analyzed, and to more comprehensively study those genes whose expression are related to recovery of function after TBI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSLATIONAL IMAGING OF METHYLPHENIDATE EXPOSURE Principal Investigator & Institution: Andersen, Susan L.; Assistant Professor; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2005 Summary: (provided by applicant): In this I/START application from a junior investigator, we propose to use magnetic resonance imaging (MRI) in animals to test the hypothesis that early exposure to methylphenidate (MPH) alters neurobiological development. Stimulants, such as MPH, are the treatment of choice for children with Attention Deficit/Hyperactivity Disorder (ADHD), which is one of the most prevalent childhood disorders and affects an average of 6% of the population. Even though stimulants have been used to treat ADHD since the 1950' s, we know very little about the long-term enduring effects of pharmacotherapy on the developing brain. Research on this topic has become even more imperative, as children are being treated more aggressively and earlier (as young as 2 years of age) with pharmacotherapy for ADHD. From the adult preclinical literature, we know that exposure to stimulants produces enduring changes in the underlying neurobiology and neuroanatomy of the reward systems. In our animal model of childhood exposure to stimulants, we have shown that pre-pubertal exposure to the stimulant MPH produces different - even opposite enduring changes than post-pubertal exposure (Andersen et al., 2002). This increase in the aversive properties of cocaine following pre-pubertal MPH exposure parallels clinical observations of reduced substance use disorder in adolescents who had received pharmacotherapy for their ADHD (Biederman et al., 1999). Funding from the I/START initiative will enable the PI to expand her basic research interests as a developmental psychopharmacologist to the more clinically relevant domain of neuroimaging. Preliminary MRI data will be collected and analyzed in animals that have been exposed to MPH pre-pubertally for the "proof of concept" that early medication produces enduring and specific changes in brain activity. These important pilot data will then serve as the basis for an R01 application that will determine the nature and mechanism by which early drug exposure imprints on brain activity in rats and humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TREATMENT OF ADHD IN CHILDREN WITH TOURETTE'S SYNDROME Principal Investigator & Institution: Como, Peter; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TREATMENT OF ADHD IN PEDIATRIC PATIENTS WITH EPILEPSY Principal Investigator & Institution: Gonzalez-Heydrich, Joseph M.; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): Epilepsy is highly prevalent and associated with increased risk for psychiatric disorders. Patients with chronic recurrent seizures are excluded from most pharmacological trials establishing standard treatments in pediatric psychiatry. Finding safe and effective treatments for psychiatric disorders in pediatric patients with epilepsy is of pressing public health importance. The purpose of this Mentored Patient-Oriented Research Development Award (K23) is for the candidate to become an independent clinical researcher in the psychopharmacologic treatment of psychiatric disorders in children and adolescents facing epilepsy. The proposal focuses on patients with comorbid ADHD and epilepsy. The project will be conducted at Children's Hospital Boston (CHB), which serves a large population of patients with epilepsy. Joseph Biederman, MD, with expertise in clinical trials in pediatric psychopharmacology will serve as the primary mentor. William R. Beardslee, MD, Chairman of Psychiatry at CHB will serve as the sponsor. Blaise Bourgeois, MD, Chairman of the Division of Epilepsy and Clinical Neurophysiology at CHB is the principal epilepsy consultant. Research plan: The aims are: 1) To perform a randomized placcbo controlled crossover trial of extended release methylphenidate (Concerta) in pediatric patients with comorbid ADHD and epilepsy; 2) To establish methods of assuring the safety of children with epilepsy in psychopharmacological clinical trials. Career development plan: The training will emphasize skills necessary for conducting randomized controlled clinical trials in youth with epilepsy comorbid with psychiatric disorders and to explore the neurobiological mechanisms underlying their increased risk for psychopathology. Didactic work in intervention research design, statistics, developmental psychopathology, and assessment methodologies for psychopathology and treatment response will complement supervision by the program consultants. The long-term goals of the candidate are to develop and evaluate treatments for children with comorbid psychiatric disorders and epilepsy as well as to investigate neurobiological correlates of the risk and response to treatment of these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DYNAMICS

VOLTAMMETRIC

ANALYSIS

OF

STRIATAL

DOPAMINE

Principal Investigator & Institution: Zhou, Fu-Ming; Neuroscience; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2004; Project Start 03-MAR-2004; Project End 31-DEC-2006 Summary: (provided by applicant): The dopamine (DA) system is intimately involved in neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity

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disorder (ADHD). Antipsychotics are often D2-like DA receptor blockers that compete with endogenous DA while ADHD is commonly treated with methylphenidate that inhibits DA transporter (DAT). Among the brain areas, the striatum has the densest DA innervation and the heaviest expression of DA receptors and DAT, indicating the importance of striatal DA signaling in brain functions. The striatal basal extracellular DA concentration ([DA]ext) is often estimated to he static and only 5-10 nM, which may increase by several fold upon external stimulation. Other transmitters, such as glutamate, can be spontaneously released from synaptic vesicles (quantal release), resulting in dynamic transmitter profiles with peaks up to I mM. We have evidence supporting the hypothesis that in the striatum DA can he spontaneously released in a similar quantal fashion, giving rise to a dynamic DA profile with high [DA]ext spikes. Our preliminary data also suggest that these spontaneous vesicular DA events are enhanced by antipsychotics and methylphenidate at clinically relevant low concentrations. Selective serotonin reuptake inhibitors (SSRIs) are an effective treatment for depression. Our data support the following hypothesis: during SSRI type antidepressant treatment, serotonin (5-HT) may be reuptaken by DA transporter (DAT) and accumulate in DA terminals in the striatum, a major DA projection area participating in reward/motivation. More importantly, this ectopically stored 5-HT may be co-released with DA, thus inducing a spatially and temporally synchronized DA and 5-HT co-signaling in the striatum. Following these working hypotheses, our goals are to use fast cyclic voltammetry at carbon fiber microelectrodes to investigate the striatal DA dynamics, its modulation and its interaction with the 5-HT system. The results will provide important new information about the dynamic nature of the striatal [DA]ext and its regulation by therapeutic agents of neuropsychiatric disorders. 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 “methylphenidate” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for methylphenidate in the PubMed Central database: •

3 4

How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis. by Schachter HM, Pham B, King J, Langford S, Moher D.; 2001 Nov 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=81663

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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Inhibition by Methylphenidate of Transport Across the Yeast Cell Membrane. by Spoerl E, Doyle RJ.; 1968 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=252368

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Prescription of methylphenidate to children and youth, 1990 --1996. by Miller AR, Lalonde CE, McGrail KM, Armstrong RW.; 2001 Nov 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=81664

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Selective effects of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study. by Vaidya CJ, Austin G, Kirkorian G, Ridlehuber HW, Desmond JE, Glover GH, Gabrieli JD.; 1998 Nov 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24401

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Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: A double blind and randomized trial [ISRCTN64132371]. by Akhondzadeh S, Mohammadi MR, Khademi M.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=400741

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

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A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the Comacs Study). Author(s): Swanson JM, Wigal SB, Wigal T, Sonuga-Barke E, Greenhill LL, Biederman J, Kollins S, Nguyen AS, DeCory HH, Hirshe Dirksen SJ, Hatch SJ; COMACS Study Group. Source: Pediatrics. 2004 March; 113(3 Pt 1): E206-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14993578

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

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A dose-response study of OROS methylphenidate in children with attentiondeficit/hyperactivity disorder. Author(s): Stein MA, Sarampote CS, Waldman ID, Robb AS, Conlon C, Pearl PL, Black DO, Seymour KE, Newcorn JH. Source: Pediatrics. 2003 November; 112(5): E404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14595084

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A double-blind, placebo-controlled study of modified-release methylphenidate in children with attention-deficit/hyperactivity disorder. Author(s): Greenhill LL, Findling RL, Swanson JM; ADHD Study Group. Source: Pediatrics. 2002 March; 109(3): E39. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11875167

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A positron emission tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predicting treatment response. Author(s): Schweitzer JB, Lee DO, Hanford RB, Tagamets MA, Hoffman JM, Grafton ST, Kilts CD. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2003 May; 28(5): 967-73. Epub 2003 March 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12700698

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A randomized, double-blind, crossover study of methylphenidate and lithium in adults with attention-deficit/hyperactivity disorder: preliminary findings. Author(s): Dorrego MF, Canevaro L, Kuzis G, Sabe L, Starkstein SE. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2002 Summer; 14(3): 289-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12154153

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Abuse and toxicity of methylphenidate. Author(s): Klein-Schwartz W. Source: Current Opinion in Pediatrics. 2002 April; 14(2): 219-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11981294

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Academic achievement and emotional status of children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment. Author(s): Hechtman L, Abikoff H, Klein RG, Weiss G, Respitz C, Kouri J, Blum C, Greenfield B, Etcovitch J, Fleiss K, Pollack S. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 July; 43(7): 812-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15213582

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ADHD treatment with once-daily OROS methylphenidate: interim 12-month results from a long-term open-label study. Author(s): Wilens T, Pelham W, Stein M, Conners CK, Abikoff H, Atkins M, August G, Greenhill L, McBurnett K, Palumbo D, Swanson J, Wolraich M. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2003 April; 42(4): 424-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12649629

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Advances in the pharmacotherapy of attention-deficit-hyperactivity disorder: focus on methylphenidate formulations. Author(s): Markowitz JS, Straughn AB, Patrick KS. Source: Pharmacotherapy. 2003 October; 23(10): 1281-99. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14594346

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An enzyme-linked immunosorbent assay (ELISA) for methylphenidate (Ritalin ) in urine. Author(s): Lewis MG, Lewis JG, Elder PA, Moore GA. Source: Journal of Analytical Toxicology. 2003 September; 27(6): 342-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14516486

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An open study of methylphenidate in bipolar depression. Author(s): El-Mallakh RS. Source: Bipolar Disorders. 2000 March; 2(1): 56-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11254021

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An open-label pilot study of methylphenidate in the treatment of cocaine dependent patients with adult attention deficit/hyperactivity disorder. Author(s): Somoza EC, Winhusen TM, Bridge TP, Rotrosen JP, Vanderburg DG, Harrer JM, Mezinskis JP, Montgomery MA, Ciraulo DA, Wulsin LR, Barrett JA. Source: Journal of Addictive Diseases : the Official Journal of the Asam, American Society of Addiction Medicine. 2004; 23(1): 77-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15077842

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Anxiety and depression symptoms and response to methylphenidate in children with attention-deficit hyperactivity disorder and tic disorder. Author(s): Gadow KD, Nolan EE, Sverd J, Sprafkin J, Schwartz J. Source: Journal of Clinical Psychopharmacology. 2002 June; 22(3): 267-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12006897

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Assessing the abuse potential of methylphenidate in nonhuman and human subjects: a review. Author(s): Kollins SH, MacDonald EK, Rush CR. Source: Pharmacology, Biochemistry, and Behavior. 2001 March; 68(3): 611-27. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11325419

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Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD. Author(s): Kirley A, Lowe N, Hawi Z, Mullins C, Daly G, Waldman I, McCarron M, O'Donnell D, Fitzgerald M, Gill M. Source: American Journal of Medical Genetics. 2003 August 15; 121B(1): 50-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12898575

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Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. Author(s): Kratochvil CJ, Heiligenstein JH, Dittmann R, Spencer TJ, Biederman J, Wernicke J, Newcorn JH, Casat C, Milton D, Michelson D. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2002 July; 41(7): 776-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12108801

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Attention deficit/hyperactivity disorder and methylphenidate. A review of height/weight, cardiovascular, and somatic complaint side effects. Author(s): Rapport MD, Moffitt C. Source: Clinical Psychology Review. 2002 November; 22(8): 1107-31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12436807

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Attention-Deficit/Hyperactivity Disorder and methylphenidate: a dose-response analysis and parent-child comparison of somatic complaints. Author(s): Rapport MD, Randall R, Moffitt C. Source: J Atten Disord. 2002 June; 6(1): 15-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12045757

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Attention-deficit/hyperactivity disorder: cognitive evoked potential (P300) topography predicts treatment response to methylphenidate. Author(s): Sangal RB, Sangal JM. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2004 January; 115(1): 188-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14706487

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Behavioral and biochemical effects of methylphenidate in schizophrenic and nonschizophrenic patients. Author(s): Sharma RP, Javaid JI, Pandey GN, Janicak PG, Davis JM. Source: Biological Psychiatry. 1991 September 1; 30(5): 459-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1657221

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Behavioral and stimulant treatment of hyperactive children: a therapy study with methylphenidate probes in a within-subject design. Author(s): Pelham WE, Schnedler RW, Bologna NC, Contreras JA. Source: J Appl Behav Anal. 1980 Summer; 13(2): 221-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7380749

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Behavioral effects of low-dose methylphenidate in childhood attention deficit disorder: implications for a mechanism of stimulant drug action. Author(s): Solanto MV. Source: J Am Acad Child Psychiatry. 1986 January; 25(1): 96-101. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3950273

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Behavioral pharmacological similarities between methylphenidate and cocaine in cocaine abusers. Author(s): Rush CR, Baker RW. Source: Experimental and Clinical Psychopharmacology. 2001 February; 9(1): 59-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11519636

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Behavioral response to methylphenidate and treatment outcome in first episode schizophrenia. Author(s): Jody D, Lieberman JA, Geisler S, Szymanski S, Alvir JM. Source: Psychopharmacology Bulletin. 1990; 26(2): 224-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2236460

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Behavioral, situational, and temporal effects of treatment of ADHD with methylphenidate. Author(s): Schachar RJ, Tannock R, Cunningham C, Corkum PV. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1997 June; 36(6): 754-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9183129

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Bioavailability of modified-release methylphenidate: influence of high-fat breakfast when administered intact and when capsule content sprinkled on applesauce. Author(s): Lee L, Kepple J, Wang Y, Freestone S, Bakhtiar R, Wang Y, Hossain M. Source: Biopharmaceutics & Drug Disposition. 2003 September; 24(6): 233-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12973820

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Biochemical differentiation of amphetamine vs methylphenidate and nomifensine in rats. Author(s): Braestrup C. Source: The Journal of Pharmacy and Pharmacology. 1977 August; 29(8): 463-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=19594

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Bioequivalence of methylphenidate immediate-release tablets using a replicated study design to characterize intrasubject variability. Author(s): Meyer MC, Straughn AB, Jarvi EJ, Patrick KS, Pelsor FR, Williams RL, Patnaik R, Chen ML, Shah VP. Source: Pharmaceutical Research. 2000 April; 17(4): 381-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10870979

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Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of "high". Author(s): Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS, Dewey SL, Hitzemann R, Gifford AN, Pappas NR. Source: The Journal of Pharmacology and Experimental Therapeutics. 1999 January; 288(1): 14-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9862747

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Blood pressure and pulse changes in hyperactive children treated with imipramine and methylphenidate. Author(s): Greenberg LM, Yellin AM. Source: The American Journal of Psychiatry. 1975 December; 132(12): 1325-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1106218

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Bone mineral density and turnover in children with attention-deficit hyperactivity disorder receiving methylphenidate. Author(s): Lahat E, Weiss M, Ben-Shlomo A, Evans S, Bistritzer T. Source: Journal of Child Neurology. 2000 July; 15(7): 436-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10921512

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Brief report: response to methylphenidate in two children with Williams syndrome. Author(s): Power TJ, Blum NJ, Jones SM, Kaplan PE. Source: Journal of Autism and Developmental Disorders. 1997 February; 27(1): 79-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9018583

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Bupropion SR vs. methylphenidate vs. placebo for attention deficit hyperactivity disorder in adults. Author(s): Kuperman S, Perry PJ, Gaffney GR, Lund BC, Bever-Stille KA, Arndt S, Holman TL, Moser DJ, Paulsen JS. Source: Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists. 2001 September; 13(3): 129-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11791949

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Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder. Author(s): Barrickman LL, Perry PJ, Allen AJ, Kuperman S, Arndt SV, Herrmann KJ, Schumacher E. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1995 May; 34(5): 649-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7775360

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Bupropion-methylphenidate combination and grand mal seizures. Author(s): Ickowicz A. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2002 October; 47(8): 790-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12420664

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Can methylphenidate facilitate sleep in children with attention deficit hyperactivity disorder? Author(s): Jerome L. Source: Journal of Child and Adolescent Psychopharmacology. 2001 Spring; 11(1): 109. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11322740

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Capillary gas chromatographic-mass spectrometric analysis of plasma methylphenidate. Author(s): Patrick KS, Jarvi EJ. Source: Journal of Chromatography. 1990 June 8; 528(1): 214-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2200800

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Carbamazepine and methylphenidate. Author(s): Gross-Tsur V. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1999 June; 38(6): 637. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10361775

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Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma. Author(s): Volkow ND, Wang GJ, Fowler JS, Molina PE, Logan J, Gatley SJ, Gifford A, Ding YS, Wong C, Pappas NR, Zhu W, Swanson JM. Source: Psychopharmacology. 2003 March; 166(3): 264-70. Epub 2003 February 13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12589522

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Cerebral arteritis following methylphenidate use. Author(s): Schteinschnaider A, Plaghos LL, Garbugino S, Riveros D, Lazarowski A, Intruvini S, Massaro M. Source: Journal of Child Neurology. 2000 April; 15(4): 265-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10805196

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Changes of the brain electrical fields during the continuous performance test in attention-deficit hyperactivity disorder-boys depending on methylphenidate medication. Author(s): Zillessen KE, Scheuerpflug P, Fallgatter AJ, Strik WK, Warnke A. Source: Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. 2001 July; 112(7): 1166-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11516728

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Characterization of methylphenidate exposures reported to a regional poison control center. Author(s): White SR, Yadao CM. Source: Archives of Pediatrics & Adolescent Medicine. 2000 December; 154(12): 1199203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11115302

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Children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment: impact on parental practices. Author(s): Hechtman L, Abikoff H, Klein RG, Greenfield B, Etcovitch J, Cousins L, Fleiss K, Weiss M, Pollack S. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 July; 43(7): 830-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15213584

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Clinical effects of a controlled trial of methylphenidate on adolescents with attention deficit disorder. Author(s): Klorman R, Brumaghim JT, Fitzpatrick PA, Borgstedt AD. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1990 September; 29(5): 702-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2228922

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Clinical effects of methylphenidate and thioridazine in intellectually subaverage children. Author(s): Aman MG, Marks RE, Turbott SH, Wilsher CP, Merry SN. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1991 March; 30(2): 246-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2016229

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Clonidine and methylphenidate. Author(s): Dech B. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1999 December; 38(12): 1469-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10596241

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Coadministration of phenelzine and methylphenidate for treatment-resistant depression. Author(s): Shelton Clauson A, Elliott ES, Watson BD, Treacy J. Source: The Annals of Pharmacotherapy. 2004 March; 38(3): 508. Epub 2004 January 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14970373

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Combined treatment with methylphenidate and citalopram for accelerated response in the elderly: an open trial. Author(s): Lavretsky H, Kim MD, Kumar A, Reynolds CF 3rd. Source: The Journal of Clinical Psychiatry. 2003 December; 64(12): 1410-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14728100

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Comparative effects of methylphenidate on ADD girls and ADD boys. Author(s): Pelham WE Jr, Walker JL, Sturges J, Hoza J. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1989 September; 28(5): 773-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2676966

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Comparative effects of methylphenidate on attention-deficit hyperactivity disorder with and without aggressive/noncompliant features. Author(s): Klorman R, Brumaghim JT, Salzman LF, Strauss J, Borgstedt AD, McBride MC, Loeb S. Source: Psychopharmacology Bulletin. 1989; 25(1): 109-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2772109

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Comparative efficacy of Adderall and methylphenidate in attentiondeficit/hyperactivity disorder: a meta-analysis. Author(s): Faraone SV, Biederman J, Roe C. Source: Journal of Clinical Psychopharmacology. 2002 October; 22(5): 468-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12352269

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Comparative efficacy of two once daily methylphenidate formulations (Ritalin LA and Concerta) and placebo in children with attention deficit hyperactivity disorder across the school day. Author(s): Lopez F, Silva R, Pestreich L, Muniz R. Source: Paediatric Drugs. 2003; 5(8): 545-55. Erratum In: Paediatr Drugs. 2003; 5(10): 661. Paediatr Drugs. 2003; 5(12): 832. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12895137

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Comparing the abuse potential of methylphenidate versus other stimulants: a review of available evidence and relevance to the ADHD patient. Author(s): Kollins SH. Source: The Journal of Clinical Psychiatry. 2003; 64 Suppl 11: 14-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14529325

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Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users. Author(s): Heil SH, Holmes HW, Bickel WK, Higgins ST, Badger GJ, Laws HF, Faries DE. Source: Drug and Alcohol Dependence. 2002 July 1; 67(2): 149-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12095664

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Correlations between motor persistence and plasma levels in methylphenidatetreated boys with ADHD. Author(s): Greenhill LL, Perel JM, Rudolph G, Feldman B, Curran S, Puig-Antich J, Gardner R. Source: The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (Cinp). 2001 June; 4(2): 207-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11466170

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Daily methylphenidate use slows the growth of children: a community based study. Author(s): Lisska MC, Rivkees SA. Source: J Pediatr Endocrinol Metab. 2003 June; 16(5): 711-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12880120

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Decreased level of EEG-vigilance in acute mania as a possible predictor for a rapid effect of methylphenidate: a case study. Author(s): Bschor T, Muller-Oerlinghausen B, Ulrich G. Source: Clin Electroencephalogr. 2001 January; 32(1): 36-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11202141

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Deficient intracortical inhibition in drug-naive children with attention-deficit hyperactivity disorder is enhanced by methylphenidate. Author(s): Moll GH, Heinrich H, Trott G, Wirth S, Rothenberger A. Source: Neuroscience Letters. 2000 April 21; 284(1-2): 121-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10771177

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Depression and dysphoria effects on the interpersonal perception of negative and positive moods and caring relationships: effects of antidepressants, amphetamine, and methylphenidate. Author(s): Janowsky DS. Source: Current Psychiatry Reports. 2003 December; 5(6): 451-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609500

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Design and rationale of controlled study of long-term methylphenidate and multimodal psychosocial treatment in children with ADHD. Author(s): Klein RG, Abikoff H, Hechtman L, Weiss G. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 July; 43(7): 792-801. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15213580

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Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies. Author(s): Swanson J, Gupta S, Lam A, Shoulson I, Lerner M, Modi N, Lindemulder E, Wigal S. Source: Archives of General Psychiatry. 2003 February; 60(2): 204-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12578439

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Differential effects of methylphenidate and dextroamphetamine on the motor activity level of hyperactive children. Author(s): Borcherding BG, Keysor CS, Cooper TB, Rapoport JL. Source: Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 1989 December; 2(4): 255-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2692588

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Differential effects of methylphenidate on attentional functions in children with attention-deficit/hyperactivity disorder. Author(s): Konrad K, Gunther T, Hanisch C, Herpertz-Dahlmann B. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 February; 43(2): 191-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14726726

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Discriminative stimulus effects of d-amphetamine, methylphenidate, and diazepam in humans. Author(s): Heishman SJ, Henningfield JE. Source: Psychopharmacology. 1991; 103(4): 436-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2062984

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Diurnal variation in methylphenidate stimulant response in major depression. Author(s): Swift RM. Source: Journal of Clinical Psychopharmacology. 1989 December; 9(6): 452. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2592594

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Do typical clinical doses of methylphenidate cause tics in children treated for attention-deficit hyperactivity disorder? Author(s): Killeen MR. Source: J Child Fam Nurs. 2000 January-February; 3(1): 46-8. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11022478

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Does extended medication with amphetamine or methylphenidate reduce growth in hyperactive children? Author(s): Sund AM, Zeiner P. Source: Nordic Journal of Psychiatry. 2002; 56(1): 53-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11869467

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Does increasing methylphenidate dose aid symptom control in ADHD? Author(s): Ibay AD, Bascelli LM, Graves RS, Hill J. Source: The Journal of Family Practice. 2003 May; 52(5): 400, 403. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12737774

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Does methylphenidate constrict cognitive functioning? Author(s): Solanto MV, Wender EH. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1989 November; 28(6): 897-902. Erratum In: J Am Acad Child Adolesc Psychiatry 1990 January; 29(1): 156. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2808260

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Dopamine transporter gene and response to methylphenidate in attentiondeficit/hyperactivity disorder. Author(s): Roman T, Szobot C, Martins S, Biederman J, Rohde LA, Hutz MH. Source: Pharmacogenetics. 2002 August; 12(6): 497-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172219

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Dopamine transporter gene, response to methylphenidate and cerebral blood flow in attention-deficit/hyperactivity disorder: a pilot study. Author(s): Rohde LA, Roman T, Szobot C, Cunha RD, Hutz MH, Biederman J. Source: Synapse (New York, N.Y.). 2003 May; 48(2): 87-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12619042

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Dopaminergic ventral tegmental neurons modulated by methylphenidate. Author(s): Prieto-Gomez B, Benitez MT, Vazquez-Alvarez AM, Yang PB, Reyes Vazquez C, Dafny N. Source: Life Sciences. 2004 February 13; 74(13): 1581-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14738903

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Dose-proportional and stereospecific pharmacokinetics of methylphenidate delivered using an osmotic, controlled-release oral delivery system. Author(s): Modi NB, Wang B, Noveck RJ, Gupta SK. Source: Journal of Clinical Pharmacology. 2000 October; 40(10): 1141-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11028253

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Dose-response effects of methylphenidate on ecologically valid measures of academic performance and classroom behavior in adolescents with ADHD. Author(s): Evans SW, Pelham WE, Smith BH, Bukstein O, Gnagy EM, Greiner AR, Altenderfer L, Baron-Myak C. Source: Experimental and Clinical Psychopharmacology. 2001 May; 9(2): 163-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11518092

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Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Author(s): Schubiner H, Saules KK, Arfken CL, Johanson CE, Schuster CR, Lockhart N, Edwards A, Donlin J, Pihlgren E. Source: Experimental and Clinical Psychopharmacology. 2002 August; 10(3): 286-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12233989

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Effect of methylphenidate on time perception in children with attentiondeficit/hyperactivity disorder. Author(s): Baldwin RL, Chelonis JJ, Flake RA, Edwards MC, Feild CR, Meaux JB, Paule MG. Source: Experimental and Clinical Psychopharmacology. 2004 February; 12(1): 57-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14769100

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Effect of methylphenidate on vital signs and adverse effects in adults with traumatic brain injury. Author(s): Alban JP, Hopson MM, Ly V, Whyte J. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. 2004 February; 83(2): 131-7; Quiz 138-41, 167. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758299

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Effects of chronic nicotine and methylphenidate in adults with attention deficit/hyperactivity disorder. Author(s): Levin ED, Conners CK, Silva D, Canu W, March J. Source: Experimental and Clinical Psychopharmacology. 2001 February; 9(1): 83-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11519638

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Effects of food on the pharmacokinetics of methylphenidate. Author(s): Midha KK, McKay G, Rawson MJ, Korchinski ED, Hubbard JW. Source: Pharmaceutical Research. 2001 August; 18(8): 1185-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11587491

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Effects of methylphenidate (Ritalin) on auditory performance in children with attention and auditory processing disorders. Author(s): Tillery KL, Katz J, Keller WD. Source: Journal of Speech, Language, and Hearing Research : Jslhr. 2000 August; 43(4): 893-901. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11386476

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Effects of methylphenidate on attention deficits after traumatic brain injury: a multidimensional, randomized, controlled trial. Author(s): Whyte J, Hart T, Vaccaro M, Grieb-Neff P, Risser A, Polansky M, Coslett HB. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. 2004 June; 83(6): 401-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15166683

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Effects of methylphenidate on impulsive choice in adult humans. Author(s): Pietras CJ, Cherek DR, Lane SD, Tcheremissine OV, Steinberg JL. Source: Psychopharmacology. 2003 December; 170(4): 390-8. Epub 2003 September 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13680085

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Effects of methylphenidate on kinematic aspects of handwriting in hyperactive boys. Author(s): Tucha O, Lange KW. Source: Journal of Abnormal Child Psychology. 2001 August; 29(4): 351-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11523840

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Effects of methylphenidate on sensitivity to reinforcement in children diagnosed with attention deficit hyperactivity disorder: an application of the matching law. Author(s): Murray LK, Kollins SH. Source: J Appl Behav Anal. 2000 Winter; 33(4): 573-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11214032

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Effects of methylphenidate treatment in children with mental retardation and ADHD: individual variation in medication response. Author(s): Pearson DA, Lane DM, Santos CW, Casat CD, Jerger SW, Loveland KA, Faria LP, Mansour R, Henderson JA, Payne CD, Roache JD, Lachar D, Cleveland LA. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 June; 43(6): 686-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15167085

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Effects of methylphenidate, desipramine, and L-dopa on attention and inhibition in children with Attention Deficit Hyperactivity Disorder. Author(s): Overtoom CC, Verbaten MN, Kemner C, Kenemans JL, van Engeland H, Buitelaar JK, van der Molen MW, van der Gugten J, Westenberg H, Maes RA, Koelega HS. Source: Behavioural Brain Research. 2003 October 17; 145(1-2): 7-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14529800

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Effects of once-daily osmotic-release methylphenidate on blood pressure and heart rate in children with attention-deficit/hyperactivity disorder: results from a one-year follow-up study. Author(s): Wilens TE, Biederman J, Lerner M; Concerta Study Group. Source: Journal of Clinical Psychopharmacology. 2004 February; 24(1): 36-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709945

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Efficacy and safety of Ritalin LA, a new, once daily, extended-release dosage form of methylphenidate, in children with attention deficit hyperactivity disorder. Author(s): Biederman J, Quinn D, Weiss M, Markabi S, Weidenman M, Edson K, Karlsson G, Pohlmann H, Wigal S. Source: Paediatric Drugs. 2003; 5(12): 833-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14658924

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Efficacy of Adderall and methylphenidate in attention deficit hyperactivity disorder: a reanalysis using drug-placebo and drug-drug response curve methodology. Author(s): Faraone SV, Pliszka SR, Olvera RL, Skolnik R, Biederman J. Source: Journal of Child and Adolescent Psychopharmacology. 2001 Summer; 11(2): 17180. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11436957

84

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Efficacy of theophylline compared to methylphenidate for the treatment of attentiondeficit hyperactivity disorder in children and adolescents: a pilot double-blind randomized trial. Author(s): Mohammadi MR, Kashani L, Akhondzadeh S, Izadian ES, Ohadinia S. Source: Journal of Clinical Pharmacy and Therapeutics. 2004 April; 29(2): 139-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15068402

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Empirical, ethical, and political perspectives on the use of methylphenidate. Author(s): McCubbin M, Cohen D. Source: Ethical Hum Sci Serv. 1999 Spring; 1(1): 81-101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15278982

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Evidence and belief in attention deficit hyperactivity disorder. Reintroduction of methylphenidate in Italy needs careful monitoring. Author(s): Bonati M, Impicciatore P, Pandolfini C. Source: Bmj (Clinical Research Ed.). 2001 March 3; 322(7285): 556. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11263458

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Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Author(s): Volkow ND, Wang GJ, Fowler JS, Telang F, Maynard L, Logan J, Gatley SJ, Pappas N, Wong C, Vaska P, Zhu W, Swanson JM. Source: The American Journal of Psychiatry. 2004 July; 161(7): 1173-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15229048

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Explosive outbursts associated with methylphenidate. Author(s): Adrian N. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2001 June; 40(6): 618-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11392335

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Family abuse of methylphenidate. Author(s): Fulton AI, Yates WR. Source: American Family Physician. 1988 August; 38(2): 143-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3407585

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Fatal pulmonary hypertension from intravenous injection of methylphenidate (Ritalin) tablets. Author(s): Lewman LV. Source: Human Pathology. 1972 March; 3(1): 67-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5060680

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Fatality resulting from methylphenidate overdose. Author(s): Levine B, Caplan YH, Kauffman G. Source: Journal of Analytical Toxicology. 1986 September-October; 10(5): 209-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3773482

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Fenfluramine and methylphenidate in children with mental retardation and ADHD: clinical and side effects. Author(s): Aman MG, Kern RA, McGhee DE, Arnold LE. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1993 July; 32(4): 851-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8340309

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Fenfluramine and methylphenidate in children with mental retardation and attention deficit hyperactivity disorder: laboratory effects. Author(s): Aman MG, Kern RA, McGhee DE, Arnold LE. Source: Journal of Autism and Developmental Disorders. 1993 September; 23(3): 491506. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8226583

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Fenfluramine and methylphenidate in children with mental retardation and borderline IQ: clinical effects. Author(s): Aman MG, Kern RA, Osborne P, Tumuluru R, Rojahn J, del Medico V. Source: Am J Ment Retard. 1997 March; 101(5): 521-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9083608

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Fixed drug eruption of the scrotum due to methylphenidate. Author(s): Cohen HA, Ashkenazi A, Nussinovitch M, Gross S, Frydman M. Source: The Annals of Pharmacotherapy. 1992 November; 26(11): 1378-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1477441

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Flurazepam effects on methylphenidate-induced stereotyped behavior. Author(s): Risch C, Kripke D, Janowsky D. Source: Psychopharmacology. 1980; 70(1): 79-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6775340

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Folie a deux with methylphenidate psychosis. Author(s): Spensley J. Source: The Journal of Nervous and Mental Disease. 1972 October; 155(4): 288-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5073360

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Forty years of methylphenidate treatment in Attention-Deficit/ Hyperactivity Disorder. Author(s): Conners CK. Source: J Atten Disord. 2002; 6 Suppl 1: S17-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12685516

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Further analysis of the separate and interactive effects of methylphenidate and common classroom contingencies. Author(s): Northup J, Fusilier I, Swanson V, Huete J, Bruce T, Freeland J, Gulley V, Edwards S. Source: J Appl Behav Anal. 1999 Spring; 32(1): 35-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10201102

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Gabapentin and methylphenidate treatment of a preadolescent with attention deficit hyperactivity disorder and bipolar disorder. Author(s): Hamrin V, Bailey K. Source: Journal of Child and Adolescent Psychopharmacology. 2001 Fall; 11(3): 301-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11642481

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Gas chromatographic/mass spectrometric analysis of methylphenidate (ritalin) in serum. Author(s): Chan YM, Soldin SJ, Swanson JM, Deber CM, Thiessen JJ, Macleod S. Source: Clinical Biochemistry. 1980 December; 13(6): 266-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7214694

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Gas chromatographic-mass spectrometric analysis of methylphenidate and phydroxymethylphenidate using deuterated internal standards. Author(s): Patrick KS, Ellington KR, Breese GR, Kilts CD. Source: Journal of Chromatography. 1985 October 11; 343(2): 329-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4066874

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Gas-chromatographic quantification of methylphenidate in plasma with use of solidphase extraction and nitrogen-sensitive detection. Author(s): Potts BD, Martin CA, Vore M. Source: Clinical Chemistry. 1984 August; 30(8): 1374-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6744589

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Gas-liquid chromatographic procedure for measurement of methylphenidate hydrochloride and its metabolite, ritalinic acid, in urine. Author(s): Wells R, Hammond KB, Rodgerson DO. Source: Clinical Chemistry. 1974 April; 20(4): 440-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4818196

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Gilles de la Tourette's syndrome following methylphenidate administration. Author(s): Golden GS. Source: Developmental Medicine and Child Neurology. 1974 February; 16(1): 76-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4521612

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Gilles de la Tourette's syndrome. Familial occurrence and precipitation by methylphenidate therapy. Author(s): Pollack MA, Cohen NL, Friedhoff AJ. Source: Archives of Neurology. 1977 October; 34(10): 630-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=269683

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Glutethimide intoxication with prolonged coma and hyperpyrexia treated with methylphenidate. Author(s): Schleissner LA. Source: Calif Med. 1966 July; 105(1): 41-4. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5946998

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Gradual vs. abrupt withdrawal of methylphenidate in two older dependent males. Author(s): Keeley KA, Licht AL. Source: Journal of Substance Abuse Treatment. 1985; 2(2): 123-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3831371

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Growth hormone and prolactin response to methylphenidate in children with attention deficit disorder. Author(s): Shaywitz BA, Shaywitz SE, Sebrechts MM, Anderson GM, Cohen DJ, Jatlow P, Young JG. Source: Life Sciences. 1990; 46(9): 625-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2308471

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Growth hormone and prolactin response to methylphenidate. Author(s): Janowsky DS, Parker D, Leichner PP. Source: Psychopharmacology Bulletin. 1976 October; 12(4): 27-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9662

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Growth hormone and prolactin secretion in adults and hyperactive children: relation to methylphenidate serum levels. Author(s): Gualtieri CT, Kanoy R, Hawk B, Koriath U, Schroeder S, Youngblood W, Breese GR, Prange AJ Jr. Source: Psychoneuroendocrinology. 1981 December; 6(4): 331-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7323251

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Growth of hyperactive children on maintenance regimen of methylphenidate. Author(s): Mattes JA, Gittelman R. Source: Archives of General Psychiatry. 1983 March; 40(3): 317-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6830410

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Growth of hyperactive children treated with methylphenidate. Author(s): Satterfield JH, Cantwell DP, Schell A, Blaschke T. Source: Archives of General Psychiatry. 1979 February; 36(2): 212-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=420542

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Growth of hyperactive children treated with methylphenidate. Author(s): Millichap JG. Source: Journal of Learning Disabilities. 1978 November; 11(9): 567-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=731121

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Growth of hyperkinetic children taking methylphenidate, dextroamphetamine, or imipramine/desipramine. Author(s): Millichap JG. Source: Pediatrics. 1978 January; 61(1): 146-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=263851

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Growth of hyperkinetic children taking methylphenidate, dextroamphetamine, or imipramine/desipramine. Author(s): Gross MD. Source: Pediatrics. 1976 September; 58(3): 423-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=958770

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Guidelines and algorithms for the use of methylphenidate in children with Attention-Deficit/ Hyperactivity Disorder. Author(s): Greenhill L, Beyer DH, Finkleson J, Shaffer D, Biederman J, Conners CK, Gillberg C, Huss M, Jensen P, Kennedy JL, Klein R, Rapoport J, Sagvolden T, Spencer T, Swanson JM, Volkow N. Source: J Atten Disord. 2002; 6 Suppl 1: S89-100. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12685523

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Haloperidol and lithium blocking of the mood response to intravenous methylphenidate. Author(s): Wald D, Ebstein RP, Belmaker RH. Source: Psychopharmacology. 1978 April 14; 57(1): 83-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=96473

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Haloperidol and methylphenidate in hyperactive children. Author(s): Werry JS, Aman MG, Lampen E. Source: Acta Paedopsychiatr. 1976 February; 42(1): 26-40. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=775883

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Handwriting deficits in children with minimal brain dysfunction: effects of methylphenidate (Ritalin) and placebo. Author(s): Lerer RJ, Artner J, Lerer MP. Source: Journal of Learning Disabilities. 1979 August-September; 12(7): 450-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=521686

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Hemiplegia after intracarotid injection of methylphenidate. Author(s): Chillar RK, Jackson AL, Alaan L. Source: Archives of Neurology. 1982 September; 39(9): 598-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7115156

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Hemispheric processing and methylphenidate effects in attention-deficit hyperactivity disorder. Author(s): Malone MA, Kershner JR, Swanson JM. Source: Journal of Child Neurology. 1994 April; 9(2): 181-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8006372

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Hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride. Author(s): Mehta H, Murray B, LoIudice TA. Source: Journal of Clinical Gastroenterology. 1984 April; 6(2): 149-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6715854

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Hepatotoxicity due to methylphenidate hydrochloride. Author(s): Goodman CR. Source: N Y State J Med. 1972 September 15; 72(18): 2339-40. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4506888

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High-dose methylphenidate treatment of attention deficit hyperactivity disorder in a preschooler. Author(s): Lipkin PH, Butz AM, Cozen MA. Source: Journal of Child and Adolescent Psychopharmacology. 2003 Spring; 13(1): 103-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12804131

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How does methylphenidate (MP) affect information processing in man? Author(s): Callaway E, Halliday R, Peeke S, Reus V. Source: Psychopharmacology Bulletin. 1982 October; 18(4): 205-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7156292

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How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis. Author(s): Schachter HM, Pham B, King J, Langford S, Moher D. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2001 November 27; 165(11): 1475-88. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11762571

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Human information-processing: some effects of methylphenidate, age, and scopolamine. Author(s): Callaway E. Source: Biological Psychiatry. 1984 May; 19(5): 649-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6733179

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Hyperactive boys almost grown up. III. Methylphenidate effects on ultimate height. Author(s): Klein RG, Mannuzza S. Source: Archives of General Psychiatry. 1988 December; 45(12): 1131-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3058089

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Hyperactivity and methylphenidate. Author(s): Klopper JN. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 1987 March 7; 71(5): 331-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3563764

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Hyperactivity and methylphenidate. Author(s): Leary PM. Source: South African Medical Journal. Suid-Afrikaanse Tydskrif Vir Geneeskunde. 1986 September 27; 70(7): 383-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3764606

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Hyperactivity and methylphenidate: rate-dependent effects on attention. Author(s): Rapport MD, DuPaul GJ. Source: International Clinical Psychopharmacology. 1986 January; 1(1): 45-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3549871

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Hyperactivity in preschoolers and the effect of methylphenidate. Author(s): Schleifer M, Weiss G, Cohen N, Elman M, Cvejic H, Kruger E. Source: The American Journal of Orthopsychiatry. 1975 January; 45(1): 38-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1089359

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Hyperkinetic behavior and learning disorders. 3. Battery of neuropsychological tests in controlled trial of methylphenidate. Author(s): Millichap JG, Aymat F, Sturgis LH, Larsen KW, Egan RA. Source: Am J Dis Child. 1968 September; 116(3): 235-44. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5676645

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Hyperkinetic/aggressive boys in treatment: predictors of clinical response to methylphenidate. Author(s): Loney J, Prinz RJ, Mishalow J, Joad J. Source: The American Journal of Psychiatry. 1978 December; 135(12): 1487-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=717562

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Hypersensitivity to methylphenidate and dextroamphetamine: a report of two cases. Author(s): Sverd J, Hurwic MJ, David O, Winsberg BG. Source: Pediatrics. 1977 January; 59(1): 115-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=840528

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Hypertensive episodes after adding methylphenidate (Ritalin) to tricyclic antidepressants. (Report of three cases and review of clinical advantages). Author(s): Flemenbaum A. Source: Psychosomatics. 1972 July-August; 13(4): 265-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4671919

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Illicit methylphenidate use in an undergraduate student sample: prevalence and risk factors. Author(s): Teter CJ, McCabe SE, Boyd CJ, Guthrie SK. Source: Pharmacotherapy. 2003 May; 23(5): 609-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12741435

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Immediate neurocognitive effects of methylphenidate on learning-impaired survivors of childhood cancer. Author(s): Thompson SJ, Leigh L, Christensen R, Xiong X, Kun LE, Heideman RL, Reddick WE, Gajjar A, Merchant T, Pui CH, Hudson MM, Mulhern RK. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 March 15; 19(6): 1802-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11251012

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Impact of methylphenidate delivery profiles on driving performance of adolescents with attention-deficit/hyperactivity disorder: a pilot study. Author(s): Cox DJ, Merkel RL, Penberthy JK, Kovatchev B, Hankin CS. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 March; 43(3): 269-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15076259

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Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial. Author(s): Greenhill LL, Swanson JM, Vitiello B, Davies M, Clevenger W, Wu M, Arnold LE, Abikoff HB, Bukstein OG, Conners CK, Elliott GR, Hechtman L, Hinshaw SP, Hoza B, Jensen PS, Kraemer HC, March JS, Newcorn JH, Severe JB, Wells K, Wigal T. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2001 February; 40(2): 180-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11211366

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Improvement of sleep and behavior by methylphenidate in Alzheimer's disease. Author(s): Kittur S, Hauser P. Source: The American Journal of Psychiatry. 1999 July; 156(7): 1116-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10401468

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In vitro hydrolysis of RR,SS-threo-methylphenidate by blood esterases--differential and enantioselective interspecies variability. Author(s): Srinivas NR, Hubbard JW, McKay G, Hawes EM, Midha KK. Source: Chirality. 1991; 3(2): 99-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1863524

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Inappropriate prescription of methylphenidate. Author(s): Cooper N. Source: N Z Med J. 2003 October 10; 116(1183): U636. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581947

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Increased methylphenidate usage for attention deficit disorder in the 1990s. Author(s): Safer DJ, Zito JM, Fine EM. Source: Pediatrics. 1996 December; 98(6 Pt 1): 1084-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8951257

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Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography. Author(s): Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K. Source: Neuroscience Letters. 2000 May 12; 285(2): 107-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10793238

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Increased urine phenylethylamine after methylphenidate treatment in children with ADHD. Author(s): Kusaga A, Yamashita Y, Koeda T, Hiratani M, Kaneko M, Yamada S, Matsuishi T. Source: Annals of Neurology. 2002 September; 52(3): 372-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12205654

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Initiating treatment with modafinil for control of excessive daytime sleepiness in patients switching from methylphenidate: an open-label safety study assessing three strategies. Author(s): Thorpy MJ, Schwartz JR, Kovacevic-Ristanovic R, Hayduk R. Source: Psychopharmacology. 2003 June; 167(4): 380-5. Epub 2003 April 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709775

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Interferon-induced fatigue in patients with melanoma: a pilot study of exercise and methylphenidate. Author(s): Schwartz AL, Thompson JA, Masood N. Source: Oncology Nursing Forum. 2002 August; 29(7): E85-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12183762

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Intranasal abuse of prescribed methylphenidate by an alcohol and drug abusing adolescent with ADHD. Author(s): Jaffe SL. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1991 September; 30(5): 773-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1938793

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Intranasal abuse of prescribed methylphenidate. Author(s): Garland EJ. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1998 December; 37(12): 1242-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9847492

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Intranasal abuse of prescribed methylphenidate. Author(s): Garland EJ. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 1998 June; 37(6): 573-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9628076

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Intravenous methylphenidate abuse. Prototype for prescription drug abuse. Author(s): Parran TV Jr, Jasinski DR. Source: Archives of Internal Medicine. 1991 April; 151(4): 781-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1849397

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Intravenous pentazocine and methylphenidate abuse during pregnancy. Maternal lifestyle and infant outcome. Author(s): Debooy VD, Seshia MM, Tenenbein M, Casiro OG. Source: Am J Dis Child. 1993 October; 147(10): 1062-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7692723

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Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Author(s): Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS, Dewey S, Ashby C, Liebermann J, Hitzemann R, et al. Source: Archives of General Psychiatry. 1995 June; 52(6): 456-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7771915

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Isolated orofacial dyskinesia: a methylphenidate-induced movement disorder. Author(s): Senecky Y, Lobel D, Diamond GW, Weitz R, Inbar D. Source: Pediatric Neurology. 2002 September; 27(3): 224-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12393134

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IV pentazocine/methylphenidate abuse--the clinical toxicity of another Ts and blues combination. Author(s): Carter HS, Watson WA. Source: Journal of Toxicology. Clinical Toxicology. 1994; 32(5): 541-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7932913

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Jakob-Creutzfeldt disease. Modification of clinical and electroencephalographic activity with methylphenidate and diazepam. Author(s): Elliott F, Gardner-Thorpe C, Barwick DD, Foster JB. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 1974 August; 37(8): 879-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4607657

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Kinetic analysis of enantiomers of threo-methylphenidate and its metabolite in two healthy subjects after oral administration as determined by a gas chromatographicmass spectrometric method. Author(s): Aoyama T, Kotaki H, Honda Y, Nakagawa F. Source: Journal of Pharmaceutical Sciences. 1990 June; 79(6): 465-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2395090

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Laboratory measures of methylphenidate effects in cocaine-dependent patients receiving treatment. Author(s): Roache JD, Grabowski J, Schmitz JM, Creson DL, Rhoades HM. Source: Journal of Clinical Psychopharmacology. 2000 February; 20(1): 61-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10653210

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Lack of effect of methylphenidate on serum growth hormone (GH), GH-binding protein, and insulin-like growth factor I. Author(s): Toren P, Silbergeld A, Eldar S, Laor N, Wolmer L, Koren S, Weitz R, Inbar D, Reiss A, Eshet R, Weizman R. Source: Clinical Neuropharmacology. 1997 June; 20(3): 264-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9197950

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Lacunar stroke associated with methylphenidate abuse. Author(s): Sadeghian H. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2004 February; 31(1): 109-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15038480

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Learning ability and methylphenidate (Ritalin) plasma concentration in hyperkinetic children. A preliminary investigation. Author(s): Kupietz SS, Winsberg BG, Sverd J. Source: J Am Acad Child Psychiatry. 1982 January; 21(1): 27-30. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7096828

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Letter: Methylphenidate reaction. Author(s): Sleator EK. Source: Pediatrics. 1975 June; 55(6): 895-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1134893

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Letter: Methylphenidate-induced tics. Author(s): Margolin DI. Source: Jama : the Journal of the American Medical Association. 1976 August 23; 236(8): 917-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=988886

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Liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry enantiomeric separation of dl-threo-methylphenidate, (Ritalin) using a macrocyclic antibiotic as the chiral selector. Author(s): Ramos L, Bakhtiar R, Majumdar T, Hayes M, Tse F. Source: Rapid Communications in Mass Spectrometry : Rcm. 1999; 13(20): 2054-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10510420

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Liquid-chromatographic analysis for methylphenidate (Ritalin) in serum. Author(s): Soldin SJ, Chan YP, Hill BM, Swanson JM. Source: Clinical Chemistry. 1979 March; 25(3): 401-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=262179

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Liquid-liquid extraction using 96-well plate format in conjunction with liquid chromatography/tandem mass spectrometry for quantitative determination of methylphenidate (Ritalin) in human plasma. Author(s): Ramos L, Bakhtiar R, Tse FL. Source: Rapid Communications in Mass Spectrometry : Rcm. 2000; 14(9): 740-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10825011

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Longitudinal assessment of methylphenidate effects on oral word production and symptoms in first-episode schizophrenia at acute and stabilized phases. Author(s): Szeszko PR, Bilder RM, Dunlop JA, Walder DJ, Lieberman JA. Source: Biological Psychiatry. 1999 March 15; 45(6): 680-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10187997

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Long-term methylphenidate therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder. Author(s): Gadow KD, Sverd J, Sprafkin J, Nolan EE, Grossman S. Source: Archives of General Psychiatry. 1999 April; 56(4): 330-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10197827

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Long-term methylphenidate treatment of hyperkinetic children. Author(s): Weiss G, Kruger E, Danielson U, Elman M. Source: Psychopharmacology Bulletin. 1974 October; 10(4): 34-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4215091

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Long-term methylphenidate use in the medically ill patient with organic mood syndrome. Author(s): Stiebel V, Kemp K. Source: Psychosomatics. 1990 Fall; 31(4): 454-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2123352

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Long-term use and discontinuation of methylphenidate with hyperactive children. Author(s): Charles L, Schain RJ, Guthrie D. Source: Developmental Medicine and Child Neurology. 1979 December; 21(6): 758-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=520713

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Low-dose methylphenidate in the very old. Author(s): Gurian B, Rosowsky E. Source: Journal of Geriatric Psychiatry and Neurology. 1990 July-September; 3(3): 152-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2282131

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Marker gene polymorphisms in hyperkinetic disorder--predictors of clinical response to treatment with methylphenidate? Author(s): Seeger G, Schloss P, Schmidt MH. Source: Neuroscience Letters. 2001 November 2; 313(1-2): 45-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11684336

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Meta-analysis of the efficacy of methylphenidate for treating adult attentiondeficit/hyperactivity disorder. Author(s): Faraone SV, Spencer T, Aleardi M, Pagano C, Biederman J. Source: Journal of Clinical Psychopharmacology. 2004 February; 24(1): 24-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709943

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Methylphenidate (OROS formulation). Author(s): Keating GM, McClellan K, Jarvis B. Source: Cns Drugs. 2001; 15(6): 495-500; Discussion 501-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11524026

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

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Methylphenidate augmentation of citalopram in elderly depressed patients. Author(s): Lavretsky H, Kumar A. Source: The American Journal of Geriatric Psychiatry : Official Journal of the American Association for Geriatric Psychiatry. 2001 Summer; 9(3): 298-303. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11481139

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Methylphenidate does not improve cognitive function in healthy sleep-deprived young adults. Author(s): Bray CL, Cahill KS, Oshier JT, Peden CS, Theriaque DW, Flotte TR, Stacpoole PW. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2004 April; 52(3): 192-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15222409

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Methylphenidate dosage for children with ADHD over time under controlled conditions: lessons from the MTA. Author(s): Vitiello B, Severe JB, Greenhill LL, Arnold LE, Abikoff HB, Bukstein OG, Elliott GR, Hechtman L, Jensen PS, Hinshaw SP, March JS, Newcorn JH, Swanson JM, Cantwell DP. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2001 February; 40(2): 188-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11211367

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Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. Author(s): Sarhill N, Walsh D, Nelson KA, Homsi J, LeGrand S, Davis MP. Source: Am J Hosp Palliat Care. 2001 May-June; 18(3): 187-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11406895

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Methylphenidate improves HIV-1-associated cognitive slowing. Author(s): Hinkin CH, Castellon SA, Hardy DJ, Farinpour R, Newton T, Singer E. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 2001 Spring; 13(2): 248-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11449032

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Methylphenidate improves response inhibition in adults with attentiondeficit/hyperactivity disorder. Author(s): Aron AR, Dowson JH, Sahakian BJ, Robbins TW. Source: Biological Psychiatry. 2003 December 15; 54(12): 1465-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675812

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Methylphenidate improves visual-spatial memory in children with attentiondeficit/hyperactivity disorder. Author(s): Bedard AC, Martinussen R, Ickowicz A, Tannock R. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 March; 43(3): 260-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15076258

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Methylphenidate improves working memory and set-shifting in AD/HD: relationships to baseline memory capacity. Author(s): Mehta MA, Goodyer IM, Sahakian BJ. Source: Journal of Child Psychology and Psychiatry, and Allied Disciplines. 2004 February; 45(2): 293-305. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14982243

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Methylphenidate in children with hyperactivity: review and cost-utility analysis. Author(s): Gilmore A, Milne R. Source: Pharmacoepidemiology and Drug Safety. 2001 March-April; 10(2): 85-94. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11499858

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Methylphenidate in stimulants abuse: three case reports. Author(s): Martinez-Cano H, Martinez-Gras I, De Iceta M, Rodao JM, Vela-Bueno A. Source: The American Journal on Addictions / American Academy of Psychiatrists in Alcoholism and Addictions. 2001 Spring; 10(2): 192-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11444161

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Methylphenidate increased regional cerebral blood flow in subjects with attention deficit/hyperactivity disorder. Author(s): Kim BN, Lee JS, Cho SC, Lee DS. Source: Yonsei Medical Journal. 2001 February; 42(1): 19-29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11293498

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Methylphenidate increases the motor effects of L-Dopa in Parkinson's disease: a pilot study. Author(s): Camicioli R, Lea E, Nutt JG, Sexton G, Oken BS. Source: Clinical Neuropharmacology. 2001 July-August; 24(4): 208-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11479391

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Methylphenidate selectively improves story retelling in children with attention deficit hyperactivity disorder. Author(s): Francis S, Fine J, Tannock R. Source: Journal of Child and Adolescent Psychopharmacology. 2001 Fall; 11(3): 217-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11642472

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Methylphenidate treatment of attention-deficit/hyperactivity disorder secondary to traumatic brain injury: a critical appraisal of treatment studies. Author(s): Jin C, Schachar R. Source: Cns Spectr. 2004 March; 9(3): 217-26. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14999162

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Methylphenidate use for the management of opioid-induced sedation. Author(s): Westberg J, Gobel BH. Source: Clinical Journal of Oncology Nursing. 2004 April; 8(2): 203-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15108423

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Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Author(s): Leonard BE, McCartan D, White J, King DJ. Source: Human Psychopharmacology. 2004 April; 19(3): 151-80. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15079851

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N of 1 study: methylphenidate in a patient with borderline personality disorder and attention deficit hyperactivity disorder. Author(s): van Reekum R, Links PS. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 1994 April; 39(3): 186-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8033025

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Naloxone augments the hypothalamic-pituitary-adrenal axis response to methylphenidate in normal subjects. Author(s): Joyce PR, Donald RA. Source: Journal of Psychiatric Research. 1987; 21(3): 297-300. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2824766

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Narcosuggestion in chronic conversion symptoms using combined intravenous amobarbital and methylphenidate. Author(s): Hurwitz TA. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 1988 March; 33(2): 147-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3365640

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Narcotics plus methylphenidate (Ritalin) for advanced cancer pain. Author(s): Bruera E, Brenneis C, Paterson AH, MacDonald RN. Source: The American Journal of Nursing. 1988 November; 88(11): 1555-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3177508

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National trends in the prevalence of attention-deficit/hyperactivity disorder and the prescribing of methylphenidate among school-age children: 1990-1995. Author(s): Robison LM, Sclar DA, Skaer TL, Galin RS. Source: Clinical Pediatrics. 1999 April; 38(4): 209-17. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10326176

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Natural social behaviors in hyperactive children: dose effects of methylphenidate. Author(s): Whalen CK, Henker B, Swanson JM, Granger D, Kliewer W, Spencer J. Source: Journal of Consulting and Clinical Psychology. 1987 April; 55(2): 187-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3571671

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Near-fatal methylphenidate misuse. Author(s): Talbot JS, Ahuja AS. Source: The British Journal of Psychiatry; the Journal of Mental Science. 2001 March; 178: 278. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11230045

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Negative ion chemical ionization for the determination of methylphenidate in human plasma by stable isotope dilution gas chromatography/mass spectrometry. Author(s): Leis HJ, Fauler G, Raspotnig G, Windischhofer W. Source: Journal of Mass Spectrometry : Jms. 2000 September; 35(9): 1100-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11006603

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Neuroendocrine responses to methylphenidate and d-amphetamine: applications to attention-deficit disorder. Author(s): Lurie S, O'Quinn A. Source: The Journal of Neuropsychiatry and Clinical Neurosciences. 1991 Winter; 3(1): 41-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7580171

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Neurogenetic determinism and the new euphenics. Child and adolescent psychiatrists use methylphenidate because it makes children better. Author(s): Williams JH. Source: Bmj (Clinical Research Ed.). 1999 May 29; 318(7196): 1488-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10419301

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Neurohormonal and behavioral response to methylphenidate in cocaine abstinence. Author(s): Elangovan N, Barbato M, Cooper T, Winsberg B. Source: Psychiatry Research. 1996 November 15; 65(2): 65-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9122287

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Neuroleptic malignant syndrome and methylphenidate. Author(s): Ehara H, Maegaki Y, Takeshita K. Source: Pediatric Neurology. 1998 October; 19(4): 299-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9831002

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Neuropharmacologic treatment of hemineglect: a case report comparing bromocriptine and methylphenidate. Author(s): Hurford P, Stringer AY, Jann B. Source: Archives of Physical Medicine and Rehabilitation. 1998 March; 79(3): 346-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9523791

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Neuropharmacology of methylphenidate and a neural substrate for childhood hyperactivity. Author(s): Gualtieri CT, Hicks RE. Source: The Psychiatric Clinics of North America. 1985 December; 8(4): 875-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2867534

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Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Author(s): Bruera E, Miller MJ, Macmillan K, Kuehn N. Source: Pain. 1992 February; 48(2): 163-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1589233

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Nonlinear kinetics of threo-methylphenidate enantiomers in a patient with narcolepsy and in healthy volunteers. Author(s): Aoyama T, Kotaki H, Sasaki T, Sawada Y, Honda Y, Iga T. Source: European Journal of Clinical Pharmacology. 1993; 44(1): 79-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8436161

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Normalizing effects of methylphenidate on hyperactive children's vigilance performance and evoked potentials. Author(s): Michael RL, Klorman R, Salzman LF, Borgstedt AD, Dainer KB. Source: Psychophysiology. 1981 November; 18(6): 665-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7313026

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Objective measurement of hyperactivity, impulsivity, and inattention in children with hyperkinetic disorders before and after treatment with methylphenidate. Author(s): Heiser P, Frey J, Smidt J, Sommerlad C, Wehmeier PM, Hebebrand J, Remschmidt H. Source: European Child & Adolescent Psychiatry. 2004 April; 13(2): 100-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15103535

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Observations on effects of a central stimulant drug (methylphenidate) in children with hyperactive behavior. Author(s): Schain RJ, Reynard CL. Source: Pediatrics. 1975 May; 55(5): 709-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1093108

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Obsessive-compulsive symptoms secondary to methylphenidate treatment. Author(s): Kotsopoulos S, Spivak M. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2001 February; 46(1): 89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11221499

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Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings. Author(s): Pelham WE, Gnagy EM, Burrows-Maclean L, Williams A, Fabiano GA, Morrisey SM, Chronis AM, Forehand GL, Nguyen CA, Hoffman MT, Lock TM, Fielbelkorn K, Coles EK, Panahon CJ, Steiner RL, Meichenbaum DL, Onyango AN, Morse GD. Source: Pediatrics. 2001 June; 107(6): E105. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11389303

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One-year follow-up of hyperactive boys treated with imipramine or methylphenidate. Author(s): Quinn PO, Rapoport JL. Source: The American Journal of Psychiatry. 1975 March; 132(3): 241-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1090193

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Optimal dosages of methylphenidate for improving the learning and behavior of hyperactive children. Author(s): Charles L, Schain R, Zelniker T. Source: Journal of Developmental and Behavioral Pediatrics : Jdbp. 1981 September; 2(3): 78-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7188579

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Optimizing ADHD therapy with sustained-release methylphenidate. Author(s): Lawrence JD, Lawrence DB, Carson DS. Source: American Family Physician. 1997 April; 55(5): 1705-9, 1711-2. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9105199

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Oral methylphenidate-alcohol co-abuse. Author(s): Barrett SP, Pihl RO. Source: Journal of Clinical Psychopharmacology. 2002 December; 22(6): 633-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12454570

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Paediatric methylphenidate (Ritalin) restrictive conditions of prescription in France. Author(s): Frances C, Hoizey G, Millart H, Trenque T. Source: British Journal of Clinical Pharmacology. 2004 January; 57(1): 115-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678352

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Palliative uses of methylphenidate in patients with cancer: a review. Author(s): Rozans M, Dreisbach A, Lertora JJ, Kahn MJ. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2002 January 1; 20(1): 335-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11773187

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Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. Author(s): Bruera E, Driver L, Barnes EA, Willey J, Shen L, Palmer JL, Escalante C. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2003 December 1; 21(23): 4439-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14645434

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Pediatric methylphenidate exposures: 7-year experience of poison centers in the United States. Author(s): Klein-Schwartz W. Source: Clinical Pediatrics. 2003 March; 42(2): 159-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12659390

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Perceptual and response interference in children with attention-deficit hyperactivity disorder, and the effects of methylphenidate. Author(s): Jonkman LM, Kemner C, Verbaten MN, Van Engeland H, Kenemans JL, Camfferman G, Buitelaar JK, Koelega HS. Source: Psychophysiology. 1999 July; 36(4): 419-29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10432791

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Pharmacokinetic considerations in the treatment of attention-deficit hyperactivity disorder with methylphenidate. Author(s): Wolraich ML, Doffing MA. Source: Cns Drugs. 2004; 18(4): 243-50. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15015904

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Pharmacokinetic interactions between cyclosporine and bupropion or methylphenidate. Author(s): Lewis BR, Aoun SL, Bernstein GA, Crow SJ. Source: Journal of Child and Adolescent Psychopharmacology. 2001 Summer; 11(2): 1938. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11436960

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Pharmacokinetics and clinical effectiveness of methylphenidate. Author(s): Kimko HC, Cross JT, Abernethy DR. Source: Clinical Pharmacokinetics. 1999 December; 37(6): 457-70. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10628897

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Pharmacokinetics of methylphenidate after oral administration of two modifiedrelease formulations in healthy adults. Author(s): Markowitz JS, Straughn AB, Patrick KS, DeVane CL, Pestreich L, Lee J, Wang Y, Muniz R. Source: Clinical Pharmacokinetics. 2003; 42(4): 393-401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12648029

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Pharmacological effects of methylphenidate on plasma homovanillic acid and growth hormone. Author(s): Sharma RP, Javaid JI, Pandey GN, Easton M, Davis JM. Source: Psychiatry Research. 1990 April; 32(1): 9-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2190251

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Poison centers' experience with methylphenidate abuse in pre-teens and adolescents. Author(s): Klein-Schwartz W, McGrath J. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2003 March; 42(3): 288-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595781

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Polymorphisms of the dopamine transporter gene: influence on response to methylphenidate in attention deficit-hyperactivity disorder. Author(s): Roman T, Rohde LA, Hutz MH. Source: American Journal of Pharmacogenomics : Genomics-Related Research in Drug Development and Clinical Practice. 2004; 4(2): 83-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15059031

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Population pharmacokinetics of methylphenidate in children with attention-deficit hyperactivity disorder. Author(s): Shader RI, Harmatz JS, Oesterheld JR, Parmelee DX, Sallee FR, Greenblatt DJ. Source: Journal of Clinical Pharmacology. 1999 August; 39(8): 775-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10434228

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Possible change in noradrenergic receptor sensitivity following methylphenidate treatment: growth hormone and MHPG response to clonidine challenge in children with attention deficit disorder and hyperactivity. Author(s): Hunt RD, Cohen DJ, Anderson G, Clark L. Source: Life Sciences. 1984 August 20; 35(8): 885-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6482679

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Prediction of clinical response in children taking methylphenidate. Author(s): Aman MG, Turbott SH. Source: Journal of Autism and Developmental Disorders. 1991 June; 21(2): 211-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1864828

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Predictors of adult height and weight in boys treated with methylphenidate for childhood behavior problems. Author(s): Kramer JR, Loney J, Ponto LB, Roberts MA, Grossman S. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2000 April; 39(4): 517-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10761355

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Prescription of methylphenidate to children and youth, 1990-1996. Author(s): Miller AR, Lalonde CE, McGrail KM, Armstrong RW. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 2001 November 27; 165(11): 1489-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11762572

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Prevalence of and change in the prescription of methylphenidate in Israel over a 2year period. Author(s): Fogelman Y, Vinker S, Guy N, Kahan E. Source: Cns Drugs. 2003; 17(12): 915-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962530

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Prevalence of methylphenidate use among adolescents in Ontario. Author(s): Ivis FJ, Adlaf EM. Source: Canadian Journal of Public Health. Revue Canadienne De Sante Publique. 1999 September-October; 90(5): 309-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10570573

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Prevalence of methylphenidate use and change over a two-year period: a nationwide study of 2- to 11-year-old Canadian children. Author(s): Romano E, Baillargeon RH, Wu HX, Robaey P, Tremblay RE. Source: The Journal of Pediatrics. 2002 July; 141(1): 71-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091854

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Quantitative capillary electrophoresis-ion-trap mass spectrometry determination of methylphenidate in human urine. Author(s): Bach GA, Henion J. Source: J Chromatogr B Biomed Sci Appl. 1998 April 10; 707(1-2): 275-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9613960

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Quantitative electroencephalography in frontotemporal dementia with methylphenidate response: a case study. Author(s): Goforth HW, Konopka L, Primeau M, Ruth A, O'Donnell K, Patel R, Poprawski T, Shirazi P, Rao M. Source: Clin Eeg Neurosci. 2004 April; 35(2): 108-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15164821

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Randomized, controlled trial of oros methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Author(s): Wolraich ML, Greenhill LL, Pelham W, Swanson J, Wilens T, Palumbo D, Atkins M, McBurnett K, Bukstein O, August G. Source: Pediatrics. 2001 October; 108(4): 883-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11581440

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Rapid improvement in academic grades following methylphenidate treatment in attention-deficit hyperactivity disorder. Author(s): Yang P, Chung LC, Chen CS, Chen CC. Source: Psychiatry and Clinical Neurosciences. 2004 February; 58(1): 37-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678455

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Rate dependency revisited: understanding the effects of methylphenidate in children with attention deficit hyperactivity disorder. Author(s): Teicher MH, Polcari A, Anderson CM, Andersen SL, Lowen SB, Navalta CP. Source: Journal of Child and Adolescent Psychopharmacology. 2003 Spring; 13(1): 41-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12804125

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Reinforcing and subject-rated effects of methylphenidate and d-amphetamine in nondrug-abusing humans. Author(s): Rush CR, Essman WD, Simpson CA, Baker RW. Source: Journal of Clinical Psychopharmacology. 2001 June; 21(3): 273-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11386490

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Reinforcing, subject-rated, and physiological effects of intranasal methylphenidate in humans: a dose-response analysis. Author(s): Stoops WW, Glaser PE, Rush CR. Source: Drug and Alcohol Dependence. 2003 August 20; 71(2): 179-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12927656

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Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Author(s): Volkow ND, Wang GJ, Fowler JS, Logan J, Franceschi D, Maynard L, Ding YS, Gatley SJ, Gifford A, Zhu W, Swanson JM. Source: Synapse (New York, N.Y.). 2002 March 1; 43(3): 181-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11793423

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Relative lack of cognitive effects of methylphenidate in elderly male volunteers. Author(s): Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ. Source: Psychopharmacology. 2003 August; 168(4): 455-64. Epub 2003 May 07. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12734634

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Response to methylphenidate in children with attention deficit hyperactivity disorder and manic symptoms in the multimodal treatment study of children with attention deficit hyperactivity disorder titration trial. Author(s): Galanter CA, Carlson GA, Jensen PS, Greenhill LL, Davies M, Li W, Chuang SZ, Elliott GR, Arnold LE, March JS, Hechtman L, Pelham WE, Swanson JM. Source: Journal of Child and Adolescent Psychopharmacology. 2003 Summer; 13(2): 12336. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12880507

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Responses to methylphenidate in Attention-Deficit/Hyperactivity Disorder and normal children: update 2002. Author(s): Rapoport JL, Inoff-Germain G. Source: J Atten Disord. 2002; 6 Suppl 1: S57-60. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12685519

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Retrospective comparison of Adderall and methylphenidate in the treatment of attention deficit hyperactivity disorder. Author(s): Grcevich S, Rowane WA, Marcellino B, Sullivan-Hurst S. Source: Journal of Child and Adolescent Psychopharmacology. 2001 Spring; 11(1): 35-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11322743

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Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: results from imaging studies. Author(s): Volkow ND, Fowler JS, Wang GJ, Ding YS, Gatley SJ. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 2002 December; 12(6): 557-66. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12468018

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Seizures associated with venlafaxine, methylphenidate, and zolpidem. Author(s): Tavakoli SA, Gleason OC. Source: Psychosomatics. 2003 May-June; 44(3): 262-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12724513

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Sequential evaluation of behavioral treatments and methylphenidate dosage for children with attention deficit hyperactivity disorder. Author(s): Gulley V, Northup J, Hupp S, Spera S, LeVelle J, Ridgway A. Source: J Appl Behav Anal. 2003 Fall; 36(3): 375-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14596580

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Serum and brain concentrations of methylphenidate: implications for use and abuse. Author(s): Swanson JM, Volkow ND. Source: Neuroscience and Biobehavioral Reviews. 2003 November; 27(7): 615-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624806

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Short-term cardiovascular effects of methylphenidate and adderall. Author(s): Findling RL, Short EJ, Manos MJ. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2001 May; 40(5): 525-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11349696

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Social functioning in children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment. Author(s): Abikoff H, Hechtman L, Klein RG, Gallagher R, Fleiss K, Etcovitch J, Cousins L, Greenfield B, Martin D, Pollack S. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 July; 43(7): 820-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15213583

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Sources of auditory selective attention and the effects of methylphenidate in children with attention-deficit/hyperactivity disorder. Author(s): Kemner C, Jonkman LM, Kenemans JL, Bocker KB, Verbaten MN, Van Engeland H. Source: Biological Psychiatry. 2004 April 1; 55(7): 776-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039009

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Steady-state pharmacokinetics and tolerability of modafinil given alone or in combination with methylphenidate in healthy volunteers. Author(s): Hellriegel ET, Arora S, Nelson M, Robertson P Jr. Source: Journal of Clinical Pharmacology. 2001 August; 41(8): 895-904. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11504278

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Stuttering priapism associated with withdrawal from sustained-release methylphenidate. Author(s): Schwartz RH, Rushton HG. Source: The Journal of Pediatrics. 2004 May; 144(5): 675-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15127013

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Symptomatic improvement in children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment. Author(s): Abikoff H, Hechtman L, Klein RG, Weiss G, Fleiss K, Etcovitch J, Cousins L, Greenfield B, Martin D, Pollack S. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 July; 43(7): 802-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15213581

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Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction. Author(s): Deutsch HM, Ye X, Shi Q, Liu Z, Schweri MM. Source: European Journal of Medicinal Chemistry. 2001 April; 36(4): 303-11. Erratum In: Eur J Med Chem 2001 November-December; 36(11-12): 961. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11461755

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The acute effect of methylphenidate on cerebral blood flow in boys with attentiondeficit/hyperactivity disorder. Author(s): Szobot CM, Ketzer C, Cunha RD, Parente MA, Langleben DD, Acton PD, Kapczinski F, Rohde LA. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2003 March; 30(3): 423-6. Epub 2003 January 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634972

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The effect of methylphenidate on three forms of response inhibition in boys with AD/HD. Author(s): Scheres A, Oosterlaan J, Swanson J, Morein-Zamir S, Meiran N, Schut H, Vlasveld L, Sergeant JA. Source: Journal of Abnormal Child Psychology. 2003 February; 31(1): 105-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12597703

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The efficacy of 2 different dosages of methylphenidate in treating adults with attention-deficit hyperactivity disorder. Author(s): Bouffard R, Hechtman L, Minde K, Iaboni-Kassab F. Source: Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2003 September; 48(8): 546-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14574830

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The hazards of legislative restraints on legislative decisions--the case of methylphenidate (ritalin) vs. paracetamol (acamol). Author(s): Apter A. Source: The Israel Journal of Psychiatry and Related Sciences. 2003; 40(3): 162-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14619674

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The influence of a token economy and methylphenidate on attentive and disruptive behavior during sports with ADHD-diagnosed children. Author(s): Reitman D, Hupp SD, O'Callaghan PM, Gulley V, Northup J. Source: Behavior Modification. 2001 April; 25(2): 305-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11317639

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Three-month treatment course of methylphenidate increases plasma levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEA-S) in attention deficit hyperactivity disorder. Author(s): Maayan R, Yoran-Hegesh R, Strous R, Nechmad A, Averbuch E, Weizman A, Spivak B. Source: Neuropsychobiology. 2003; 48(3): 111-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14586159

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Toward individualized evidence-based medicine: five "N of 1" trials of methylphenidate in geriatric patients. Author(s): Jansen IH, Olde Rikkert MG, Hulsbos HA, Hoefnagels WH. Source: Journal of the American Geriatrics Society. 2001 April; 49(4): 474-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11347795

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Treatment effects of methylphenidate on behavioral adjustment in children with mental retardation and ADHD. Author(s): Pearson DA, Santos CW, Roache JD, Casat CD, Loveland KA, Lachar D, Lane DM, Faria LP, Cleveland LA. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2003 February; 42(2): 209-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12544181

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Treatment effects of methylphenidate on cognitive functioning in children with mental retardation and ADHD. Author(s): Pearson DA, Santos CW, Casat CD, Lane DM, Jerger SW, Roache JD, Loveland KA, Lachar D, Faria LP, Payne CD, Cleveland LA. Source: Journal of the American Academy of Child and Adolescent Psychiatry. 2004 June; 43(6): 677-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15167084

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Unexpected interaction of methylphenidate (Ritalin) with anaesthetic agents. Author(s): Ririe DG, Ririe KL, Sethna NF, Fox L. Source: Paediatric Anaesthesia. 1997; 7(1): 69-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9041578

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Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. Author(s): Portenoy RK. Source: Journal of Pain and Symptom Management. 1989 September; 4(3): Suppl 3: 2,4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2778354

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Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. Author(s): Bruera E, Brenneis C, Paterson AH, MacDonald RN. Source: Journal of Pain and Symptom Management. 1989 March; 4(1): 3-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2703735

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Use of methylphenidate for attention deficit hyperactivity disorder. Author(s): Broste SM. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 1990 November 15; 143(10): 995, 998. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2073256

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Use of methylphenidate for attention deficit hyperactivity disorder. Author(s): Lexchin J. Source: Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne. 1991 May 15; 144(10): 1209-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2025813

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Use of methylphenidate for attention-deficit hyperactivity disorder in patients with epilepsy or electroencephalographic abnormalities. Author(s): Gucuyener K, Erdemoglu AK, Senol S, Serdaroglu A, Soysal S, Kockar AI. Source: Journal of Child Neurology. 2003 February; 18(2): 109-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12693777

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Use of methylphenidate in a patient with glaucoma and attention-deficit hyperactivity disorder: a clinical dilemma. Author(s): Bartlik B, Harmon G. Source: Archives of General Psychiatry. 1997 February; 54(2): 188-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9040288

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Use of methylphenidate in the treatment of children with autistic disorder. Author(s): Quintana H, Birmaher B, Stedge D, Lennon S, Freed J, Bridge J, Greenhill L. Source: Journal of Autism and Developmental Disorders. 1995 June; 25(3): 283-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7559293

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Use of methylphenidate. Author(s): Myers WC, Stewart JT. Source: Hosp Community Psychiatry. 1989 July; 40(7): 754-5. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2777235

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Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Author(s): Volkow ND, Swanson JM. Source: The American Journal of Psychiatry. 2003 November; 160(11): 1909-18. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14594733

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Venlafaxine augmentation with methylphenidate for treatment-refractory depression: a case report. Author(s): Bader GM, Hawley JM, Short DD. Source: Journal of Clinical Psychopharmacology. 1998 June; 18(3): 255-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9617988

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Ventricular tachycardia associated with methylphenidate. Author(s): Langlois Y. Source: Can Med Assoc J. 1968 April 6; 98(14): 698. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5646109

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Ventricular tachycardia associated with the administration of methylphenidate during guanethidine therapy. Author(s): Deshmankar BS, Lewis JA. Source: Can Med Assoc J. 1967 November 4; 97(19): 1166-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6057135

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Vigilance and human attention under conditions of methylphenidate and secobarbital intoxication: an assessment using brain potentials. Author(s): Hink RF, Fenton WH Jr, Tinklenberg JR, Pfefferbaum A, Kopell BS. Source: Psychophysiology. 1978 March; 15(2): 116-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=652905

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Visual event related potentials after methylphenidate and sodium valproate in children with attention deficit hyperactivity disorder. Author(s): Frank Y. Source: Clin Electroencephalogr. 1993 January; 24(1): 19-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8420693

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Visual evoked potential changes induced by methylphenidate in hyperactive children: dose/response effects. Author(s): Halliday R, Callaway E, Naylor H. Source: Electroencephalography and Clinical Neurophysiology. 1983 March; 55(3): 25867. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6186457

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What are the long-term effects of methylphenidate treatment? Author(s): Volkow ND, Insel TR. Source: Biological Psychiatry. 2003 December 15; 54(12): 1307-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675792

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What the multimodal treatment study of children with attention deficit/hyperactivity disorder did and did not say about the use of methylphenidate for attention deficits. Author(s): Carey WB. Source: Pediatrics. 2000 April; 105(4 Pt 1): 863-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10742336

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Which boys respond to stimulant medication? A controlled trial of methylphenidate in boys with disruptive behaviour. Author(s): Taylor E, Schachar R, Thorley G, Wieselberg HM, Everitt B, Rutter M. Source: Psychological Medicine. 1987 February; 17(1): 121-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3554290

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Withdrawn, apathetic geriatric patients responsive to methylphenidate. Author(s): Kaplitz SE. Source: Journal of the American Geriatrics Society. 1975 June; 23(6): 271-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1092749

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

Finding Nutrition Studies on Methylphenidate 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 “methylphenidate” (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 “methylphenidate” (or a synonym): •

A slow start to the new millennium. Zyvox, Concerta and Mifeprex headline the year. Source: Cornell, S Adv-Nurse-Pract. 2000 December; 8(12): 62-4 1096-6293

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Adverse response to methylphenidate in combination with valproic acid. Author(s): Child Development Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Source: Gara, L Roberts, W J-Child-Adolesc-Psychopharmacol. 2000 Spring; 10(1): 39-43 1044-5463

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Altered responsiveness to cocaine in rats exposed to methylphenidate during development. Author(s): Department of Psychiatry, Harvard Medical School and McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02478, USA. [email protected] Source: Andersen, Susan L Arvanitogiannis, Andreas Pliakas, Andrea M LeBlanc, Celeste Carlezon, William A Jr Nat-Neurosci. 2002 January; 5(1): 13-4 1097-6256

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An experimental comparison of Pycnogenol and methylphenidate in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). Author(s): The Attention Deficit Center in St. Louis 63141, MO. Source: Tenenbaum, S Paull, J C Sparrow, E P Dodd, D K Green, L J-Atten-Disord. 2002 September; 6(2): 49-60 1087-0547

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Analgesic action of methylphenidate on parkinsonian sensory symptoms. Mechanisms and pathophysiological implications. Author(s): Department of Neurology, University School of Medicine, Turin, Italy. Source: Cantello, R Aguggia, M Gilli, M Delsedime, M Riccio, A Rainero, I Mutani, R Arch-Neurol. 1988 September; 45(9): 973-6 0003-9942

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Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine. Author(s): Psychobiology Section, National Institute on Drug Abuse, Division of Intramural Research, Baltimore, MD 21224, USA. [email protected] Source: Izenwasser, S Coy, A E Ladenheim, B Loeloff, R J Cadet, J L French, D Eur-JPharmacol. 1999 June 4; 373(2-3): 187-93 0014-2999

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Comparable changes in synaptic dopamine induced by methylphenidate and by cocaine in the baboon brain. Author(s): Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA. [email protected] Source: Volkow, N D Fowler, J S Gatley, S J Dewey, S L Wang, G J Logan, J Ding, Y S Franceschi, D Gifford, A Morgan, A Pappas, N King, P Synapse. 1999 January; 31(1): 5966 0887-4476

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Dopamine-transporter occupancy after intravenous doses of cocaine and methylphenidate in mice and humans. Author(s): Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. [email protected] Source: Gatley, S J Volkow, N D Gifford, A N Fowler, J S Dewey, S L Ding, Y S Logan, J Psychopharmacology-(Berl). 1999 September 1; 146(1): 93-100 0033-3158

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Effect of food on the pharmacokinetics of osmotic controlled-release methylphenidate HCl in healthy subjects. Author(s): Department of Clinical Pharmacology, ALZA Corp, 1900 Charleston Road, Mountain View, CA 94039, USA. [email protected]

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Source: Modi, N B Wang, B Hu, W T Gupta, S K Biopharm-Drug-Dispos. 2000 January; 21(1): 23-31 0142-2782 •

Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists? Author(s): Department of Chemistry, Washington State University, Pullman, USA. Source: Wayment, H K Deutsch, H Schweri, M M Schenk, J O J-Neurochem. 1999 March; 72(3): 1266-74 0022-3042

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Effects of repeated methylphenidate treatment in the young rat: sensitization of both locomotor activity and stereotyped sniffing. Author(s): Department of Psychology, California State University, San Bernardino 92407-2397, USA. [email protected] Source: McDougall, S A Collins, R L Karper, P E Watson, J B Crawford, C A Exp-ClinPsychopharmacol. 1999 August; 7(3): 208-18 1064-1297

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Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats. Author(s): Departments of Cell Biology and Anatomy, Finch University of Health Sciences/The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA. Source: Brandon, C L Marinelli, M Baker, L K White, F J Neuropsychopharmacology. 2001 November; 25(5): 651-61 0893-133X

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Response to growth hormone in attention deficit hyperactivity disorder: effects of methylphenidate and pemoline therapy. Author(s): Department of Pediatrics, Louisiana State University School of Medicine, New Orleans, Louisiana 70112, USA. Source: Rao, J K Julius, J R Breen, T J Blethen, S L Pediatrics. 1998 August; 102(2 Pt 3): 497-500 0031-4005

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Separation of ritalin racemate and its by-product racemates by capillary electrophoresis. Author(s): Novartis Pharmaceuticals Corp., Chemical & Analytical R & D Department, East Hanover, NJ 07936, USA. [email protected] Source: Huang, W X Gao, Q Harris, M Fazio, S D Vivilecchia, R V Electrophoresis. 2001 September; 22(15): 3226-31 0173-0835

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Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning. Author(s): Department of Psychiatry & Neuroscience Program, Harvard Medical School and Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, MA 02478, USA. Source: Davids, Eugen Zhang, Kehong Tarazi, Frank I Baldessarini, Ross J Psychopharmacology-(Berl). 2002 February; 160(1): 92-8 0033-3158

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The concurrent use of lithium and methylphenidate in a child. Source: Licamele, W L Goldberg, R L J-Am-Acad-Child-Adolesc-Psychiatry. 1989 September; 28(5): 785-7 0890-8567

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The use of methylphenidate in the treatment of refractory neurocardiogenic syncope. Author(s): Department of Medicine, Medical College of Ohio, Toledo 43699, USA. Source: Grubb, B P Kosinski, D Mouhaffel, A Pothoulakis, A Pacing-Clin-Electrophysiol. 1996 May; 19(5): 836-40 0147-8389

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Treatment for hyperactive children: homeopathy and methylphenidate compared in a family setting. Author(s): Spezialarzt FMH fur Kinder und Jugendliche, FA Homoopathie SVHA, Laupen, Switzerland. [email protected] Source: Frei, H Thurneysen, A Br-Homeopath-J. 2001 October; 90(4): 183-8 0007-0785

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

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CHAPTER 3. ALTERNATIVE MEDICINE AND METHYLPHENIDATE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to methylphenidate. 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 methylphenidate 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 “methylphenidate” (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 methylphenidate: •

A 55-year-old man with attention-deficit/hyperactivity disorder, 1 year later. Author(s): Parker RA, Hartman EE. Source: Jama : the Journal of the American Medical Association. 1999 May 26; 281(20): 1945. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10349899

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A longitudinal study of short- and long-term activity levels in male and female spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rats. Author(s): Ferguson SA, Cada AM. Source: Behavioral Neuroscience. 2003 April; 117(2): 271-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12708524

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A pilot study of antihypertensive therapy in cerebrovascular disease. Author(s): Meyer JS, Eadie GA, Ericsson AD, Hoobler SW, MacMahon HR. Source: Journal of the American Geriatrics Society. 1967 April; 15(4): 313-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5335634

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A review of nonvalidated and complementary therapies for cluster headache. Author(s): Bilchik TR. Source: Current Pain and Headache Reports. 2004 April; 8(2): 157-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14980151

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A review of psychophysiological research with hyperkinetic children. Author(s): Hastings JE, Barkley RA. Source: Journal of Abnormal Child Psychology. 1978 December; 6(4): 413-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=215613

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A slow start to the new millennium. Zyvox, Concerta and Mifeprex headline the year. Author(s): Cornell S. Source: Adv Nurse Pract. 2000 December; 8(12): 62-4. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12397912

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A treatment trial of delayed sleep phase syndrome with triazolam. Author(s): Ozaki N, Iwata T, Itoh A, Ohta T, Okada T, Kasahara Y. Source: Jpn J Psychiatry Neurol. 1989 March; 43(1): 51-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2739169

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Acute challenge ERP as a prognostic of stimulant therapy outcome in attention-deficit hyperactivity disorder. Author(s): Young ES, Perros P, Price GW, Sadler T. Source: Biological Psychiatry. 1995 January 1; 37(1): 25-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7893855

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ADHD, Ritalin, and big brother. Author(s): Miller AL. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2000 October; 5(5): 401. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11056410

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An experimental comparison of Pycnogenol and methylphenidate in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). Author(s): Tenenbaum S, Paull JC, Sparrow EP, Dodd DK, Green L.

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Source: J Atten Disord. 2002 September; 6(2): 49-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12142861 •

Anti-depressant chemotherapy, 1965. Rapid response to serotonin precursor potentiated by Ritalin. Author(s): Robie TR, Flora A. Source: Psychosomatics. 1965 September-October; 6(5): 351-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5319249

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Attention deficit/hyperactivity disorder (ADHD) in children: rationale for its integrative management. Author(s): Kidd PM. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2000 October; 5(5): 402-28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11056411

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Auditory attention in hyperactive children: effects of stimulant medication on dichotic listening performance. Author(s): Hiscock M, Kinsbourne M, Caplan B, Swanson JM. Source: Journal of Abnormal Psychology. 1979 February; 88(1): 27-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=422801

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Boys will be boys: fathers' perspectives on ADHD symptoms, diagnosis, and drug treatment. Author(s): Singh I. Source: Harvard Review of Psychiatry. 2003 November-December; 11(6): 308-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14713567

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Characterization of tiagabine (NO-328), a new potent and selective GABA uptake inhibitor. Author(s): Nielsen EB, Suzdak PD, Andersen KE, Knutsen LJ, Sonnewald U, Braestrup C. Source: European Journal of Pharmacology. 1991 April 24; 196(3): 257-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1832636

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Clinical studies with propericiazine (R.P. 8909). Author(s): St Jean A, Sterlin C, Noe W, Ban TA. Source: Dis Nerv Syst. 1967 August; 28(8): 526-31. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4383004

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Cocaine abuse and its treatment. Author(s): Resnick RB, Resnick EB.

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Source: The Psychiatric Clinics of North America. 1984 December; 7(4): 713-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6522310 •

Controversies in ADHD. Fundamental questions being answered slowly, but scientifically. Author(s): Flick GL. Source: Adv Nurse Pract. 2002 February; 10(2): 34-6, 39-43. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12400297

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Crash treatment for melancholia. Resistant to other recently developed methods. Author(s): Robie TR. Source: J Med Soc N J. 1970 August; 67(8): 488-93. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5310707

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Daily activity and persistent sleep-wake schedule disorders. Author(s): Ohta T, Iwata T, Kayukawa Y, Okada T. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1992 July; 16(4): 529-37. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1641496

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Differential effects of methylphenidate on reticular formation and thalamic neuronal activity. Author(s): Shih TM, Khachaturian ZS, Barry H 3rd, Reisler KL. Source: Psychopharmacologia. 1975 October 14; 44(1): 11-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1197575

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Discriminative stimulus properties of (-)ephedrine. Author(s): Young R, Glennon RA. Source: Pharmacology, Biochemistry, and Behavior. 1998 July; 60(3): 771-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9678664

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EEG aspects in the diagnosis and treatment of minimal brain dysfunction. Author(s): Satterfield JH, Lesser LI, Saul RE, Cantwell DP. Source: Annals of the New York Academy of Sciences. 1973 February 28; 205: 274-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4511281

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EEG issues in children with minimal brain dysfunction. Author(s): Satterfield JH. Source: Semin Psychiatry. 1973 February; 5(1): 35-46. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4803377


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Effects of extract of Cistus populifolius L. on the central nervous system. Author(s): de Andres AI, Gomez-Serranillos MP, Iglesias I, Villar AM. Source: Phytotherapy Research : Ptr. 1999 November; 13(7): 575-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10548749

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Effects of TENS and methylphenidate in tuberculous meningo-encephalitis. Author(s): Scherder EJ, Van Deursen S, Van Manen SR, Ferenschild K, Simis R, Vuyk PJ. Source: Brain Injury : [bi]. 2001 June; 15(6): 545-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11394974

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Efficacy or effectiveness: which comes first, the cure or the treatment? Author(s): Oster MI. Source: Am J Clin Hypn. 2003 July; 46(1): 3-10. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12894927

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Electrodermal correlates of hyperactivity in children. Author(s): Satterfield JH, Dawson ME. Source: Psychophysiology. 1971 March; 8(2): 191-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5089415

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Emerging drugs of abuse in Connecticut. Author(s): Weiner AL. Source: Conn Med. 2000 January; 64(1): 19-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10697361

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Evoked potentials in hyperkinetic and normal children under certainty and uncertainty: a placebo and methylphenidate study. Author(s): Prichep LS, Sutton S, Hakerem G. Source: Psychophysiology. 1976 September; 13(5): 419-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=972965

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Methylphenidate (ritalin) abuse and methadone maintenance. Author(s): Raskind M, Bradford T. Source: Dis Nerv Syst. 1975 January; 36(1): 9-12. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1109888

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Neurofeedback treatment for attention-deficit/hyperactivity disorder in children: a comparison with methylphenidate. Author(s): Fuchs T, Birbaumer N, Lutzenberger W, Gruzelier JH, Kaiser J. Source: Applied Psychophysiology and Biofeedback. 2003 March; 28(1): 1-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12737092

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Operant conditioning of EEG rhythms and ritalin in the treatment of hyperkinesis. Author(s): Shouse MN, Lubar JF. Source: Biofeedback Self Regul. 1979 December; 4(4): 299-312. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=526475

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Outcome-based comparison of Ritalin versus food-supplement treated children with AD/HD. Author(s): Harding KL, Judah RD, Gant C. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2003 August; 8(3): 319-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12946241

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Relative efficacy of ritalin and biofeedback treatments in the management of hyperactivity. Author(s): Potashkin BD, Beckles N. Source: Biofeedback Self Regul. 1990 December; 15(4): 305-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2275943

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The anorexient activity of Kalio-kund (Dioscorea bulbifera Linn.), methylphenidate and cocaine in rats: a preliminary study. Author(s): Jindal MN, Kelkar VV, Doctor RB. Source: The Indian Journal of Medical Research. 1969 June; 57(6): 1075-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5823172

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The effect of methylphenidate on cardiovascular sensory differentiation on the hyperkinetic syndrome. Author(s): Butter HJ, Lapierre YD. Source: Int J Clin Pharmacol Biopharm. 1975 June; 11(4): 309-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1099022

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The impact of recent lawsuits on methylphenidate sales. Author(s): Safer DJ. Source: Clinical Pediatrics. 1994 March; 33(3): 166-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8194294

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Treatment for hyperactive children: homeopathy and methylphenidate compared in a family setting. Author(s): Frei H, Thurneysen A. Source: Br Homeopath J. 2001 October; 90(4): 183-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11680802


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Use of medical services by methylphenidate-treated children in the general population. Author(s): Miller AR, Brehaut JC, Raina P, McGrail KM, Armstrong RW. Source: Ambulatory Pediatrics : the Official Journal of the Ambulatory Pediatric Association. 2004 March-April; 4(2): 174-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15018602

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

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

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

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

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

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

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

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

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

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

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

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

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

The following is a specific Web list relating to methylphenidate; 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 Alzheimer's Disease Source: Integrative Medicine Communications; www.drkoop.com Attention Deficit Disorder Source: Prima Communications, Inc.www.personalhealthzone.com Attention Deficit Hyperactivity Disorder Source: Integrative Medicine Communications; www.drkoop.com

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Attention Deficit-Hyperactivity Disorder Source: Healthnotes, Inc.; www.healthnotes.com Depression Source: Integrative Medicine Communications; www.drkoop.com •

Herbs and Supplements Astragalus Mem Alternative names: Huang-Qi; Astragalus membranaceus Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Ginseng (Panax) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10029,00.html Methylphenidate Source: Healthnotes, Inc.; www.healthnotes.com Mixed Amphetamines Source: Healthnotes, Inc.; www.healthnotes.com

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

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CHAPTER 4. DISSERTATIONS ON METHYLPHENIDATE Overview In this chapter, we will give you a bibliography on recent dissertations relating to methylphenidate. 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 “methylphenidate” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on methylphenidate, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Methylphenidate 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 methylphenidate. 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: •

An evaluation of methylphenidate preference in adults diagnosed with attentiondeficit/hyperactivity disorder by MacDonald, Emily Kathleen, PhD from WESTERN MICHIGAN UNIVERSITY, 2003, 52 pages http://wwwlib.umi.com/dissertations/fullcit/3123760

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Causal attributions made by parents of children taking methylphenidate for Attention deficit hyperactivity disorder by Jenson, Cary, PhD from VIRGINIA COMMONWEALTH UNIVERSITY, 1996, 110 pages http://wwwlib.umi.com/dissertations/fullcit/9627437

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Dosage effects of methylphenidate on the activity level of hyperactive children by WITT, PETER ARTHUR, PHD from UNIVERSITY OF ILLINOIS AT URBANACHAMPAIGN, 1971, 111 pages http://wwwlib.umi.com/dissertations/fullcit/7212442

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Effects of methylphenidate on information processing and reading in a group of hyperactive children by BALLINGER, CAROLYN LOIS TUCKER, PHD from UNIVERSITY OF WASHINGTON, 1982, 93 pages http://wwwlib.umi.com/dissertations/fullcit/8218198

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Effects of methylphenidate on right hemisphere functioning in ADHD by CampbellCholvat, Lorraine, PhD from UNIVERSITY OF TORONTO (CANADA), 1993, 139 pages http://wwwlib.umi.com/dissertations/fullcit/NN86280

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Effects of methylphenidate on the executive function performance of African American children with attention-deficit hyperactivity disorder by Hazel-Fernandez, Leslie Ann, PhD from THE UNIVERSITY OF ROCHESTER, 2004, 110 pages http://wwwlib.umi.com/dissertations/fullcit/3114927

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PARENTS' DECISION-MAKING PROCESS IN METHYLPHENIDATE ADMINISTRATION: EDUCATIONAL POLICY CONSIDERATIONS by SLIMMER, LYNDA WALTON, PhD from UNIVERSITY OF ILLINOIS AT CHICAGO, 1984, 127 pages http://wwwlib.umi.com/dissertations/fullcit/8411339

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THE DIFFERENTIAL DOSE EFFECTS OF METHYLPHENIDATE ON HYPERACTIVE CHILDREN AND THEIR MOTHERS by LIPTON, MERYL ESTA, PHD from UNIVERSITY OF MINNESOTA, 1980, 240 pages http://wwwlib.umi.com/dissertations/fullcit/8025476

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The effect of methylphenidate and amygdalectomy on active avoidance performance in the rat by Yeudall, Lorne T, ADVDEG from UNIVERSITY OF ALBERTA (CANADA), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK06771

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The effects of methylphenidate dose on attention and nonverbal learning in children with attention-deficit hyperactivity disorder by O'Toole, Kathleen Mary, PhD from GEORGIA STATE UNIVERSITY, 1994, 98 pages http://wwwlib.umi.com/dissertations/fullcit/9507429

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THE EFFECTS OF METHYLPHENIDATE DURING REST, EXERCISE, AND RECOVERY UPON THE CIRCULORESPIRATORY RESPONSES OF HYPERACTIVE CHILDREN. by BALLARD, JOYCE ELAINE, PHD from UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN, 1975, 240 pages http://wwwlib.umi.com/dissertations/fullcit/7514079

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THE EFFECTS OF METHYLPHENIDATE ON LEARNING IN HYPERACTIVE CHILDREN: THE STIMULUS EQUIVALENCE PARADIGM by VYSE, STUART ARTHUR, PhD from UNIVERSITY OF RHODE ISLAND, 1987, 130 pages http://wwwlib.umi.com/dissertations/fullcit/8800163

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The effects of methylphenidate on self-regulatory speech of children with attention deficit hyperactivity disorder by Coffey, Laura Denton, PhD from INDIANA STATE UNIVERSITY, 1993, 155 pages http://wwwlib.umi.com/dissertations/fullcit/9322597

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THE EFFECTS OF METHYLPHENIDATE ON THE ATTENTION SPAN AND LEARNING PERFORMANCE OF HYPERACTIVE CHILDREN. by KOZUCH, DONNA PARKO, PHD from THE AMERICAN UNIVERSITY, 1977, 85 pages http://wwwlib.umi.com/dissertations/fullcit/7804614

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THE EFFECTS OF METHYLPHENIDATE ON THE READING BEHAVIORS OF ELEMENTARY SCHOOL CHILDREN DIAGNOSED AS HYPERACTIVE by HYND, CYNTHIA R., EducatD from UNIVERSITY OF GEORGIA, 1984, 376 pages http://wwwlib.umi.com/dissertations/fullcit/8421123

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The effects of methylphenidate on the repeated acquisition performance of children with attention deficit disorder by Giuliano, Christopher Paul, PhD from WESTERN MICHIGAN UNIVERSITY, 1991, 65 pages http://wwwlib.umi.com/dissertations/fullcit/9201559

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The utility of Reading to Read with boys with ADHD during optimal versus nonoptimal methylphenidate effect windows by Kastner, Joseph William, PhD from THE UNIVERSITY OF SOUTHERN MISSISSIPPI, 1997, 100 pages http://wwwlib.umi.com/dissertations/fullcit/9809151

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VERBAL AND PORTEUS MAZE PERFORMANCE OF LEARNING DISABLED CHILDREN: EFFECTS OF METHYLPHENIDATE AND INPUT ORGANIZATION by FRESTON, CYRUS WHEELOCK, II, PHD from THE UNIVERSITY OF TEXAS AT AUSTIN, 1971, 133 pages http://wwwlib.umi.com/dissertations/fullcit/7215757

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 METHYLPHENIDATE 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 “methylphenidate” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on methylphenidate, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Methylphenidate By performing a patent search focusing on methylphenidate, 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 methylphenidate: •

7-amino-2-heptenoates and their use in the preparation of methylphenidate Inventor(s): Fox; Martin Edward (Cambridge, GB), Paul; Jane Marie (Cambridge, GB) Assignee(s): Medeva Europe Limited (GB) Patent Number: 6,031,124 Date filed: September 25, 1998 Abstract: The subject invention pertains to compounds of the formula Y.sup.1 Y.sup.2 N--(CH.sub.2).sub.4 --CH.dbd.C(Ph)--X wherein Y.sup.1 and Y.sup.2 are independently H or a removable blocking group, or Y.sup.1 and Y.sup.2 together are a removable divalent blocking group; and X is COOCH.sub.3 or a group convertible thereto. Such a compound may be cyclised, by Michael addition, to give methylphenidate, if necessary after removing blocking group(s) and converting X to COOCH.sub.3. The subject invention also pertains to methods for preparing compounds of the invention. Excerpt(s): This invention relates to the synthesis of methylphenidate by cyclisation of new 7-amino-2-heptenoates. Methylphenidate has utility as a therapeutic agent, e.g. in the treatment of attention-deficient hyperactivity disorder. It was first prepared as a mixture of the erythro and threo racemates. U.S. Pat. No. 2,957,880 discloses its synthesis and also studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo diastereomer. wherein R* is the chiral auxiliary.alpha.methylbenzylamine and R is lower alkyl. This structure is indicated as suitable for cyclisation to 1-(1-phenylethyl)-2-hydroxy-5-piperidinone, en route to antihistaminic agents. Web site: http://www.delphion.com/details?pn=US06031124__

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Chronic, bolus administration of D-threo methylphenidate Inventor(s): Dariani; Maghsoud M. (Fanwood, NJ), Zeitlin; Andrew L. (Millington, NJ), Zeldis; Jerome B. (Princeton, NJ) Assignee(s): Celegene Corporation (Warren, NJ) Patent Number: 5,922,736 Date filed: September 29, 1997 Abstract: Chronic bolus administration of D-threo methylphenidate is provided. The administration of the D-threo isomer eliminates adverse side effects associated with the DL racemate, and provides improved effectiveness. The compositions and methods of the invention are useful in treating nervous system disorders including attention deficit disorder, attention deficit hyperactivity disorder, and cognitive decline associated with systemic diseases such as acquired immunodeficiency syndrome. Excerpt(s): The present invention is directed to methods and compositions for treating nervous system disorders such as attention deficit disorder, attention deficit hyperactivity disorder, cognitive decline associated with acquired immunodeficiency syndrome, and similar conditions. The methods involve the administration of a single, bolus dose of a composition comprising D-threo methylphenidate. The compositions are substantially free of L-threo methylphenidate and of erythro forms of

Patents 133

methylphenidate. Attention Deficit Disorder (ADD), a commonly diagnosed nervous system illness in children, is generally treated with methylphenidate hydrochloride (available commercially as, e.g., Ritalin.RTM.). Symptoms of ADD include distractibility and impulsivity. A related disorder, termed Attention Deficit Hyperactivity Disorder (ADHD), is further characterized by symptoms of hyperactivity, and is also treated with methylphenidate hydrochloride. Methylphenidate drugs have also been used to treat cognitive decline in patients with Acquired Immunodeficiency Syndrome (AIDS) or AIDS related conditions. See, e.g., Brown, G., Intl J. Psych. Med. 25(1): 21-37 (1995); Holmes et al., J. Clin. Psychiatry 50: 5-8 (1989). Clinically, the threo pair of enanitiomers of methylphenidate hydrochloride is generally administered for the treatment of ADD and ADHD. The hydrochloride salt is commonly referred to simply as "methylphenidate". Unless indicated otherwise, the term "methylphenidate" is used broadly herein to include methylphenidate and pharmaceutically acceptable salts thereof, including methylphenldate hydrochloride. Web site: http://www.delphion.com/details?pn=US05922736__ •

Compositions and methods for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with methylphenidate Inventor(s): Dixon; Terese A. (Miami, FL), Mantelle; Juan (Miami, FL) Assignee(s): Noven Pharmaceuticals, NC. (Miami, FL) Patent Number: 6,210,705 Date filed: September 30, 1998 Abstract: The invention relates to a method of treating Attention Deficit Disorder (ADD) and Attention Deficit/Hyperactivity Disorder (ADHD) and compositions for topical application of methylphenidate comprising methylphenidate in a flexible, finite system wherein the methylphenidate is present in an amount sufficient to achieve substantially zero order kinetics for delivery to the skin or mucosa of a patient in need thereof over a period of time at least 10 hours. Excerpt(s): The present invention relates to compositions and methods of treatment of Attention Deficit Disorder (ADD) and Attention Deficit/Hyperactivity Disorder (ADHD) by means of topical application of methylphenidate in a pharmaceutically acceptable adhesive carrier, in an amount sufficient to achieve substantially zero-order kinetics over a period of at least 10 hours. Attention Deficit Disorder (ADD) and Attention Deficit/Hyperactivity Disorder (ADHD) (severally and collectively hereinafter referred to as "AD") are developmental disorders of self-control. They consist of problems with attention span, impulse control and activity level. These problems are reflected in impairment of a person's will or capacity to control his or her own behavior relative to the passage of time and to keep future goals and consequences in mind. Traditionally, methylphenidate has been used as the drug of choice for the treatment of AD in both children and adults for several reasons. Methylphenidate, described in U.S. Pat. No. 2,957,880, is a central nervous system stimulant. Though not an amphetamine, methylphenidate functions in a similar way in the brain. The current commercially available dosage form (Ritalin.RTM. tablets) and available strengths of the tablets fall short of providing effective treatment for a significant portion of the patient's waking hours. Methylphenidate has a short duration of action of from about 2 to 4 hours. A controlled release tablet of methylphenidate is commercially available, but is available only in one strength. This product, which was designed to eliminate the need for multiple administration of a tablet during the school day for children and reduce dosing

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to either once or twice a day, falls short of providing effective treatment for a significant portion of the patient's waking hours. Web site: http://www.delphion.com/details?pn=US06210705__ •

Enantopselective synthesis of methyl phenidate Inventor(s): Axten; Jeffrey M. (Philadelphia, PA), Krim; Lori (Philadelphia, PA), Winklter; Jeffrey David (Wynnewood, PA) Assignee(s): The Trustees of the University of Pennsylvania (Philadelphia, PA) Patent Number: 6,025,502 Date filed: March 19, 1999 Abstract: The invention relates to an enantioselective method of making methylphenidate and derivatives thereof. The method involves use of a rhodium catalyst, and selectively produces the D-enantiomer of the methylphenidate derivative in excess of the L-enantiomer thereof. Furthermore, the method selectively produces the threo-diastereomer in excess of the erythro-diastereomer. The method is thus suitable for synthesis of D-threo-methylphenidate (the biologically active form of this compound) and derivatives thereof. Excerpt(s): The field of the invention is synthesis of methylphenidate and derivatives thereof. Methylphenidate (Ritalin,.TM. Ciba-Geigy Corporation, Summit, N.J.) is the most commonly prescribed psychotropic medication for children in the United States. It is used primarily for the treatment of children diagnosed with attention deficit disorder (ADD). Methylphenidate is synonymous with methyl.alpha.-phenyl-2piperidineacetate,.alpha.-phenyl-2-piperidineacetate methyl ester, methyl phenidylacetate, and methylphenidan. The biologically active form of methylphenidate is the D-threo enantiomer. Methylphenidate is sold, in the form of the hydrochloride salt, as the product Ritalin.TM. and its generic equivalents. A comprehensive description of the compound is found in Padmanabhan (1981, Analytical Profiles of Drug Substances v. 10, Florey, Ed., Academic Press, New York). D-threomethylphenidate is a mild central nervous system stimulant. Its mode of action in humans is not fully understood, but presumably involves activation of the brain stem arousal system to effect stimulation of the patient. Dosing and administration information, contraindications, warnings, and precautions pertaining to administration of methylphenidate to humans is available in the art (e.g. Physician's Desk Reference.RTM., Medical Economics Co., Inc., Montvale, N.J., 51st ed., 1997; PDR.RTM. Generics.TM., Medical Economics Co., Inc., Montvale, N.J., 2nd ed., 1996). Methylphenidate is the treatment of choice for attention deficit disorder, and is also used in the treatment of narcolepsy, minimal cerebral dysfunction, and other conditions. In addition, methylphenidate and its analogs have been proposed as cocaine antagonists for treatment of cocaine abuse and addiction (e.g. International Patent Application PCT/US99/00711 and Deutsch et al., 1996, J. Med. Chem. 39:1201-1209). Web site: http://www.delphion.com/details?pn=US06025502__

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Method of treating attention deficit disorders with d-threo methylphenidate Inventor(s): Dariani; Maghsoud M. (Fanwood, NJ), Stirling; David I. (Branchburg, NJ), Zeitlin; Andrew L. (Millington, NJ) Assignee(s): Celgene Corporation (Warren, NJ) Patent Number: 5,908,850 Date filed: April 2, 1997 Abstract: Methods for treating Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, AIDS Dementia Complex and cognitive decline in HIV-AIDS while minimizing drug hypersensitivity, toxicity, side effects, euphoric effect, and drug abuse potential by administration of d-threo-methylphenidate or pharmaceutically acceptable salts thereof. Excerpt(s): The present invention relates to methods of treating certain Central Nervous System disorders such as Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), HIV/AIDS cognitive decline, and AIDS Dementia Complex with decreased side effects, reduced euphoric effect, and reduced drug abuse potential. Attention Deficit Disorder (ADD) is the most commonly diagnosed illness in children. Patrick et al., J. Pharmacol. & Exp. Therap., 241:152-158 (1987). Symptoms of ADD include distractibility and impulsivity. A related disorder, termed Attention Deficit Hyperactivity Disorder (ADHD), is further characterized by increased symptoms of hyperactivity in patients. Racemic methylphenidate (e.g., Ritalin.RTM.) is a mild Central Nervous System stimulant with pharmacological activity qualitatively similar to amphetamines, and has been the drug of choice for symptomatic treatment of ADD in children. Greenhill, L., Child & Adol. Psych. Clin. N.A., Vol. 4, Number 1:123-165 (1995). Current administration of racemic methylphenidate, however, results in notable side effects such as anorexia, weight loss, insomnia, dizziness and dysphoria. Additionally, racemic methylphenidate which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for substance abuse in patients. At least 70% of HIV-infected individuals who have developed Acquired Immunodeficiency Syndrome (AIDS) eventually manifest cognitive defects, and many display signs and symptoms of dementia. See Navia et al., Annals of Neurology, 19:517-524 (1986). Complaints of forgetfulness, loss of concentration, fatigue, depression, loss of attentiveness, mood swings, personality change, and thought disturbance are common in patients with Human Immunodeficiency Virus (HIV) disease. Douzenis et al., Proc. 7th Int'l. Conf. AIDS, 1, MB, 2135:215 (1991); Holmes et al., J. Clin. Psychiatry, 50:5-8 (1989). Racemic methylphenidate has been used to treat cognitive decline in AIDS/ARC patients. Brown, G., Intl. J. Psych. Med. 25(1): 21-37 (1995). As described above, racemic methylphenidate which is a Schedule II controlled substance, produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for drug abuse in AIDS patients. Web site: http://www.delphion.com/details?pn=US05908850__

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Methylphenidate modified release formulations Inventor(s): Bettman; Marie J. (Clayton, OH), Hensley; Dan L. (Huber Heights, OH), Percel; Phillip J. (Troy, OH), Venkatesh; Gopi M. (Dayton, OH), Vishnupad; Krishna S. (Dayton, OH) Assignee(s): Eurand America, Inc. (Vandalia, OH) Patent Number: 6,344,215 Date filed: October 27, 2000 Abstract: A pharmaceutical MR (modified release) multiparticulate dosage form such as a capsule (once-a-day MR Capsule) of Methylphenidate indicated for the treatment of children with attention deficit hyperactivity disorder (ADHD), capable of delivering a portion of the dose for rapid onset of action and the remainder of the dose in a controlled manner for about 12 hours, is composed of a multitude of multicoated particles made of two populations of drug layered beads, IR (immediate release) and ER (extended release) Beads. The IR beads preferably are made by layering an aqueous solution comprising a drug and a binder on to non-pareil sugar spheres and then applying a seal coat to the drug coated cores. The ER Beads are made by applying an extended release coating of a water insoluble dissolution rate controlling polymer such as ethylcellulose to IR Beads. The MR Capsules are manufactured by filling IR and ER Beads in a proper ratio; the dose and the ratio required for an efficacious, cost effective and patient compliant treatment of children with ADHD were determined from extensive clinical investigations and in vitro- in vivo correlations performed as per FDA Guidelines, Guidance for Industry: Extended Release Oral Dosage Forms. Excerpt(s): Methylphenidate Hydrochloride, a scheduled II controlled substance, is currently marketed as a mild central nervous system (CNS) stimulant and the drug of choice for treatment of ADD and ADHA in children. The drug is well absorbed throughout the gastrointestinal tract. However, it has an extremely short half-life, which necessitates a multi-dose treatment regimen for conventional (immediate release) dosage forms such as currently available 5, 10, and 20 mg tablets. Due to high C.sub.max, oral administration of 10 and 20 mg Ritalin.RTM. is reported to result in notable side effects such as anorexia, weight loss, dizziness, etc. Furthermore, it requires the hyperactive children to be dosed in school thus causing hardship to school authorities as well as parents. The drawback of methylphenidate is that it also produces a euphoric effect when administered intravenously or through inhalation, thus presenting a high potential for substance abuse. Sustained release formulations for oncea-day dosing, such as 20 mg Ritalin SR.RTM. tablets currently available from Novartis and Geneva (generic version), were developed with the objective of providing efficacy for 8 hours, thereby improving compliance and reducing the incidence of diversion. However, there are reports which strongly suggest that the sustained release formulations exhibit a slower onset of action/efficacy compared to the immediate release dosage forms (W.E. Pelham et al., "Sustained Release And Standard Methylphenidate Effects On Cognitive And Social Behavior In Children With Attention Deficit Disorder," Pediatrics, Vol. 80, pp 491-501 (1987)). Recently, OROS.RTM. (methylphenidate HCl) has been approved by FDA. It is a new osmotic controlled release once-a-day oral dosage form with a drug overcoat, that is designed to deliver a portion of the dose for rapid onset of action and deliver the remainder of the dose in a controlled manner for about 10 hours. The manufacturing cost of this complicated dosage form is expected to be very high and hence resulting in a high cost of treatment. Hence, there is a dire need to develop modified release dosage forms with moderate cost of goods and having not only a rapid onset of action but also with a significantly longer

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duration of action. U.S. Pat. No. 5,908,850 assigned to Celgene Corporation discloses a method for treating children with the above disability to be treated using a sustained release dosage form containing d-threo-methylphenidate or pharmaceutically acceptable salts thereof thus minimizing hyperactivity and side effects. However, it does not address how it avoids dosing in school, thereby minimizing potential drug abuse. Web site: http://www.delphion.com/details?pn=US06344215__ •

Pharmaceutical dosage form for pulsatile delivery of d-threo-methylphenidate and a second CNS stimulant Inventor(s): Midha; Kamal K. (Hamilton, BM), Teicher; Martin H. (Waltham, MA) Assignee(s): Pharmaquest Ltd. (Hamilton, BM) Patent Number: 6,217,904 Date filed: April 6, 2000 Abstract: Novel pharmaceutical dosage forms provide for pulsatile delivery of d-threomethylphenidate and a second CNS stimulant, i.e., release encapsulated drug in spaced apart "pulses." The second CNS stimulant may be an analeptic agent or a psychostimulant, with analeptic agents preferred. The dosage forms may comprise capsules housing compressed tablets or drug-containing beads or particles, or may comprise a tablet with the first, second and optionally third dosage units each representing an integral and discrete segment thereof. Methods of treatment using the pharmaceutical dosage forms are provided as well. Excerpt(s): The present invention relates generally to drug delivery, and more specifically relates to novel pharmaceutical dosage forms that provide pulsatile delivery of d-threo-methylphenidate in combination with a second CNS stimulant. The invention additionally relates to methods for administering methylphenidate using the novel dosage forms. Pharmaceutical dosage forms are known which provide a variety of drug release profiles, including immediate release, sustained release, and delayed release. That is, it may be desirable, for a particular drug, to prevent drug release after drug administration until a certain amount of time has passed (so-called "timed release"), to provide substantially continuous release over a predetermined time period (so-called "sustained release") or to provide release immediately following drug administration (i.e., "immediate release"). For some types of drugs, it is preferred to release the drug in "pulses," wherein a single dosage form provides for an initial dose of drug followed by a release-free interval, after which a second dose of drug is released, followed by one or more additional release-free intervals and drug release "pulses." Pulsatile drug delivery is useful, for example, with active agents that have short half-lives and must be administered two or three times daily, with active agents that are extensively metabolized presystemically, and with active agents which lose the desired therapeutic effect when constant blood levels are maintained. These types of agents have pharmacokinetic-pharmacodynamic relationships that are best described by a clockwise "hysteresis loop." A drug dosage form that provides a pulsatile drug release profile is also useful for minimizing the abuse potential of certain types of drugs, i.e., drugs for which tolerance, addiction and deliberate overdose can be problematic. Because a precise and effective pulsatile drug delivery system is difficult to formulate and manufacture, there are few such dosage forms that have been commercialized. There are, however, several patents and literature references pertaining to pulsatile drug delivery. See, for example, U.S. Pat. No. 5,413,777 to Sheth et al., directed to a pulsatile once-a-day delivery system for the administration of minocycline; U.S. Pat. No.

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5,260,068 to Chen, directed to a multiparticulate pulsatile drug delivery system; U.S. Pat. No. 4,777,049 to Magruder et al., directed to an osmotic delivery system for constant release of a drug with intermittent release "pulses"; U.S. Pat. No. 5,391,381 to Wong et al., directed to a drug dispenser for delivering individual drug-containing units in a "pulsatile" manner; PCT Publication No. WO 98/32424, pertaining to pulsatile delivery of diltiazem hydrochloride; U.S. Pat. Nos. 5,472,708 and 5,260,069 to Chen; Ishino et al. (1992) "Design and Preparation of Pulsatile Release Tablet as a New Oral Drug Delivery System," Chem. Pharm. Bull. 40(11):3036-3041; Cohen et al. (1994), "Pulsatile Release from Microencapsulated Liposomes," J. Liposome Res. 349-360; and Gazzaniga et al. (1994), "Chronotopic Drug Delivery Systems for Pulsatile and/or Site-Specific Release," 21.sup.st. Proc. Int. Symp. Controlled Release Bioact. Mater., pp. 744-745. Web site: http://www.delphion.com/details?pn=US06217904__ •

Process for preparing the d-threo isomer of methylphenidate hydrochloride Inventor(s): Har; Denis (Harrison, NJ), Prashad; Mahavir (Montville, NJ) Assignee(s): Novartris AG (Basel, CH) Patent Number: 6,100,401 Date filed: April 20, 1998 Abstract: A process for preparing the d-threo isomer of methylphenidate hydrochloride comprising resolving the racemic mixture of threo methylphenidate hydrochloride with dibenzoyl-D-tartaric acid to obtain a dibenzoyl-D-tartrate salt enriched with the d-threo isomer of methylphenidate in a first step, basifying the tartrate salt to obtain the free base form of the d-threo isomer of methylphenidate in a second step, converting the free base to the hydrochloride salt form of the d-threo isomer of methylphenidate in high optical purity in a third step, and recrystallizing the hydrochloride salt form to obtain the desired d-threo isomer in a higher optical purity. Excerpt(s): The present invention relates to the area of resolution processes and, more particularly, relates to an improved process for preparing the d-threo isomer of methylphenidate hydrochloride employing dibenzoyl-D-tartaric acid as the resolving agent. Methylphenidate was first prepared as a mixture of the erythro and threo racemates. Subsequent studies of the two racemic mixtures revealed that the therapeutic activity resides in the threo diastereomer. Racemic threo methylphenidate hydrochloride is a mild nervous system stimulant which is marketed for the treatment of children with Attention Deficit Hyperactivity Disorder (ADHD). Further studies of the threo diastereomer revealed that the preferred therapeutic activity resides in the dthreo (or 2R,2'R enantiomer. More particularly, it has been found that the d-threo enantiomer is between five and thirty-eight times more active then the corresponding lthreo enantiomer. In addition, it has been shown that there are significant metabilic differences between the two enantiomers. Web site: http://www.delphion.com/details?pn=US06100401__

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Resolution of threo-methylphenidate Inventor(s): Zavareh; Hooshang Shahriari (Cambridge, GB) Assignee(s): Medeva Europe Limited (GB) Patent Number: 6,121,453 Date filed: September 8, 1998 Abstract: A process for preparing substantially single enantiomer d-threomethylphenidate, proceeds by means of a classical salt resolution using (-)menthoxyacetic acid. Excerpt(s): This invention relates to the resolution of threo methylphenidate via crystallisation of diastereomeric salts. Methylphenidate was first prepared as a mixture of the erythro and threo racemates. U.S. Pat. No. 2,957,880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo diastereomer. The resolution of threo methylphenidate can be achieved using the expensive resolving agent 1,1'-binaphthyl-2,2'-diylhydrogen phosphate, a process first reported by Patrick et al (The Journal of Pharmacology and Experimental Therapeutics, 241:152-158 (1987)), and subsequently used by other workers in the field (e.g. Aoyama et al, Journal of Chromatography, 494:420 (1989)). This is perceived to be a more efficient procedure than the method disclosed in U.S. Pat. No. 2,957,880, wherein the corresponding amide of erythro methylphenidate (i.e. R--CONR.sub.2 rather than R-CON.sub.2 Me) is resolved with tartaric acid prior to amide hydrolysis and equilibration at the benzylic centre, followed by esterification of the resultant threo-acid. Web site: http://www.delphion.com/details?pn=US06121453__

Patent Applications on Methylphenidate 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 methylphenidate: •

Composition comprising methylphenidate and another drug Inventor(s): Pope, Nicholas Robert; (Cambridge, GB), Richards, Andrew John McGlashan; (Cambridge, GB) Correspondence: Saliwanchik Lloyd & Saliwanchik; A Professional Association; 2421 N.W. 41st Street; Suite A-1; Gainesville; FL; 326066669 Patent Application Number: 20030049205 Date filed: October 21, 2002 Abstract: A process of treating a subject that is undergoing methylphenidate therapy and concomitant therapy with another drug undergoes or interferes with P.sub.450 metabolism, wherein the methylphenidate is d-threo-methylphenidate. Excerpt(s): This invention relates to a new composition comprising methylphenidate and another drug, and also to new ways or using known drugs including d-threo-

9

This has been a common practice outside the United States prior to December 2000.

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methylphenidate (abbreviated herein as dtmp). Methylphenidate is a known drug (although it is a controlled substance). It is used primarily to treat hyperactive children. Methylphenidate is a chiral molecule. The properties of the enantiomers have been investigated to some extent, although the drug is still administered as the racemate. It is generally thought that dtmp is the active material, and that its antipode (ltmp) is metabolized more rapidly. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and method for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with methylphenidate Inventor(s): Dixon, Terese A.; (Miami, FL), Mantelle, Juan; (Miami, FL) Correspondence: Foley And Lardner; Suite 500; 3000 K Street NW; Washington; DC; 20007; US Patent Application Number: 20020102291 Date filed: December 21, 2001 Abstract: The invention relates to a method of treating Attention Deficit Disorder (ADD) and Attention Deficit/Hyperactivity Disorder (ADHD) and compositions for topical application of methylphenidate comprising methylphenidate in a flexible, finite system wherein said composition comprises about 10 to 30 wt % methylphenidate, about 30 to 50 wt % acrylic adhesive, and about 30 to 50 wt % silicone adhesive and wherein said methylphenidate is delivered to a subject in need thereof such that the plasma concentration of methylphenidate increases over a period of about 6-16 hours, and more preferably over a period of about 6-12 hours followed by a steady decrease in plasma concentration of methylphenidate. Excerpt(s): This application is a continuation in part of U.S. patent application Ser. No. 09/618,626, filed Jul. 18, 2000, which is a Divisional Application of U.S. patent application Ser. No. 09/163,351, filed Sep. 30, 1998, now U.S. Pat. No. 6,210,705, which claims the benefit of U.S. provisional Application Ser. No. 60/069,510, filed Dec. 15, 1997, now abandoned. These applications are hereby incorporated by reference in their entirety. The present invention relates to compositions and methods for the treatment of Attention Deficit Disorder (ADD) and Attention Deficit/Hyperactivity Disorder (ADHD) by means of topical application of methylphenidate. Attention Deficit Disorder (ADD) and Attention Deficit/Hyperactivity Disorder (ADHD) (severally and collectively hereinafter referred to as "AD") are developmental disorders of self-control. They consist of problems with attention span, impulse control, and activity level. These problems are reflected in impairment of a person's will or capacity to control his or her own behavior relative to the passage of time and to keep future goals and consequences in mind. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Controlled/modified release oral methylphenidate formulations Inventor(s): Darke, Andrew; (Ontario, CA), Goldenheim, Paul D.; (Wilton, CT), Krishnamurthy, Thinnayam N.; (Ontario, CA), Oshlack, Benjamin; (New York, NY), Sackler, Richard S.; (Greenwich, CT) Correspondence: Davidson, Davidson & Kappel, Llc; 485 Seventh Avenue, 14th Floor; New York; NY; 10018; US Patent Application Number: 20040131680 Date filed: December 19, 2003 Abstract: The invention is directed to oral modified/controlled release methylphenidate formulations which provide a rapid initial onset of effect and a prolonged duration of effect. Preferably, the peak concentration is lower than that provided by the reference standard for immediate release methylphenidate formulations, and the duration of effect falls rapidly at the end of the dosing interval so as not to affect the appetite of the patient at dinner nor the patient's sleep thereafter. Excerpt(s): This application claims priority from U.S. Provisional Application No. 60/112,667, filed Dec. 17, 1998, the disclosure of which is hereby incorporated by reference. Sustained release dosage forms are central in the search for improved therapy, both through improved patient compliance and decreased incidences of adverse drug reactions. It is the intent of all sustained release formulations to provide a longer period of pharmacologic action after administration than is ordinarily obtained after administration of immediate-release dosage forms. Sustained release compositions may be used to delay absorption of a medicament until it has reached certain portions of the alimentary tract, and maintain a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered. Such longer periods of response provide for many therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations. Thus, therapy may be continued without interrupting the sleep of the patient, which is of special importance, for example, when treating a patient for moderate to severe pain (e.g., a post-surgery patient, a cancer patient, etc.), or for those patients who experience migraine headaches on awakening, as well as for the debilitated patient for whom sleep is essential. A further general advantage of longer acting drug preparations is improved patient compliance resulting from the avoidance of missed doses through patient forgetfulness. Unless conventional rapid acting drug therapy is carefully administered at frequent intervals to maintain effective steady state blood levels of the drug, peaks and valleys in the blood level of the active drug occurs because of the rapid absorption, systemic excretion of the compound and through metabolic inactivation, thereby producing special problems in maintenance therapy of the patient. In view of this, it is considered a goal of many skilled in the art that a controlled release dosage form will ideally provide therapeutic concentration of the drug in blood that is maintained throughout the dosing interval with a reduction in the peak/trough concentration ratio. Central to the development process are the many variables that influence the in vivo release and subsequent absorption of the active ingredients from the gastrointestinal tract. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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DELIVERY OF MULTIPLE DOSES OF MEDICATIONS Inventor(s): DARIANI, MAGHSOUD M.; (FANWOOD, NJ), MEHTA, ATUL M.; (RAMSEY, NJ), ZEITLIN, ANDREW L.; (MILLINGTON, NJ) Correspondence: Woodcock Washburn Kurtz; Mackiewicz & Norris; One Liberty Place 46th; Philadelphia; PA; 19103 Patent Application Number: 20030113373 Date filed: March 11, 1998 Abstract: Dosage forms for oral administration of a methylphenidate drug are provided. The dosage forms provide a substantially immediate dose of methylphenidate upon ingestion, followed by one or more additional doses at predetermined times. By providing such a drug release profile, the dosage forms eliminate the need for a patient to carry an additional dose for ingestion during the day. The dosage forms and methods provided are useful in administering methylphenidate and pharmaceutically acceptable salts thereof, which generally require one or more doses throughout the day. Excerpt(s): This application is a divisional application of application Ser. No. 08/892,190, which is a continuation in part of application Ser. No. 08/567,131, filed Dec. 4, 1995; application Ser. No. 08/583,317, filed Jan. 5, 1996; and application Ser. No. 08/647,642, filed May 15, 1996. The present invention relates to improved dosing of medications. In particular, the present invention relates to improved dosing of a medication whereby two or more effective, time-separated doses may be provided by administration of a single dosage unit. The second, and any later, dose is time-delayed following administration. Based on predictable in vitro release times, the dosage forms can be formulated to deliver delayed doses in vivo at desired times. The dosage forms and methods of the present invention are particularly suitable for the administration of methylphenidate hydrochloride, and especially for the administration of a single isomer, d-threo-methylphenidate hydrochloride. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Detection of abused substances and their metabolites using nucleic acid sensor molecules Inventor(s): Seiwert, Scott; (Pacifica, CA) Correspondence: Mcdonnell Boehnen Hulbert & Berghoff; 300 South Wacker Drive; Suite 3200; Chicago; IL; 60606; US Patent Application Number: 20030224435 Date filed: May 16, 2003 Abstract: Nucleic acid sensor molecules (allozymes, allosteric ribozymes, allosteric DNAzymes), aptamers and methods are provided for the detection and quantitation of small molecules, including drugs, drug analogs, and drug metabolites, for example recreational drugs, mood-altering drugs, and performance enhancing drugs such as 4MTA (4-methylthioamphetamine), Alpha-ethyltryptamine, Amphetamine, Amyl nitrite, Benzocaine, Cocaine, Dimethyltryptamine, Ecstasy (MDA, MDMA, MDEA), Ephedrine, Erythropoietine (Epogen), Fentanyl, Gamma Hydroxybutyrate (GHB), GBL (Gamma butyrolactone), GHB (Gamma Hydroxybutyrate), Hashish, Heroin, Isobutyl nitrite, Ketamine, Lidocaine, LSD (Lysergic acid diethylamide), Mannitol, Marijuana (THC),

Patents 143

Mescaline, Methadone, Methamphetamine, Methaqualone, Methcathinone, Methylphenidate (ritalin), Morphine, Nexus (2CB), Nicotine, Opium, Oxycodone, OxyContin, PCP (phencyclidine), Peyote, Phenobarbital, Procaine, Psilocybin, Psilocybin/psilocin, Pseudoephedrine, Rohypnol, Scopolamine, Steroids, Strychnine, and Talwin. Also provided are kits for detection. The nucleic acid sensor molecules, methods and kits provided herein can be used in diagnositic applications for detecting drugs, analogs, and metabolites thereof. Excerpt(s): This patent application claims the benefit of U.S. Ser. No. 60/381,006, filed May 16, 2002. This application is hereby incorporated by reference herein in its entirety including the drawings. This invention relates generally to the field of drug and drug metabolite detection in biological samples. More specifically, it provides a system for detecting or confirming the presence of a particular drug analyte in a sample that potentially contains interfering substances. This invention specifically relates to novel molecular sensors that utilize enzymatic nucleic acid constructs whose activity can be modulated by the presence or absence of signaling agents that include compounds and substances of abuse, such as recreational drugs, mood altering drugs, performance enhancing drugs, analgesics, and metabolites thereof. The present invention further relates to the use of the enzymatic nucleic acid constructs as molecular sensors capable of modulating the activity, function, or physical properties of other molecules useful in detecting compounds and substances of abuse and metabolites thereof. The invention also relates to the use of the enzymatic nucleic acid constructs as diagnostic reagents, useful in identifying such signaling agents in a variety of applications, for example, in screening biological samples or fluids for compounds and substances of abuse and metabolites thereof. The ability to perform rapid screening tests in diagnostic analysis of biological samples has been considerably facilitated by the evolving art of immunoassay. Antibodies can be raised that have exquisite specificity and sensitivity for small molecules of diagnostic interest, such as drugs and drug metabolites. In combination with other reagents that have a separating or labeling function, specific antibodies can be used as part of a rapid screening test for the presence of the small molecule in a clinical sample. Similarly, nucleic acid technology can be applied to develop polynucleotide based detection systems comprising nucleic acid molecules with high affinity for a particular small molecule target. Furthermore, the functionality of enzymatic nucleic acid molecules can be coupled with these recognition properties in the design of nucleic acid sensor molecules having both recognition and signal generating capability. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

METHOD AND SYNERGISTIC COMPOSITION FOR TREATING ATTENTION DEFICIT/HYPERACTIVITY DISORDER Inventor(s): Lang, Philip C.; (Toms River, NJ) Correspondence: Delio & Peterson; 121 Whitney Avenue; New Haven; CT; 06510 Patent Application Number: 20030044472 Date filed: August 28, 2001 Abstract: A composition and method for treating Attention Deficit/Hyperactivity Disorder (ADHD) is provided which composition can be used both with and without ethical drugs now used to treat ADHD. The composition contains dimethylaminoethanol (DMAE), omega 3-fatty acids, betaine, oligomeric proanthocyanidins (OPC), folic acid, vitamins C, E, B.sub.12, B.sub.6, B.sub.5 and beta-

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carotene and minerals (calcium, magnesium, zinc and selenium). Ethical drugs such as amphetamines, methylphenidate HCl and pemoline are known to control ADHD, but each has significant side effects when used in their therapeutic dose. When combining the composition of the invention with such ethical drugs, the amount of the ethical drug can be lowered below a level which causes undesirable side effects which is an important feature of the invention. Preferred compositions of the invention contain one or more of lecithin, choline, 5-hydroxytryptophan, tyrosine, Reishi Extract, Kava Extract, Gingko, Ginseng and St. John's Wort. Excerpt(s): The present invention relates to a composition and method for treating Attention Deficit/Hyperactivity Disorder. Attention Deficit/Hyperactivity Disorder (ADHD) is the fastest growing childhood disorder in the United States. About four million children and thirteen million adults suffer from attention deficit in the U.S. Diagnostic and Statistical Manual of Mental Disorders (DSM IV) categorization of ADHD includes terms such as "inattention, impulsiveness and hyperactivity". Three subtypes are recognized ADHD: Combined type; ADHD, Predominately Inattentive Type; and ADHD, Predominately Hyperactive/Impulsive Type. The Predominately Inattentive Type makes careless mistakes, cannot keep focused on a task, and loses attention and interest quickly. Often the person appears not to listen as if their mind is "someplace else". The predominately Hyperactive/Impulsive Type is characterized by fidgetiness, excessive unproductive movement, impulsiveness, inappropriate behavior, making noise, impatience, touching things or being disruptive. Depending on age and development stage, ADHD sufferers may exhibit low frustration tolerance, temper outbursts, stubbornness, making demands, mood lability, rejection by peers and poor self-esteem. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for preventing abuse of methylphenidate Inventor(s): Midha, Kamal K.; (Hamilton, BM) Correspondence: Reed & Eberle Llp; 800 Menlo Avenue, Suite 210; Menlo Park; CA; 94025; US Patent Application Number: 20030170181 Date filed: December 16, 2002 Abstract: A method is provided for treating a patient with a methylphenidate-responsive condition that is at a risk of abusing or becoming addicted to methylphenidate. The patient is first evaluated for an elevated risk of drug abuse or addiction through psychological evaluations and then treated with a methylphenidate product that includes an emesis-inducing agent that is inert when ingested orally and only produces emesis when snorted or taken intravenously or a topical analgesic that is inert when ingested orally and only produces irritation when snorted or taken intravenously. The method includes delivering the methylphenidate in a pulsatile delivery system such that the emesis-inducing agent or the topical analgesic is included in one of the pulsatile dosages. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 09/992,353, filed Nov. 13, 2001, which is a continuation of U.S. patent application Ser. No. 09/544,732, filed Apr. 6, 2000, and issued as U.S. Pat. No. 6,340,476 on Jan. 22, 2002, which claimed priority under 35 U.S.C.sctn.119(e)(1) to U.S. Provisional Patent Application Serial No. 60/127,984, filed Apr. 6, 1999. The disclosures of the

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aforementioned patent applications are incorporated by reference herein. The present invention relates generally to the fields of drug delivery, pharmacology, and medicine. More specifically, the invention relates to a method of reducing the likelihood of abuse of methylphenidate by administering a methylphenidate product that is formulated to prevent abuse of the drug. The methylphenidate product may be administered to the patient via a pulsatile drug release system. The drug as used in therapy is a racemic mixture of the d- and l-threo enantiomers, which have been acknowledged as more active than the erythro pair. The racemic d,l-threo methylphenidate (hereinafter referred to as "methylphenidate," "d,l-MPH," or "MPH") is a short-acting stimulant with a duration of action of one to four hours and a pharmacokinetic elimination half-life of two to three hours. Maximum drug concentration after oral administration occurs at about two hours, at which time, the methylphenidate has been absorbed from the gastrointestinal tract and has passed into the systemic circulation including the brain. It is believed that once in the brain, methylphenidate influences neurotransmitters by inhibiting the uptake of dopamine in the striatum. Kimko, H. C., et al., "Pharmacokinetics and Clinical Effectiveness of Methylphenidate," Clinical Pharmacokinetics 37(b):457-470 (December, 1999). The therapeutic dosage for methylphenidate is typically very low with tablets being dispensed in 5 mg, 10 mg, and 20 mg dosages, concentrations often referred to as "microdoses." Side effects of the drug in its therapeutic dosages include anorexia, weight loss, insomnia, dizziness, and dysphoria. See, e.g., U.S. Pat. No. 6,410,746 to Davies. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate Inventor(s): Faleck, Herbert; (West Orange, NJ), Khetani, Vikram; (Jersey City, NJ), Zeldis, Jerome B.; (Princeton, NJ) Correspondence: Woodcock Washburn Kurtz; Mackiewicz & Norris Llp; One Liberty Place - 46th Floor; Philadelphia; PA; 19103; US Patent Application Number: 20020022640 Date filed: July 12, 2001 Abstract: In one aspect, the present invention is directed to methods for treating fatigue, neurobehavioral slowing and other cognitive disorders and defects due to cancers and treatments associated with cancers, and similar conditions. In a further aspect, the present invention is directed to methods for treating disorders related to menopause, including executive function defects. The methods involve the administration of a composition comprising D-threo methylphenidate that is substantially free of L-threo methylphenidate and of erythro forms of methylphenidate. Excerpt(s): This application is a continuation in part of U.S. Ser. No. 09/318,151, filed May 25, 1999, which is a continuation in part of U.S. Ser. No. 08/583,317 filed Jan. 5, 1996, now U.S. Pat. No. 5,773,756, and a continuation in part of U.S. Ser. No. 08/827,230, filed Apr. 2, 1997, now U.S. Pat. No. 5,908,850, which is continuation of U.S. Ser. No. 08/567,131, filed Dec. 4, 1995. The contents of each of the foregoing applications are incorporated herein by reference in their entirety. Advanced cancer typically produces severe pain in patients. This pain is often controlled by the administration of large doses of analgesics, including opioid analgesics. However, the pain relief is often accompanied by undesirable side-effects such as unacceptable sedation and/or a decrease in cognitive function. These side effects have a significant negative impact on the quality of life of the

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patient. In addition, cancer patients often display one or more of a decrease in cognitive function, fatigue, and neurobehavioral slowing that is unrelated to the administration of analgesics, but may be related to the underlying cancer, the treatment of the cancer, or both. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Multi-spike release formulation for oral drug delivery Inventor(s): Steiner, Solomon S.; (Mount Kisco, NY) Correspondence: Patrea L. Pabst; Holland & Knight Llp; Suite 2000, One Atlantic Center; 1201 West Peachtree Street, N.E.; Atlanta; GA; 30309-3400; US Patent Application Number: 20010046472 Date filed: January 19, 2001 Abstract: Methylphenidate or other drugs are provided in a formulation for oral administration that releases the drug in two or more pharmacokinetic spikes, by combining different release forms in a single formulation. In a preferred embodiment for methylphenidate, the first pharmacokinetic spike is achieved by the release of tastemasked methylphenidate which is not enterically coated, while a second pharmacokinetic spike is achieved by the release of methylphenidate in a finely divided form from enterically coated pellets or microparticles formulated for rapid release following dissolution of the enteric coating. A critical aspect of the formulation is the inclusion of excipients that create a burst release following the initial rapid release and uptake. The formulation can be administered as a paste, jelly, suspension, or fast dissolving wafer. To manipulate the dose, the formulation can be provided, for example, as a paste packaged in a tube similar to those used to dispense toothpaste. Excerpt(s): The present invention is generally in the field of pharmaceutical formulations, and more particularly related to methods and compositions for controlling the pharmacokinetic profile of drugs, such as methylphenidate, which are used in pharmaceutical applications. This application claims priority to U.S. Ser. No. 60/176,853 filed Jan. 19, 2000. Methylphenidate (trade name RITALIN.TM.) is used to treat hyperactivity and attention deficit disorder (ADD) in children. While it is very effective when administered orally, the effects only last for only about three to four hours. It would be desirable to have a dose form that could be administered in the morning and maintain the child throughout the school day. Typical slow release formulations are not suitable because they produce a continuous slow release, approaching a zero order kinetic release profile. Methylphenidate, however, requires a spike or "saw tooth" (i.e. multi-spike) kinetic profile to be effective in the treatment of ADD. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Oral controlled release dosage form Inventor(s): Chen, Chih-Ming; (Taipei, TW), Cheng, Xiu Xiu; (Weston, FL), Dixit, Manesh; (Sunrise, FL), Xie, Jianbo; (Davie, FL) Correspondence: Martin P. Endres, ESQ.; Hedman & Costigan, P.C.; 1185 Avenue OF The Americas; New York; NY; 10036; US Patent Application Number: 20040156896 Date filed: December 2, 2003 Abstract: A dosage form that provides a controlled release solid dosage form for the oral administration of a central nervous system stimulant, preferably methylphenidate hydrochloride. Excerpt(s): The present application claims priority to U.S. Provisional Patent No. 60/431,954, filed Dec. 9, 2002. The present invention relates to the improved dosing of medication. Specifically, this invention improves the therapeutic effect of a central nervous system stimulant such as methylphenidate hydrochloride by delivering the medication over a predetermined period of time. In the present invention an initial immediate dose of the central nervous system stimulant is delivered followed by a second controlled dose of the medication from a single oral dosage form. The invention helps improve patient compliance and decreases the need for additional daily doses of the medication. Methylphenidate is a central nervous system stimulant used to treat Attention-Deficit Disorder (ADD) and Attention-Deficit Hyperactivity Disorder (ADHD), available commercially as, e.g. RITALIN SR.RTM., CONCERTA.TM., METADATE.TM. CD capsules and METEADATE.TM. ER Tablets. The beneficial results seen by clinicians in the treatment of ADD and ADHD has resulted in widespread use of methylphenidate in more than two million patients annually. Methylphenidate exists in four separate optical isomers, 1-threo, d-erythro, d-threo and 1-erythro, with the threo pair of enantiomers (racemate) of methylphenidate hydrochloride generally administered for the treatment of ADD and ADHD. Methylphenidate hydrochloride is a mild central nervous system stimulant with pharmacological properties similar to that of amphetamines. The side effects which are associated with the use of methylphenidate include anorexia, weight loss, insomnia, dizziness and dysphoria. Methylphenidate is categorized by the DEA as a Schedule II controlled substance because it produces a euphoric effect when administered intravenously or through inhalation or ingestion, and thus carries a high potential for abuse. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Pharmaceutical composition which reduces or eliminates drug abuse potential Inventor(s): Joshi, Yatindra; (Princeton, NJ), Somma, Russell; (Sparta, NJ) Correspondence: Thomas Hoxie; Novartis Corporation; Patent And Trademark Dept; 564 Morris Avenue; Summit; NJ; 079011027 Patent Application Number: 20020187192 Date filed: August 30, 2001 Abstract: A pharmaceutical composition which reduces or eliminates the drug abuse potential of central nervous system stimulant comprising: (a) a drug selected from the group consisting of methylphenidate, amphetamine, methamphetamine, and combinations thereof; and (b) a gel forming polymer wherein the gel forming polymer is

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a polymer that forms a gel when contacted with moisture or placed in an aqueous solution. The present invention is based on the discovery that a central nervous system stimulant such as methylphenidate in combination with a gel forming polymer reduces or eliminates drug abuse potential by swelling in the presence of moisture, and thus, preventing nasal absorption and injectability of the drug. Excerpt(s): The present invention relates to a pharmaceutical composition which reduces or eliminates drug abuse potential. More specifically, the composition comprises a central nervous system stimulant and a gel forming polymer. Methylphenidate, which is commercially available under the trademark Ritalin.RTM. from Novartis Pharmaceuticals Corporation, is a central nervous system stimulant. Other examples of central nervous stimulants are amphetamine and methamphetamine. Central nervous stimulants activate the brain stem arousal system to effect stimulation of the patient. Methylphenidate is the most commonly prescribed psychotropic medication for children in the United States, primarily for the treatment of children diagnosed with attention deficit disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD), and thus, is widely available. In addition, methylphenidate has been found to be particularly useful for treating Acquired Immunodeficiency Syndrome (AIDS) patients who suffer from cognitive decline. See Navia et al., Annals of Neurology, 19:517-524 (1986). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pharmaceutical dosage form for pulsatile delivery of methylphenidate Inventor(s): Chungi, Shubha; (Sharon, MA), Iorio, Theodore L.; (Millis, MA), Midha, Kamal K.; (Hamilton, CA) Correspondence: Reed & Associates; 800 Menlo Avenue; Suite 210; Menlo Park; CA; 94025; US Patent Application Number: 20020058061 Date filed: November 13, 2001 Abstract: Novel pharmaceutical dosage forms provide for pulsatile delivery of methylphenidate, i.e., release encapsulated drug in spaced apart "pulses." The dosage forms are comprised of first, second and optionally third dosage units, with each dosage unit having a different drug release profile. The dosage forms may comprise capsules housing compressed tablets or drug-containing beads or particles, or may comprise a single tablet with the first, second and optionally third dosage units each representing an integral and discrete segment thereof. Methods of treatment using the pharmaceutical dosage forms are provided as well. Excerpt(s): This application claims priority to U.S. Provisional Patent Application Ser. No. 60/127,984, filed Apr. 6, 1999. The present invention relates generally to drug delivery, and more specifically relates to novel pharmaceutical dosage forms that provide pulsatile delivery of methylphenidate. The invention additionally relates to methods for administering methylphenidate using the novel dosage forms. Pharmaceutical dosage forms are known which provide a variety of drug release profiles, including immediate release, sustained release, and delayed release. That is, it may be desirable, for a particular drug, to prevent drug release after drug administration until a certain amount of time has passed (so-called "timed release"), to provide substantially continuous release over a predetermined time period (so-called "sustained release") or to provide release immediately following drug administration

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(i.e., "immediate release"). For some types of drugs, it is preferred to release the drug in "pulses," wherein a single dosage form provides for an initial dose of drug followed by a release-free interval, after which a second dose of drug is released, followed by one or more additional release-free intervals and drug release "pulses." Pulsatile drug delivery is useful, for example, with active agents that have short half-lives and must be administered two or three times daily, with active agents that are extensively metabolized presystemically, and with active agents which lose the desired therapeutic effect when constant blood levels are maintained. These types of agents have pharmacokinetic-pharmacodynamic relationships that are best described by a clockwise "hysteresis loop." A drug dosage form that provides a pulsatile drug release profile is also useful for minimizing the abuse potential of certain types of drugs, i.e., drugs for which tolerance, addiction and deliberate overdose can be problematic. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pulse dosage formulations of methylphenidate and method to prepare same Inventor(s): Krsek, George; (Tucson, AZ) Correspondence: Dale F. Regelman; Hayes, Soloway, Hennessey,; Grossman, & Hage, P.C.; 130 W. Cushing Street; Tucson; AZ; 85701; US Patent Application Number: 20030129229 Date filed: January 3, 2002 Abstract: Dosage forms comprising pulse release formulations for oral administration of a Methylphenidate drug are provided. The dosage forms provide a substantially immediate dose of methylphenidate upon ingestion, followed by one or more additional doses at predetermined times. By providing such a drug release profile, the dosage forms eliminate the need for a patient to carry an additional dose for ingestion during the day. The dosage forms and methods provided are useful in administering Methylphenidate and pharmaceutically acceptable salts thereof, which generally require one or more doses throughout the day. Excerpt(s): Applicant's invention relates to improved dosing of medications. In particular, the present invention relates to improved dosing of a medication whereby two or more effective pulse dosages may be provided by administration of a pulse release formulation. Effective administration of the second pulse dosage is time-delayed following oral ingestion of Applicant's pulse release formulation. Applicant's dosage forms and methods are particularly suitable for the administration of methylphenidate hydrochloride, and especially for the administration of a single isomer, d-threomethylphenidate hydrochloride ("DTMP"). Applicant's method of administration of a pulse release formulation which contains a first pulse release dosage in combination with a second pulse release dosage provides for reduced abuse potential, improved convenience of administration, and better patient compliance, especially when methylphenidate is used to treat certain central nervous system disorders. Attention Deficit Disorder (ADD), a commonly diagnosed nervous system illness in children, is often treated with methylphenidate hydrochloride. Methylphenidate is sold in commerce under the name Ritalin.RTM. Ritalin is a registered trademark owned by Novartis Corporation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Single isomer methylphenidate and resolution process Inventor(s): Harris, Michael Christopher James; (Cambridge, GB), Zavareh, Hooshang; (Cambridge, GB) Correspondence: Saliwanchik Lloyd & Saliwanchik; A Professional Association; 2421 N.W. 41st Street; Suite A-1; Gainesville; FL; 326066669 Patent Application Number: 20010014687 Date filed: April 17, 2001 Abstract: Single isomer methylphenidate, selected from the d- and l-threo-enantiomers, has been obtained in purified form, to the extent of less than 2% by weight of a contaminant selected from resolving agent and ritalinic acid. This is achieved by resolution of a mixture of enantiomers using an O,O'-diaroyltartaric acid as resolving agent. Excerpt(s): This invention relates to the resolution of threo methylphenidate via crystallisation of diastereomeric salts, and to the especially pure enantiomers thus obtained. Methylphenidate is a therapeutic agent that is widely used in the treatment of attention-deficient hyperactivity disorder. It is a controlled substance. Methylphenidate was first prepared as a mixture of the erythro and threo racemates. U.S. Pat. No. 2,957,880 discloses studies upon the two racemic mixtures, which revealed that the therapeutic activity resides in the threo diastereomer. It is now considered that it is the d-threo [or (R,R)] enantiomer that has the preferred therapeutic activity. Uses of this enantiomer are disclosed in PCT/GB96/01688, PCT/GB96/01689 and PCT/GB96/01690, the contents of which are incorporated herein by reference. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of methylphenidate compounds to enhance memory Inventor(s): Epstein, Mel; (Bristol, RI), Wiig, Kjesten A.; (Providence, RI) Correspondence: Ropes & Gray; One International Place; Boston; MA; 02110-2624; US Patent Application Number: 20020132793 Date filed: February 28, 2002 Abstract: The present invention makes available methods and reagents for facilitating memory, e.g., to increase memory function such as long-term memory and recall ability. Memory is increased by increasing attention and long term consolidation. Excerpt(s): This application is a continuation-in-part of U.S. Ser. No. 09/941,238 filed Aug. 28, 2001, and also claims priority to U.S. Provisional Patent Application No. 60/228,478 filed on Aug. 28, 2000 and to U.S. Provisional Patent Application No. 60/235,972 filed on Sep. 28, 2000, the specifications of each of which are incorporated by reference herein. The term "memory" subsumes many different processes and requires the function of many different brain areas. Overall, human memory provides declarative recall, e.g., for facts and events accessible to conscious recollection, and non-declarative recall, e.g., procedural memory of skills and operations not stored regarding time and place. Research in recent years has provided information necessary to many of the various components of memory and identify associated brain regions. A newly acquired experience initially is susceptible to various forms of disruption. With time, however, the new experience becomes resistant to disruption. This observation has been interpreted to indicate that a labile, working, short-term memory is consolidated into a

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more stable, long-term memory. Behavioral research has found that the human mind consolidates memory at certain key time intervals. The initial phase of memory consolidation occurs in the first few minutes after we are exposed to a new idea or learning experience. The next phase occurs over a longer period of time, such as during sleep. If a learning experience has on-going meaning to us, the next week or so serves as a further period of memory consolidation. In effect, in this phase, the memory moves from short-term to long-term storage. 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 methylphenidate, 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 “methylphenidate” (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 methylphenidate. You can also use this procedure to view pending patent applications concerning methylphenidate. 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 METHYLPHENIDATE Overview This chapter provides bibliographic book references relating to methylphenidate. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on methylphenidate 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 “methylphenidate” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “methylphenidate” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “methylphenidate” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

21st Century Complete Medical Guide to Attention Deficit Hyperactivity Disorder (ADD or ADHD), Ritalin and other Treatment Options, Authoritative CDC, NIH, and FDA Documents, Clinical References, and Practical Information for Patients and Physicians (CD-ROM) by PM Medical Health News; ISBN: 159248669X; http://www.amazon.com/exec/obidos/ASIN/159248669X/icongroupinterna

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Is Ritalin Wrong for Our Hyperactive Kids/Cassette; ISBN: 9990990999; http://www.amazon.com/exec/obidos/ASIN/9990990999/icongroupinterna

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The Effects of the Use of Methylphenidate in the Treatment of Attention Deficit Hyperactivity Disorder Diagnosed Children; ISBN: 0788102281; http://www.amazon.com/exec/obidos/ASIN/0788102281/icongroupinterna

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Without Ritalin [DOWNLOAD: MICROSOFT READER] by Samuel A. Berne; ISBN: B000096B49; http://www.amazon.com/exec/obidos/ASIN/B000096B49/icongroupinterna

Chapters on Methylphenidate In order to find chapters that specifically relate to methylphenidate, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and methylphenidate 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 “methylphenidate” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on methylphenidate: •

Stimulants Source: in Barkley, R.A. Taking Charge of ADHD: The Complete, Authoritative Guide for Parents. New York, NY: Guilford Press. 2000. p. 269-287. Contact: Available from Guilford Publications. 72 Spring Street, New York, NY 10012. (800) 365-7006. Fax (212) 966-6708. E-mail: [email protected]. Website: www.guilford.com. PRICE: $18.95 plus shipping and handling. ISBN: 1572305606. Summary: Children whose problems with attention, overactivity, and lack of inhibition reach a certain level have a developmental disability known as attention deficit hyperactivity disorder (ADHD). This chapter on medications (drug therapy) is from a book intended to help parents who are raising a child with ADHD and for others who wish to know more about the disorder and its management. The author's main goal is to empower parents to take charge of the care of these often demanding children in a way that ensures the health of the entire family, collectively and individually. In this chapter, the author focuses on stimulants, the drugs most commonly used, noting that stimulants have been shown to be effective in improving behavior, academic work, and social adjustment in 50 to 95 percent of children with ADHD. The author offers up to date information on the stimulant medications. The brand names of these medications include Ritalin (methylphenidate), Dexedrine (d amphetamine), Adderall (d and l amphetamine combination), and Cylert (pemoline). The author begins by refuting myths about these drugs, and encouraging readers to gather information from their physicians and from reference tools. The author then describes how the stimulants work, what the drugs do for behavior and emotions, how the drugs change learning and academic performance, the effect of these medications on social behavior, how long the effects of the drugs last, possible side effects (decreased appetite, increased heart rate and blood pressure, increased brain electrical activity, insomnia, nervous tics, temporary psychosis, long term effects), deciding about stimulant use in an individual child, how stimulants are prescribed, and when the medicines should be stopped. 1 figure.

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Treatment Strategies for Memory Disorders: Pharmacologic Treatment Source: in Khan, A.U. Clinical Disorders of Memory. New York, NY: Plenum Publishing Corporation. 1986. p. 239-247. Contact: Available from Plenum Publishing Corporation. 233 Spring Street, New York, NY 10013. ISBN: 030642259X.

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Summary: This chapter discusses various drugs that have been used in the treatment of memory disorders. A fairly large number of drugs have been tried in the treatment of senile dementia and in the improvement of memory deficits suffered by the elderly. Most of these drugs can be categorized under six classes: cholinergic drugs; central nervous system stimulants; nootropic drugs; vasodilators; convulsant stimulants; anabolic agents; GABA-ergic drugs; and neuropeptides. Particular attention is given to cholinergic drugs which are used to enhance the cholinergic activity of the brain, physostigmine, arecoline, choline and lecithin, central nervous system stimulants, methylphenidate, magnesium pemoline. Research drugs also are discussed.

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CHAPTER 7. PERIODICALS AND NEWS ON METHYLPHENIDATE Overview In this chapter, we suggest a number of news sources and present various periodicals that cover methylphenidate.

News Services and Press Releases One of the simplest ways of tracking press releases on methylphenidate 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 “methylphenidate” (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 methylphenidate. 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 “methylphenidate” (or synonyms). The following was recently listed in this archive for methylphenidate: •

Celltech says Metadate better than Concerta during school day Source: Reuters Industry Breifing Date: March 08, 2004

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FDA rejects methylphenidate patch to treat ADHD Source: Reuters Medical News Date: April 28, 2003

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German insurer warns of steep rise in Ritalin use Source: Reuters Health eLine Date: January 27, 2003

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German health insurance chief warns of "alarming increase" in Ritalin use Source: Reuters Industry Breifing Date: January 27, 2003

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Once-daily version of Ritalin approved by US FDA Source: Reuters Medical News Date: June 06, 2002

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Once-daily version of Novartis' Ritalin wins FDA approval Source: Reuters Industry Breifing Date: June 06, 2002

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New dosage strength for Alza's Concerta cleared by FDA Source: Reuters Industry Breifing Date: April 02, 2002

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Janssen-Cilag launches once-daily methylphenidate in UK Source: Reuters Industry Breifing Date: February 25, 2002

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Alpharma wins FDA okay for new generic Ritalin dosages Source: Reuters Industry Breifing Date: February 06, 2002

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Childhood methylphenidate treatment reduces adult cocaine response Source: Reuters Industry Breifing Date: December 05, 2001

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Single-isomer Ritalin to help Celgene maintain profitability, analysts say Source: Reuters Industry Breifing Date: November 15, 2001

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Some kids on Ritalin sell the drug to classmates Source: Reuters Health eLine Date: November 13, 2001

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Once-daily Ritalin product receives FDA approvable letter Source: Reuters Medical News Date: October 02, 2001

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Once-daily Ritalin close to FDA approval Source: Reuters Health eLine Date: October 02, 2001

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Novartis, Celgene once-daily Ritalin product receives FDA approvable letter Source: Reuters Industry Breifing Date: October 02, 2001

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Govt. report downplays Ritalin abuse in schools Source: Reuters Health eLine Date: September 19, 2001

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FDA grants approvable letter for new Ritalin formulation Source: Reuters Industry Breifing Date: August 22, 2001

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Connecticut Ritalin law targets schools, not docs Source: Reuters Health eLine Date: July 25, 2001

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Biovail, Celgene file Ritalin formulation for Canadian approval Source: Reuters Industry Breifing Date: July 10, 2001

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Once-daily extended-release methylphenidate for ADHD can replace t.i.d. dosing Source: Reuters Industry Breifing Date: June 04, 2001

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Once-daily methylphenidate for pediatric ADHD is approvable by FDA Source: Reuters Medical News Date: March 19, 2001

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Judge in US rejects Ritalin complaints Source: Reuters Industry Breifing Date: March 14, 2001

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Study suggests Ritalin abuse occurs on campus Source: Reuters Health eLine Date: December 29, 2000

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Celgene files Ritalin formulation with FDA, earns $5 million milestone Source: Reuters Industry Breifing Date: December 27, 2000

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Alza 's Concerta for ADHD helps drive company growth Source: Reuters Industry Breifing Date: November 29, 2000

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UK drug watchdog approves Ritalin use Source: Reuters Industry Breifing Date: October 31, 2000

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Lawsuits allege conspiracy in Ritalin use; Congressman urges probe of abuses Source: Reuters Industry Breifing Date: September 15, 2000

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Lawsuits allege Ritalin conspiracy; Congressman orders probe Source: Reuters Health eLine Date: September 14, 2000

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UK mulls restricting Ritalin use Source: Reuters Industry Breifing Date: September 12, 2000

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UK reexamines Ritalin use in children Source: Reuters Health eLine Date: September 11, 2000

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Alza licenses Concerta from Crescendo; drug will be costliest on ADHD market Source: Reuters Industry Breifing Date: August 03, 2000

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Once-daily controlled-release methylphenidate effective as ADHD treatment Source: Reuters Medical News Date: May 19, 2000

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Alza's Concerta for ADD/ADHD deemed approvable by FDA Source: Reuters Industry Breifing Date: May 19, 2000

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Alza study suggests extended-release methylphenidate is efficacious Source: Reuters Industry Breifing Date: May 08, 2000

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White House plan aims to curb Ritalin use Source: Reuters Health eLine Date: March 20, 2000

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Short trial useful for parents deciding about methylphenidate for their children Source: Reuters Medical News Date: December 28, 1999 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “methylphenidate” (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

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you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “methylphenidate” (or synonyms). If you know the name of a company that is relevant to methylphenidate, 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 “methylphenidate” (or synonyms).

Academic Periodicals covering Methylphenidate Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to methylphenidate. In addition to these sources, you can search for articles covering methylphenidate 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 8. 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 methylphenidate. 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 methylphenidate. 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 methylphenidate: Dexmethylphenidate •

Systemic - U.S. Brands: Focalin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500373.html

Methylphenidate •

Systemic - U.S. Brands: Concerta; Metadate CD; Ritalin; Ritalin-SR http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202361.html

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. Or, you may be able to access these sources from your local medical library.

Mosby’s Drug Consult Mosby’s Drug Consult database (also available on CD-ROM and book format) covers 45,000 drug products including generics and international brands. It provides prescribing information, drug interactions, and patient information. Subscription information is available at the following hyperlink: http://www.mosbysdrugconsult.com/. PDRhealth The PDRhealth database is a free-to-use, drug information search engine that has been written for the public in layman’s terms. It contains FDA-approved drug information adapted from the Physicians’ Desk Reference (PDR) database. PDRhealth can be searched by brand name, generic name, or indication. It features multiple drug interactions reports. Search PDRhealth at http://www.pdrhealth.com/drug_info/index.html. Other Web Sites Drugs.com (www.drugs.com) reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. (http://www.medletter.com/) which allows users to download articles on various drugs and therapeutics for a nominal fee. If you have any questions about a medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1-888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

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APPENDICES

167

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

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

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

•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

•

National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

•

National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

•

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

•

National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

•

National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

•

National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

•

National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

•

National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

•

National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

•

Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

•

National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

•

National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

•

Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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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

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

•

Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

•

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

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

•

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 “methylphenidate” (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 4067 59 759 3 45 4933

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 “methylphenidate” (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/.

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.

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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 methylphenidate 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 methylphenidate. 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 methylphenidate. 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 “methylphenidate”:

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Attention Deficit Disorder with Hyperactivity http://www.nlm.nih.gov/medlineplus/attentiondeficitdisorderwithhyperactivity. html Autism http://www.nlm.nih.gov/medlineplus/autism.html Child Mental Health http://www.nlm.nih.gov/medlineplus/childmentalhealth.html Liver Cancer http://www.nlm.nih.gov/medlineplus/livercancer.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 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 methylphenidate. 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: •


•

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

•

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

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

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

•

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

•

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

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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to methylphenidate. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with methylphenidate. 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 methylphenidate. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “methylphenidate” (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 “methylphenidate”. 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 “methylphenidate” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months.

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The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “methylphenidate” (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.21

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

21

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)22: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

•

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

•

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

•

California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

•

California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

•

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

•

California: Gateway Health Library (Sutter Gould Medical Foundation)

•

California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

•

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

•

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

•

California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

•

California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

•

California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

•

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

•

California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

•

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

•

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

•

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

22

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

•

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

•

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

•

Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

•

Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

•

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

•

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

•

Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

•

Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

•

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

•

Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

•

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

•

Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

•

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

•

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

•

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

•

Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

•

Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

•

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

•

Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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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

•

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

•

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

•

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

•

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

•

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

•

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

•

Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

•

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

•

Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

•

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

•

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

•

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

•

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

•

Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

•

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

•

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

•

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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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

•

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

•

New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

•

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

•

New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

•

New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

•

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

•

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

•

Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

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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

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MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

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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

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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

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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

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MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

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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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METHYLPHENIDATE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 5-Hydroxytryptophan: Precursor of serotonin used as antiepileptic and antidepressant. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acquired Immunodeficiency Syndrome: An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive Tlymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. [NIH] Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] 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] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex

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characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Agoraphobia: Obsessive, persistent, intense fear of open places. [NIH] Alertness: A state of readiness to detect and respond to certain specified small changes occurring at random intervals in the environment. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] 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] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH]

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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] Amantadine: An antiviral that is used in the prophylactic or symptomatic treatment of Influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino acid: Any organic compound containing an amino (-NH2 and a carboxyl (- COOH) group. The 20 a-amino acids listed in the accompanying table are the amino acids from which proteins are synthesized by formation of peptide bonds during ribosomal translation of messenger RNA; all except glycine, which is not optically active, have the L configuration. Other amino acids occurring in proteins, such as hydroxyproline in collagen, are formed by posttranslational enzymatic modification of amino acids residues in polypeptide chains. There are also several important amino acids, such as the neurotransmitter y-aminobutyric acid, that have no relation to proteins. Abbreviated AA. [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] Amnestic: Nominal aphasia; a difficulty in finding the right name for an object. [NIH] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Amygdala: Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the brain, within the temporal lobe. The amygdala is part of the limbic system. [NIH]

Anabolic: Relating to, characterized by, or promoting anabolism. [EU] 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] Anaesthetic: 1. Pertaining to, characterized by, or producing anaesthesia. 2. A drug or agent that is used to abolish the sensation of pain. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Anal Fissure: A small tear in the anus that may cause itching, pain, or bleeding. [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] 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]

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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] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] 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] 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] Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]

Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on 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] Antiepileptic: An agent that combats epilepsy. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with

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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] Antihypertensive: An agent that reduces high blood pressure. [EU] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] 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] Antispasmodic: An agent that relieves spasm. [EU] Antitussive: An agent that relieves or prevents cough. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Apomorphine: A derivative of morphine that is a dopamine D2 agonist. It is a powerful emetic and has been used for that effect in acute poisoning. It has also been used in the diagnosis and treatment of parkinsonism, but its adverse effects limit its use. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Arecoline: An alkaloid obtained from the betel nut (Areca catechu), fruit of a palm tree. It is an agonist at both muscarinic and nicotinic acetycholine receptors. It is used in the form of various salts as a ganglionic stimulant, a parasympathomimetic, and a vermifuge, especially

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in veterinary practice. It has been used as a euphoriant in the Pacific Islands. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteritis: Inflammation of an artery. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspartate: A synthetic amino acid. [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] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] 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] Atropine: A toxic alkaloid, originally from Atropa belladonna, but found in other plants, mainly Solanaceae. [NIH] Attenuated: Strain with weakened or reduced virulence. [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] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autoreceptors: Transmitter receptors on or near presynaptic terminals (or varicosities) which are sensitive to the transmitter(s) released by the terminal itself. Receptors for the hormones released by hormone-releasing cells are also included. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as

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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] Behavior Therapy: The application of modern theories of learning and conditioning in the treatment of behavior disorders. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [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] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] 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] 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] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Flow Velocity: A value equal to the total volume flow divided by the cross-sectional area of the vascular bed. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found

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in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone metastases: Cancer that has spread from the original (primary) tumor to the bone. [NIH]

Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] 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 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] Bromocriptine: A semisynthetic ergot alkaloid that is a dopamine D2 agonist. It suppresses prolactin secretion and is used to treat amenorrhea, galactorrhea, and female infertility, and has been proposed for Parkinson disease. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Buprenorphine: A derivative of the opioid alkaloid thebaine that is a more potent and

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longer lasting analgesic than morphine. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use. [NIH] Bupropion: A unicyclic, aminoketone antidepressant. The mechanism of its therapeutic actions is not well understood, but it does appear to block dopamine uptake. The hydrochloride is available as an aid to smoking cessation treatment. [NIH] Butorphanol: A synthetic morphinan analgesic with narcotic antagonist action. It is used in the management of severe pain. [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] 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] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carcinogenic: Producing carcinoma. [EU] Cardiac: Having to do with the heart. [NIH] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] 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] 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] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [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

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reference; same as inferior, in human anatomy. [EU] Caudate Nucleus: Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. [NIH] Causal: Pertaining to a cause; directed against a cause. [EU] Causality: The relating of causes to the effects they produce. Causes are termed necessary when they must always precede an effect and sufficient when they initiate or produce an effect. Any of several factors may be associated with the potential disease causation or outcome, including predisposing factors, enabling factors, precipitating factors, reinforcing factors, and risk factors. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] 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] Central Nervous System Stimulants: A loosely defined group of drugs that tend to increase behavioral alertness, agitation, or excitation. They work by a variety of mechanisms, but usually not by direct excitation of neurons. The many drugs that have such actions as side effects to their main therapeutic use are not included here. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebral hemispheres: The two halves of the cerebrum, the part of the brain that controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. The right hemisphere controls muscle movement on the left side of the body, and the left hemisphere controls muscle movement on the right side of the body. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] 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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Chemotherapy: Treatment with anticancer drugs. [NIH] Child Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders in children. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Citalopram: A selective neuronal serotonin reuptake inhibitor and a clinically effective antidepressant with tolerable side effects. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia (TD) in preference to tricyclic antidepressants, which aggravate this condition. [NIH]

Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coca: Any of several South American shrubs of the Erythroxylon genus (and family) that yield cocaine; the leaves are chewed with alum for CNS stimulation. [NIH] Cocaethylene: Hard drug formed by cocaine and alcohol. [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

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mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [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] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Cognitive behavior therapy: A system of psychotherapy based on the premise that distorted or dysfunctional thinking, which influences a person's mood or behavior, is common to all psychosocial problems. The focus of therapy is to identify the distorted thinking and to replace it with more rational, adaptive thoughts and beliefs. [NIH] Colloidal: Of the nature of a colloid. [EU] Coloboma: Congenital anomaly in which some of the structures of the eye are absent due to incomplete fusion of the fetal intraocular fissure during gestation. [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 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

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as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] 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] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computer Systems: Systems composed of a computer or computers, peripheral equipment, such as disks, printers, and terminals, and telecommunications capabilities. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Concept Formation: A cognitive process involving the formation of ideas generalized from the knowledge of qualities, aspects, and relations of objects. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Consolidation: The healing process of a bone fracture. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constrict: Tighten; narrow. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [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 clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH]

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Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] 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 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] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] 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] Curative: Tending to overcome disease and promote recovery. [EU] 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] 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] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] 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]

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Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [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] Deoxyglucose: 2-Deoxy-D-arabino-hexose. An antimetabolite of glucose with antiviral activity. [NIH] 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] Dermis: A layer of vascular connective tissue underneath the epidermis. The surface of the dermis contains sensitive papillae. Embedded in or beneath the dermis are sweat glands, hair follicles, and sebaceous glands. [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] Desipramine: A tricyclic dibenzazepine compound that potentiates neurotransmission. Desipramine selectively blocks reuptake of norepinephrine from the neural synapse, and also appears to impair serotonin transport. This compound also possesses minor anticholingeric activity, through its affinity to muscarinic receptors. [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] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diastolic pressure: The lowest pressure to which blood pressure falls between contractions of the ventricles. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Diffuse Axonal Injury: A relatively common sequela of blunt head injury, characterized by a global disruption of axons throughout the brain. Associated clinical features may include neurobehavioral manifestations; persistent vegetative state; dementia; and other disorders.

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[NIH]

Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Diltiazem: A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of the calcium ion in membrane functions. It is also teratogenic. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Discrimination Learning: Learning that is manifested in the ability to respond differentially to various stimuli. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Dispenser: Glass, metal or plastic shell fitted with valve from which a pressurized formulation is dispensed; an instrument for atomizing. [NIH] Disposition: A tendency either physical or mental toward certain diseases. [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] 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] 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 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

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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] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Combinations: Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. It is differentiated from combination drug therapy in which two or more drugs are administered separately for a combined effect. [NIH] Drug Evaluation: Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals. [NIH] Drug Hypersensitivity: Immunologically mediated adverse reactions to medicinal substances used legally or illegally. [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] Duodenum: The first part of the small intestine. [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] Dysphoria: Disquiet; restlessness; malaise. [EU] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service

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produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] 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] Electroencephalography: Recording of electric currents developed in the brain by means of electrodes applied to the scalp, to the surface of the brain, or placed within the substance of the brain. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

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] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryology: The study of the development of an organism during the embryonic and fetal stages of life. [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]

Emetic: An agent that causes vomiting. [EU] Emollient: Softening or soothing; called also malactic. [EU] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]

Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalitis, Viral: Inflammation of brain parenchymal tissue as a result of viral infection. Encephalitis may occur as primary or secondary manifestation of Togaviridae infections; Herpesviridae infections; Adenoviridae infections; Flaviviridae infections; Bunyaviridae infections; Picornaviridae infections; Paramyxoviridae infections; Orthomyxoviridae infections; Retroviridae infections; and Arenaviridae infections. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous)

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production. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] Energetic: Exhibiting energy : strenuous; operating with force, vigour, or effect. [EU] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Entorhinal Cortex: Cortex where the signals are combined with those from other sensory systems. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme-Linked Immunosorbent Assay: An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. [NIH] Ephedrine: An alpha- and beta-adrenergic agonist that may also enhance release of norepinephrine. It has been used in the treatment of several disorders including asthma, heart failure, rhinitis, and urinary incontinence, and for its central nervous system stimulatory effects in the treatment of narcolepsy and depression. It has become less extensively used with the advent of more selective agonists. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] 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]

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Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [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] Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethical drug: Restricted to sale only on a doctor's prescription. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evacuation: An emptying, as of the bowels. [EU] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Evoked Potentials: The electric response evoked in the central nervous system by stimulation of sensory receptors or some point on the sensory pathway leading from the receptor to the cortex. The evoked stimulus can be auditory, somatosensory, or visual, although other modalities have been reported. Event-related potentials is sometimes used synonymously with evoked potentials but is often associated with the execution of a motor, cognitive, or psychophysiological task, as well as with the response to a stimulus. [NIH] Excipients: Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form; a binder, matrix, base or diluent in pills, tablets, creams, salves, etc. [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] Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH]

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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]

Fecal Incontinence: Failure of voluntary control of the anal sphincters, with involuntary passage of feces and flatus. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Fentanyl: A narcotic opioid drug that is used in the treatment of pain. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [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] Flatus: Gas passed through the rectum. [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] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Follow-Up Studies: Studies in which individuals or populations are followed to assess the outcome of exposures, procedures, or effects of a characteristic, e.g., occurrence of disease. [NIH]

Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH]

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Fourth Ventricle: An irregularly shaped cavity in the rhombencephalon, between the medulla oblongata, the pons, and the isthmus in front, and the cerebellum behind. It is continuous with the central canal of the cord below and with the cerebral aqueduct above, and through its lateral and median apertures it communicates with the subarachnoid space. [NIH]

Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Functional magnetic resonance imaging: A noninvasive tool used to observe functioning in the brain or other organs by detecting changes in chemical composition, blood flow, or both. [NIH]

Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] 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] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Geriatric: Pertaining to the treatment of the aged. [EU] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU]

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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]

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] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Guanethidine: An antihypertensive agent that acts by inhibiting selectively transmission in post-ganglionic adrenergic nerves. It is believed to act mainly by preventing the release of norepinephrine at nerve endings and causes depletion of norepinephrine in peripheral sympathetic nerve terminals as well as in tissues. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] 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] 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]

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Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Heat Stroke: A condition characterized by cessation of sweating, hot dry skin, delirium, collapse, and coma and resulting from prolonged exposure to high environmental temperature. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] 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]

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]

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] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] 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] Horseradish Peroxidase: An enzyme isolated from horseradish which is able to act as an antigen. It is frequently used as a histochemical tracer for light and electron microscopy. Its antigenicity has permitted its use as a combined antigen and marker in experimental immunology. [NIH] Hydrocodone: Narcotic analgesic related to codeine, but more potent and more addicting by weight. It is used also as cough suppressant. [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] Hyperkinesis: Excessive movement of muscles of the body as a whole, which may be associated with organic or psychological disorders. [NIH] Hyperphagia: Ingestion of a greater than optimal quantity of food. [NIH] Hyperpyrexia: Exceptionally high fever either in comparison of the fever usually accompanying a particular disease or absolutely (as in heat stroke). [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] Hypomania: An abnormality of mood resembling mania (persistent elevated or expansive mood, hyperactivity, inflated self-esteem, etc.) but of lesser intensity. [EU] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] 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]

Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

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] Immunohistochemistry: Histochemical localization of immunoreactive substances using

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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] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] 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] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU] Infant, Newborn: An infant during the first month after birth. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

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] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Innervation: 1. The distribution or supply of nerves to a part. 2. The supply of nervous energy or of nerve stimulus sent to a part. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU]

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Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Interindividual: Occurring between two or more individuals. [EU] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interpersonal Relations: The reciprocal interaction of two or more persons. [NIH] 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] Intraocular: Within the eye. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] 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]

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Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] 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] Kinetic: Pertaining to or producing motion. [EU] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Lactation: The period of the secretion of milk. [EU] 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 troublesome effect. [NIH] Laxative: An agent that acts to promote evacuation of the bowel; a cathartic or purgative. [EU]

Learning Disorders: Conditions characterized by a significant discrepancy between an individual's perceived level of intellect and their ability to acquire new language and other cognitive skills. These disorders may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. [NIH] Lesion: An area of abnormal tissue change. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Levo: It is an experimental treatment for heroin addiction that was developed by German scientists around 1948 as an analgesic. Like methadone, it binds with opioid receptors, but it is longer acting. [NIH] Levodopa: The naturally occurring form of dopa and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonism and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [NIH] 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

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behaviors (feeding, mating, emotion). For most authors, it includes the amygdala, epithalamus, gyrus cinguli, hippocampal formation (see hippocampus), hypothalamus, parahippocampal gyrus, septal nuclei, anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipid: Fat. [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 scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Locomotion: Movement or the ability to move from one place or another. It can refer to humans, vertebrate or invertebrate animals, and microorganisms. [NIH] Locomotor: Of or pertaining to locomotion; pertaining to or affecting the locomotive apparatus of the body. [EU] Locus Coeruleus: Bluish region in the superior angle of the fourth ventricle floor, corresponding to melanin-like pigmented nerve cells which lie lateral to the pontomesencephalic central gray (griseum centrale). It is also known as nucleus pigmentosus pontis. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] 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] Lutein Cells: The cells of the corpus luteum which are derived from the granulosa cells and the theca cells of the Graafian follicle. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH]

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Lymphoblasts: Interferon produced predominantly by leucocyte cells. [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] Lymphocyte Count: A count of the number of lymphocytes in the blood. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Malaise: A vague feeling of bodily discomfort. [EU] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Mania: Excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behaviour, and elevation of mood. [EU] Manic: Affected with mania. [EU] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mean blood pressure: The average blood pressure, taking account of the rise and fall that occurs with each heartbeat. It is often estimated by multiplying the diastolic pressure by two, adding the systolic pressure, and then dividing this sum by three. [NIH] Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] 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] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment.

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Melanoma usually begins in a mole. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Memory Disorders: Disturbances in registering an impression, in the retention of an acquired impression, or in the recall of an impression. Memory impairments are associated with dementia; craniocerebraltrauma; encephalitis; alcoholism (see also alcohol amnestic disorder); schizophrenia; and other conditions. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Menopause: Permanent cessation of menstruation. [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Meperidine: 1-Methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester. A narcotic analgesic that can be used for the relief of most types of moderate to severe pain, including postoperative pain and the pain of labor. Prolonged use may lead to dependence of the morphine type; withdrawal symptoms appear more rapidly than with morphine and are of shorter duration. [NIH] Mesencephalic: Ipsilateral oculomotor paralysis and contralateral tremor, spasm. or choreic movements of the face and limbs. [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] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Methamphetamine: A central nervous system stimulant and sympathomimetic with actions and uses similar to dextroamphetamine. The smokable form is a drug of abuse and is referred to as crank, crystal, crystal meth, ice, and speed. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH]

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Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling. [NIH] 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] Mineral Oil: A mixture of liquid hydrocarbons obtained from petroleum. It is used as laxative, lubricant, ointment base, and emollient. [NIH] Minocycline: A semisynthetic staphylococcus infections. [NIH]

antibiotic

effective

against

tetracycline-resistant

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] 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 absorbed into the portal circulation. (From Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 8th ed, p415) EC 1.4.3.4. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH]

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Monotherapy: A therapy which uses only one drug. [EU] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Motor Activity: The physical activity of an organism as a behavioral phenomenon. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Nalbuphine: A narcotic used as a pain medication. It appears to be an agonist at kappa opioid receptors and an antagonist or partial agonist at mu opioid receptors. [NIH] Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Narcosis: A general and nonspecific reversible depression of neuronal excitability, produced by a number of physical and chemical aspects, usually resulting in stupor. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] 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]

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Nerve Endings: Specialized terminations of peripheral neurons. Nerve endings include neuroeffector junction(s) by which neurons activate target organs and sensory receptors which transduce information from the various sensory modalities and send it centrally in the nervous system. Presynaptic nerve endings are presynaptic terminals. [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] Neuroanatomy: Study of the anatomy of the nervous system as a specialty or discipline. [NIH]

Neurobehavioral Manifestations: Signs and symptoms of higher cortical dysfunction caused by organic conditions. These include certain behavioral alterations and impairments of skills involved in the acquisition, processing, and utilization of knowledge or information. [NIH]

Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] 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] Neuropeptides: Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the nervous system. [NIH] Neuropsychological Tests: Tests designed to assess neurological function associated with certain behaviors. They are used in diagnosing brain dysfunction or damage and central nervous system disorders or injury. [NIH] Neuropsychology: A branch of psychology which investigates the correlation between experience or behavior and the basic neurophysiological processes. The term neuropsychology stresses the dominant role of the nervous system. It is a more narrowly defined field than physiological psychology or psychophysiology. [NIH] Neurosciences: The scientific disciplines concerned with the embryology, anatomy, physiology, biochemistry, pharmacology, etc., of the nervous sytem. [NIH] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]

Neurotoxin: A substance that is poisonous to nerve tissue. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine,

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epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] 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] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. 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] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleus Accumbens: Collection of pleomorphic cells in the caudal part of the anterior horn of the lateral ventricle, in the region of the olfactory tubercle, lying between the head of the caudate nucleus and the anterior perforated substance. It is part of the so-called ventral striatum, a composite structure considered part of the basal ganglia. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oncology: The study of cancer. [NIH] On-line: A sexually-reproducing population derived from a common parentage. [NIH]

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Opacity: Degree of density (area most dense taken for reading). [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] 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] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [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]

Orofacial: Of or relating to the mouth and face. [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] 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] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxycodone: Semisynthetic derivative of codeine that acts as a narcotic analgesic more potent and addicting than codeine. [NIH] Oxytocin: A nonapeptide posterior pituitary hormone that causes uterine contractions and stimulates lactation. [NIH] Paired-Associate Learning: Learning in which the subject must respond with one word or syllable when presented with another word or syllable. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it

Dictionary 221

may be inherited as an autosomal dominant trait. [NIH] Parasympathomimetic: 1. Producing effects resembling those of stimulation of the parasympathetic nerve supply to a part. 2. An agent that produces effects similar to those produced by stimulation of the parasympathetic nerves. Called also cholinergic. [EU] Parietal: 1. Of or pertaining to the walls of a cavity. 2. Pertaining to or located near the parietal bone, as the parietal lobe. [EU] Parietal Lobe: Upper central part of the cerebral hemisphere. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Paroxetine: A serotonin uptake inhibitor that is effective in the treatment of depression. [NIH]

Parturition: The act or process of given birth to a child. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [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] Pelvic: Pertaining to the pelvis. [EU] Pemoline: A central nervous system stimulant used in fatigue and depressive states and to treat hyperkinetic disorders in children. [NIH] Penicillin: An antibiotic drug used to treat infection. [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] 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] Personality Disorders: A major deviation from normal patterns of behavior. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] PH: The symbol relating the hydrogen ion (H+) concentration or activity of a solution to that of a given standard solution. Numerically the pH is approximately equal to the negative logarithm of H+ concentration expressed in molarity. pH 7 is neutral; above it alkalinity increases and below it acidity increases. [EU] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of

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mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [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] Phencyclidine: A hallucinogen formerly used as a veterinary anesthetic, and briefly as a general anesthetic for humans. Phencyclidine is similar to ketamine in structure and in many of its effects. Like ketamine, it can produce a dissociative state. It exerts its pharmacological action through inhibition of NMDA receptors (receptors, N-methyl-Daspartate). As a drug of abuse, it is known as PCP and Angel Dust. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] 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] 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] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Physostigmine: A cholinesterase inhibitor that is rapidly absorbed through membranes. It can be applied topically to the conjunctiva. It also can cross the blood-brain barrier and is used when central nervous system effects are desired, as in the treatment of severe anticholinergic toxicity. [NIH] 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]

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Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Pleomorphic: Occurring in various distinct forms. In terms of cells, having variation in the size and shape of cells or their nuclei. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] 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] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] 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] Postherpetic Neuralgia: Variety of neuralgia associated with migraine in which pain is felt in or behind the eye. [NIH] Postoperative: After surgery. [NIH] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Postural: Pertaining to posture or position. [EU] Potentiate: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH]

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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] Precipitating Factors: Factors associated with the definitive onset of a disease, illness, accident, behavioral response, or course of action. Usually one factor is more important or more obviously recognizable than others, if several are involved, and one may often be regarded as "necessary". Examples include exposure to specific disease; amount or level of an infectious organism, drug, or noxious agent, etc. [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] 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] 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] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prescription drug abuse: Using two or more drugs interchangeably in an attempt to counteract the adverse effects of one with the other or to potentiate the effects of one with the other, so that an interdependent habit requiring both is formed. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Presynaptic Terminals: The distal terminations of axons which are specialized for the release of neurotransmitters. Also included are varicosities along the course of axons which have similar specializations and also release transmitters. Presynaptic terminals in both the central and peripheral nervous systems are included. [NIH] 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] Problem Solving: A learning situation involving more than one alternative from which a selection is made in order to attain a specific goal. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an

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antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [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] Propoxyphene: A narcotic analgesic structurally related to methadone. Only the dextroisomer has an analgesic effect; the levo-isomer appears to exert an antitussive effect. [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] 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] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proxy: A person authorized to decide or act for another person, for example, a person having durable power of attorney. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU]

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Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Psychopathology: The study of significant causes and processes in the development of mental illness. [NIH] Psychopharmacology: The study of the effects of drugs on mental and behavioral activity. [NIH]

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 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] 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 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]

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]

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Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] Raclopride: A substituted benzamide that has antipsychotic properties. It is a dopamine D2 receptor antagonist. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] 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] Radiopharmaceuticals: Drugs containing a radioactive substance that are used in the diagnosis and treatment of cancer and in pain management of bone metastases. Also called radioactive drugs. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] 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] Rationalize: To attribute one's actions to rational and creditable motives without adequate analysis of the true and unconscious motives. [NIH] Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego function. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recovery of Function: A partial or complete return to the normal or proper physiologic

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activity of an organ or part following disease or trauma. [NIH] Rectal: By or having to do with the rectum. The rectum is the last 8 to 10 inches of the large intestine and ends at the anus. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] 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] Reliability: Used technically, in a statistical sense, of consistency of a test with itself, i. e. the extent to which we can assume that it will yield the same result if repeated a second time. [NIH]

Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] 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] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] Reticular: Coarse-fibered, netlike dermis layer. [NIH] Reticular Formation: A region extending from the pons & medulla oblongata through the mesencephalon, characterized by a diversity of neurons of various sizes and shapes, arranged in different aggregations and enmeshed in a complicated fiber network. [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] Retrospective: Looking back at events that have already taken place. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the

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retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Ritalin: Drug used to treat hyperactive children. [NIH] Saline: A solution of salt and water. [NIH] Satiation: Full gratification of a need or desire followed by a state of relative insensitivity to that particular need or desire. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [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] Scrotum: In males, the external sac that contains the testicles. [NIH] Secobarbital: A barbiturate that is used as a sedative. Secobarbital is reported to have no anti-anxiety activity. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH]

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Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] 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] Sequela: Any lesion or affection following or caused by an attack of disease. [EU] Sequester: A portion of dead bone which has become detached from the healthy bone tissue, as occurs in necrosis. [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] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Sibutramine: A drug used for the management of obesity that helps reduce food intake and is indicated for weight loss and maintenance of weight loss when used in conjunction with a reduced-calorie diet. It works to suppress the appetite primarily by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin. Side effects include dry mouth, headache, constipation, insomnia, and a slight increase in average blood pressure. In some patients it causes a higher blood pressure increase. [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] Signs and Symptoms: Clinical manifestations that can be either objective when observed by

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a physician, or subjective when perceived by the patient. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoking Cessation: Discontinuation of the habit of smoking, the inhaling and exhaling of tobacco smoke. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social 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] 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] 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] 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] Spectroscopic: The recognition of elements through their emission spectra. [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] Sperm: The fecundating fluid of the male. [NIH] Sphincters: Any annular muscle closing an orifice. [NIH]

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Spike: The activation of synapses causes changes in the permeability of the dendritic membrane leading to changes in the membrane potential. This difference of the potential travels along the axon of the neuron and is called spike. [NIH] 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] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Stabilizer: A device for maintaining constant X-ray tube voltage or current. [NIH] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Standardize: To compare with or conform to a standard; to establish standards. [EU] Staphylococcus: A genus of gram-positive, facultatively anaerobic, coccoid bacteria. Its organisms occur singly, in pairs, and in tetrads and characteristically divide in more than one plane to form irregular clusters. Natural populations of Staphylococcus are membranes of warm-blooded animals. Some species are opportunistic pathogens of humans and animals. [NIH] Startle Reaction: A complex involuntary response to an unexpected strong stimulus usually auditory in nature. [NIH] Steady state: Dynamic equilibrium. [EU] Stereotyped Behavior: Relatively invariant mode of behavior elicited or determined by a particular situation; may be verbal, postural, or expressive. [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] Steroids: Drugs used to relieve swelling and inflammation. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Street Drugs: Drugs obtained and often manufactured illegally for the subjective effects they are said to produce. They are often distributed in urban areas, but are also available in suburban and rural areas, and tend to be grossly impure and may cause unexpected toxicity. [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] Stria: 1. A streak, or line. 2. A narrow bandlike structure; a general term for such longitudinal collections of nerve fibres in the brain. [EU] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH]

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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] Stupor: Partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation. Also, in psychiatry, a disorder marked by reduced responsiveness. [EU] 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] Subiculum: A region of the hippocampus that projects to other areas of the brain. [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] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [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] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of disease. [NIH] Symptomatology: 1. That branch of medicine with treats of symptoms; the systematic discussion of symptoms. 2. The combined symptoms of a disease. [EU] Synapse: The region where the processes of two neurons come into close contiguity, and the nervous impulse passes from one to the other; the fibers of the two are intermeshed, but, according to the general view, there is no direct contiguity. [NIH] 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

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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] Syncope: A temporary suspension of consciousness due to generalized cerebral schemia, a faint or swoon. [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Systolic pressure: The highest pressure to which blood pressure rises with the contraction of the ventricles. [NIH] Tachycardia: Excessive rapidity in the action of the heart, usually with a heart rate above 100 beats per minute. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Telecommunications: Transmission of information over distances via electronic means. [NIH]

Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Testicles: The two egg-shaped glands found inside the scrotum. They produce sperm and male hormones. Also called testes. [NIH] Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [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]

Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more

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prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [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] 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] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Tic: An involuntary compulsive, repetitive, stereotyped movement, resembling a purposeful movement because it is coordinated and involves muscles in their normal synergistic relationships; tics usually involve the face and shoulders. [EU] Time Perception: The ability to estimate periods of time lapsed or duration of time. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Token Economy: A practice whereby tokens representing money, toys, candy, etc., are given as secondary reinforcers contingent upon certain desired behaviors or performances. [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] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU] Topical: On the surface of the body. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and

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pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Tramadol: A narcotic analgesic proposed for severe pain. It may be habituating. [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] 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]

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] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tubercle: A rounded elevation on a bone or other structure. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [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] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH]

Dictionary 237

Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterine Contraction: Contraction of the uterine muscle. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [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] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vegetative: 1. Concerned with growth and with nutrition. 2. Functioning involuntarily or unconsciously, as the vegetative nervous system. 3. Resting; denoting the portion of a cell cycle during which the cell is not involved in replication. 4. Of, pertaining to, or characteristic of plants. [EU] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venlafaxine: An antidepressant drug that is being evaluated for the treatment of hot flashes in women who have breast cancer. [NIH] Venous: Of or pertaining to the veins. [EU] Venter: Belly. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Ventral Tegmental Area: A region in the mesencephalon which is dorsomedial to the substantia nigra and ventral to the red nucleus. The mesocortical and mesolimbic dopaminergic systems originate here, including an important projection to the nucleus accumbens. Overactivity of the cells in this area has been suspected to contribute to the positive symptoms of schizophrenia. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the

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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] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [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] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the 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] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] 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]

239

INDEX 5 5-Hydroxytryptophan, 144, 185 A Aberrant, 64, 185 Acetylcholine, 185, 195, 218, 219 Acidity, 185, 221 Acquired Immunodeficiency Syndrome, 132, 135, 148, 185 Acute lymphoblastic leukemia, 35, 185 Acute lymphocytic leukemia, 185 Acyl, 185, 204 Adaptability, 185, 194 Adaptation, 185, 223 Adenine, 185 Adenosine, 37, 185, 193, 222, 235 Adjustment, 45, 111, 154, 185 Adjuvant, 38, 112, 185 Adolescence, 19, 49, 53, 185 Adrenal Medulla, 186, 193, 203, 219 Adrenergic, 64, 186, 189, 200, 203, 207, 233 Adverse Effect, 24, 82, 186, 189, 224, 230 Afferent, 20, 186, 224 Affinity, 46, 52, 54, 143, 186, 190, 199, 231 Age Groups, 16, 25, 40, 41, 49, 186 Age of Onset, 62, 186 Aged, 80 and Over, 186 Agonist, 10, 19, 26, 36, 52, 56, 64, 66, 186, 189, 192, 193, 200, 203, 217, 219 Agoraphobia, 186, 209, 220 Alertness, 60, 186, 193, 194 Algorithms, 88, 186, 191 Alimentary, 141, 186 Alkaline, 186, 193 Alkaloid, 186, 189, 190, 192, 195, 217, 219, 229, 234 Alleles, 52, 186, 213 Allergen, 186, 230 Alpha Particles, 186, 227 Alternative medicine, 160, 187 Amantadine, 66, 187 Amenorrhea, 187, 192 Amino acid, 187, 188, 190, 200, 206, 207, 221, 222, 223, 225, 230, 233, 236 Amino Acid Sequence, 187, 188, 206 Amnestic, 187, 215 Amygdala, 187, 213, 234 Anabolic, 155, 187 Anaesthesia, 112, 187, 210

Anaesthetic, 112, 187 Anal, 3, 73, 83, 86, 109, 187, 205, 213 Anal Fissure, 3, 187 Analeptic, 137, 187 Analgesic, 116, 144, 187, 193, 196, 209, 212, 215, 217, 220, 225, 236 Analog, 41, 56, 187 Analogous, 55, 187, 236 Anaphylatoxins, 188, 196 Anatomical, 50, 59, 188, 195, 210, 216, 229 Anemia, 57, 188, 205 Anesthetics, 188, 191, 203 Animal model, 15, 20, 23, 31, 48, 59, 64, 66, 188 Anions, 188, 211 Anorexia, 135, 136, 145, 147, 188 Antagonism, 18, 188, 193, 200, 235 Antecedent, 32, 188 Antibacterial, 188, 231 Antibiotic, 95, 188, 216, 221, 224, 231, 234 Antibodies, 20, 143, 188, 207, 210, 214, 223 Antibody, 186, 188, 189, 196, 203, 204, 207, 208, 209, 210, 212, 214, 216, 227, 230, 231, 238 Anticholinergic, 188, 222 Anticoagulant, 188, 225 Anticonvulsant, 188, 237 Antiepileptic, 185, 188 Antigen, 186, 188, 189, 196, 203, 208, 209, 210, 214, 216, 230 Antigen-Antibody Complex, 189, 196 Antihypertensive, 120, 189, 207 Antimetabolite, 189, 199 Antipsychotic, 189, 227 Antispasmodic, 189, 220, 229 Antitussive, 189, 220, 225 Antiviral, 187, 189, 199 Anus, 187, 189, 192, 228 Anxiety, 44, 71, 189, 220, 224, 229 Apomorphine, 36, 59, 64, 189 Apoptosis, 66, 189 Aqueous, 136, 148, 189, 198 Arecoline, 155, 189 Arginine, 188, 190, 219 Arterial, 190, 209, 225, 234 Arteries, 190, 192, 198, 215, 226 Arterioles, 190, 192, 193 Arteritis, 76, 190

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Artery, 190, 198, 226 Aseptic, 190, 232 Aspartate, 190, 212, 222 Assay, 19, 59, 190, 209 Astrocytes, 190, 216 Atmospheric Pressure, 95, 190 Atrophy, 190, 218 Atropine, 190, 229 Attenuated, 9, 31, 32, 50, 190, 200 Atypical, 10, 190 Auditory, 16, 82, 109, 121, 190, 204, 224, 232 Autoimmune disease, 190, 217 Autonomic, 185, 189, 190, 219, 221, 233 Autoreceptors, 36, 190 Axons, 190, 199, 224 B Bacteria, 185, 188, 189, 190, 191, 199, 205, 215, 216, 231, 232, 236 Bactericidal, 190, 204 Barbiturate, 190, 229 Basal Ganglia, 31, 45, 189, 191, 213, 219 Behavior Therapy, 191 Benign, 191, 207, 217, 227 Benzene, 19, 191 Bile, 54, 191, 213 Bile Acids, 191 Bile Acids and Salts, 191 Binding Sites, 5, 54, 60, 191 Biochemical, 73, 74, 186, 189, 191, 230 Biological Transport, 191, 200 Biomarkers, 53, 191 Biotechnology, 68, 69, 160, 169, 191 Bipolar Disorder, 71, 86, 191 Bladder, 191, 197, 210, 217, 225, 237 Blood Coagulation, 191, 192, 193, 235 Blood Flow Velocity, 37, 191 Blood Glucose, 191, 208, 211 Blood Platelets, 191, 230 Blood pressure, 9, 74, 83, 154, 189, 192, 193, 199, 209, 214, 216, 226, 230, 231, 234 Blood vessel, 192, 193, 194, 195, 197, 203, 213, 231, 232, 234, 235, 237 Blood-Brain Barrier, 192, 212, 222 Body Fluids, 191, 192, 231, 236 Bolus, 132, 192 Bolus infusion, 192 Bone Marrow, 185, 191, 192, 198, 209 Bone metastases, 192, 227 Bone scan, 192, 229 Bowel, 3, 187, 192, 211, 212, 232 Bowel Movement, 192, 232

Brachytherapy, 192, 211, 212, 227, 238 Bradykinin, 192, 219 Brain Stem, 134, 148, 192, 194 Bromocriptine, 101, 192 Bronchi, 192, 203, 234, 236 Bronchial, 192, 234 Buprenorphine, 9, 192 Bupropion, 65, 75, 104, 193 Butorphanol, 9, 193 C Caffeine, 37, 187, 193 Calcium, 144, 193, 196, 200 Capillary, 75, 106, 117, 192, 193, 237 Capsules, 136, 137, 147, 148, 193, 201 Carcinogenic, 191, 193, 210, 225 Cardiac, 193, 203, 217 Cardiovascular, 9, 43, 72, 76, 109, 124, 187, 193, 230 Cardiovascular disease, 10, 193 Carotene, 144, 193 Case report, 99, 101, 113, 193, 195 Catecholamine, 30, 50, 193, 200, 222 Cations, 193, 211 Caudal, 193, 199, 209, 219, 223 Caudate Nucleus, 194, 219 Causal, 127, 194, 211 Causality, 21, 194 Cell Death, 47, 66, 189, 194, 217 Cell Survival, 66, 194 Central Nervous System Infections, 194, 207 Central Nervous System Stimulants, 155, 194 Cerebellar, 24, 31, 33, 194, 228 Cerebellum, 31, 194, 206, 223, 228 Cerebral, 12, 19, 37, 50, 51, 76, 81, 99, 110, 134, 191, 192, 194, 203, 204, 205, 206, 221, 226, 234 Cerebral Cortex, 19, 50, 194, 204, 205 Cerebral hemispheres, 191, 192, 194, 234 Cerebrovascular, 12, 34, 120, 193, 194 Cerebrum, 194, 234 Chemotactic Factors, 194, 196 Chemotherapy, 15, 57, 121, 195 Child Psychiatry, 4, 39, 73, 95, 195 Chin, 195, 215 Cholesterol, 191, 195, 198 Choline, 144, 155, 195 Cholinergic, 20, 155, 189, 195, 219, 221 Chromatin, 189, 195 Chromosome, 64, 195, 213

241

Chronic, 3, 9, 12, 13, 18, 20, 24, 34, 39, 44, 49, 52, 53, 57, 59, 67, 82, 96, 100, 116, 132, 193, 195, 210, 213 Circadian, 9, 195 Citalopram, 34, 77, 97, 195 Clear cell carcinoma, 195, 199 Clinical Medicine, 195, 224 Clinical study, 195, 197 Clinical trial, 4, 13, 17, 34, 38, 46, 58, 67, 169, 195, 198, 201, 225, 227 Cloning, 38, 191, 195 Coca, 195 Cocaethylene, 45, 195 Codeine, 196, 209, 220 Cognition, 14, 27, 30, 53, 196 Cognitive behavior therapy, 10, 196 Colloidal, 196, 202 Coloboma, 64, 196 Comorbidity, 7, 43, 44, 62, 196 Complement, 67, 188, 196, 206, 230 Complementary and alternative medicine, 119, 126, 196 Complementary medicine, 119, 196 Compliance, 10, 136, 141, 197 Computational Biology, 169, 197 Computed tomography, 92, 197, 229 Computer Systems, 18, 197 Computerized axial tomography, 197, 229 Computerized tomography, 197 Concept Formation, 28, 197 Conception, 197, 205, 232 Concomitant, 44, 45, 139, 197 Conjunctiva, 197, 222 Connective Tissue, 192, 197, 199, 206 Consciousness, 187, 197, 198, 200, 226, 234 Consolidation, 150, 151, 197 Constipation, 3, 189, 197, 230 Constrict, 80, 197 Consultation, 35, 42, 197 Continuous infusion, 102, 197 Contraindications, ii, 134, 197 Controlled clinical trial, 34, 67, 197 Controlled study, 13, 70, 79, 198 Coordination, 194, 198, 217 Coronary, 193, 198, 215 Coronary heart disease, 193, 198 Coronary Thrombosis, 198, 215 Cortex, 6, 20, 45, 198, 203, 204, 224, 228 Cortical, 6, 10, 20, 25, 27, 32, 45, 51, 198, 218, 224, 229 Cranial, 194, 198, 207, 221 Craniocerebral Trauma, 198, 207

Curative, 198, 235 Cyclic, 68, 193, 198, 207, 219, 235 Cyclosporine, 104, 198 Cytoplasm, 189, 198, 203, 234 D Dehydroepiandrosterone, 111, 198 Deletion, 64, 189, 198 Delusions, 198, 226 Dementia, 107, 135, 155, 185, 189, 198, 199, 215 Dendrites, 198, 199, 218 Dendritic, 198, 214, 232 Density, 21, 74, 199, 220 Dental Caries, 199, 205 Dentate Gyrus, 199, 208 Deoxyglucose, 52, 199 Depressive Disorder, 199, 213 Dermis, 199, 228 DES, 19, 188, 199 Desipramine, 83, 88, 199 Dextroamphetamine, 45, 79, 88, 91, 187, 199, 215 Diabetes Mellitus, 199, 208 Diagnostic procedure, 131, 160, 199 Diastole, 199 Diastolic, 9, 199, 209, 214 Diastolic pressure, 199, 209, 214 Diencephalon, 199, 209, 224, 234 Diffuse Axonal Injury, 51, 199 Diffusion, 12, 191, 200 Digestion, 186, 191, 192, 200, 211, 213, 232 Diltiazem, 138, 200 Dilution, 101, 200 Direct, iii, 21, 26, 28, 34, 40, 44, 45, 48, 49, 163, 194, 195, 200, 228, 233 Discrete, 137, 148, 200 Discrimination, 11, 19, 23, 37, 56, 200 Discrimination Learning, 23, 200 Disinfectant, 200, 204 Dispenser, 138, 200 Disposition, 53, 73, 200 Dissociation, 186, 200, 211 Diuresis, 193, 200, 234 Dizziness, 135, 136, 145, 147, 200, 220 Dopa, 83, 99, 200, 212 Dopamine, 4, 5, 10, 14, 17, 18, 19, 20, 21, 22, 23, 25, 26, 30, 31, 32, 33, 35, 36, 38, 39, 40, 41, 43, 45, 46, 47, 48, 49, 51, 52, 54, 55, 56, 59, 63, 64, 65, 67, 74, 76, 80, 81, 84, 92, 105, 108, 116, 117, 145, 187, 189, 192, 193, 196, 199, 200, 212, 216, 219, 222, 227

242

Methylphenidate

Dopamine Agonists, 49, 55, 56, 200 Dorsal, 21, 27, 200, 223 Dorsum, 200, 201 Dosage Forms, 136, 137, 141, 142, 148, 149, 201 Dose-dependent, 18, 31, 32, 52, 201 Double-blind, 15, 16, 34, 38, 41, 43, 44, 61, 62, 70, 81, 84, 201 Drive, ii, vi, 5, 20, 64, 115, 159, 201 Drug Combinations, 47, 201 Drug Evaluation, 44, 201 Drug Hypersensitivity, 135, 201 Drug Interactions, 53, 164, 201 Drug Monitoring, 53, 201 Drug Tolerance, 201, 235 Duodenum, 191, 201, 232 Dyskinesia, 36, 94, 189, 195, 201 Dyslexia, 201, 212 Dysphoria, 79, 135, 145, 147, 201 E Effector, 185, 196, 201 Efferent, 20, 201 Elastic, 8, 202 Elasticity, 8, 202 Elective, 202 Electroencephalography, 107, 114, 202 Electrolyte, 202, 231 Electrons, 202, 211, 227 Electrophoresis, 106, 117, 202 Electrophysiological, 60, 202 Emaciation, 185, 202 Embryo, 202, 210 Embryology, 202, 218 Emesis, 144, 202 Emetic, 189, 202 Emollient, 202, 216, 219 Empirical, 8, 42, 84, 202 Encapsulated, 137, 148, 202 Encephalitis, 123, 202, 215 Encephalitis, Viral, 202 Endogenous, 68, 200, 202, 203 Endorphins, 203, 219 Endothelial cell, 54, 192, 203, 235 Endothelium, 203, 219 Endothelium-derived, 203, 219 Endotoxins, 196, 203 Energetic, 60, 203 Enkephalins, 203, 219 Entorhinal Cortex, 203, 208 Environmental Health, 168, 170, 203 Enzymatic, 143, 187, 193, 196, 199, 203, 204

Enzyme, 71, 201, 203, 207, 209, 216, 225, 233, 235, 238 Enzyme-Linked Immunosorbent Assay, 71, 203 Ephedrine, 122, 142, 203 Epidemic, 30, 63, 203, 232 Epidemiological, 22, 62, 203 Epinephrine, 76, 186, 200, 203, 219, 236 Epitope, 5, 204 Ergot, 192, 204 Erythrocytes, 188, 192, 204, 230 Esterification, 139, 204 Estrogen, 30, 204, 225 Ethanol, 44, 195, 204 Ethical drug, 143, 204 Eukaryotic Cells, 204, 210 Evacuation, 197, 204, 212 Evoke, 204, 232 Evoked Potentials, 59, 102, 204 Excipients, 146, 204 Excitation, 194, 204, 218 Exhaustion, 188, 204 Exogenous, 47, 202, 204 External-beam radiation, 204, 212, 227, 238 Extracellular, 14, 18, 38, 45, 60, 68, 108, 190, 197, 204, 216, 231 Extracellular Space, 14, 204, 216 Extraction, 86, 96, 204 Extrapyramidal, 187, 189, 200, 204 F Family Planning, 169, 204 Fat, 21, 73, 191, 192, 193, 198, 205, 213, 217 Fathers, 121, 205 Fatigue, 57, 93, 98, 104, 135, 145, 146, 205, 208, 221 Fecal Incontinence, 3, 205, 210 Feces, 197, 205, 232 Fentanyl, 9, 142, 205 Fetus, 27, 205, 224 Fissure, 196, 199, 205, 224 Fixation, 205, 230 Flatus, 205, 206 Fluorine, 17, 205 Fluoxetine, 60, 65, 205 Folate, 205 Fold, 63, 68, 205 Folic Acid, 143, 205 Follow-Up Studies, 14, 205 Forearm, 192, 205 Fossa, 194, 205 Fourth Ventricle, 206, 213

243

Frontal Lobe, 28, 206, 224 Functional magnetic resonance imaging, 6, 32, 33, 206 G Gamma Rays, 206, 227 Ganglia, 31, 185, 206, 218, 221, 233 Gap Junctions, 206, 234 Gas, 45, 50, 75, 86, 94, 101, 200, 205, 206, 209, 219 Gasoline, 191, 206 Gastric, 201, 206 Gastrin, 206, 208 Gastrointestinal, 136, 141, 145, 192, 203, 204, 206, 230, 233, 236 Gastrointestinal tract, 136, 141, 145, 204, 206, 230, 236 Gene, 14, 18, 30, 32, 40, 41, 45, 46, 47, 54, 64, 65, 80, 81, 97, 105, 186, 191, 206, 223 Gene Expression, 18, 31, 40, 45, 65, 206 Genetic Code, 206, 219 Genetic Engineering, 191, 195, 206 Genetics, 26, 58, 72, 206 Genotype, 17, 31, 32, 33, 206, 222 Geriatric, 33, 96, 97, 111, 114, 206 Gestation, 30, 196, 206 Gland, 186, 207, 220, 225, 229, 232, 235 Glioma, 97, 207 Glomerular, 207, 228 Glucose, 191, 199, 207, 208, 211 Glutamate, 68, 207 Glutamic Acid, 205, 207, 219 Glutathione Peroxidase, 207, 230 Glycine, 187, 191, 207, 219 Glycoprotein, 54, 207, 235 Governing Board, 207, 224 Grasses, 205, 207 Guanethidine, 113, 207 Guanylate Cyclase, 207, 219 H Habituation, 59, 207 Haematemesis, 202, 207 Half-Life, 136, 145, 207 Hallucinogen, 207, 222 Haptens, 186, 207 Headache, 120, 193, 207, 208, 230 Headache Disorders, 207, 208 Heart attack, 193, 208 Heart failure, 203, 208 Heartbeat, 208, 214 Heat Stroke, 208, 209 Hemoglobin, 188, 204, 208 Hemorrhage, 198, 207, 208, 232

Hemorrhoids, 4, 208 Hemostasis, 208, 230 Heredity, 206, 208 Heterogeneity, 186, 208 Hippocampus, 19, 28, 53, 199, 208, 213, 233 Homeostasis, 65, 208 Homogeneous, 39, 208, 221 Homologous, 186, 208, 230, 233 Hormonal, 57, 190, 208 Hormonal therapy, 57, 208 Hormone, 14, 30, 87, 95, 105, 117, 190, 199, 203, 206, 208, 209, 211, 220, 224, 225, 235 Hormone therapy, 208, 209 Horseradish Peroxidase, 203, 209 Hydrocodone, 8, 209 Hydrogen, 185, 207, 209, 216, 219, 221, 225 Hydrolysis, 92, 139, 209, 223, 225 Hyperkinesis, 124, 209 Hyperphagia, 20, 209 Hyperpyrexia, 87, 209 Hypersensitivity, 91, 186, 209, 230 Hypertension, 10, 193, 207, 209 Hypomania, 39, 209 Hypothalamic, 100, 209 Hypothalamus, 10, 199, 209, 213 I Imipramine, 74, 88, 103, 209 Immune response, 185, 188, 190, 207, 209, 230, 233, 238 Immunization, 209, 230 Immunoassay, 143, 203, 209 Immunodeficiency, 133, 135, 185, 209 Immunohistochemistry, 40, 209 Immunologic, 194, 209, 210, 227 Immunology, 185, 186, 209, 210 Impairment, 9, 34, 37, 62, 92, 133, 140, 201, 210, 215, 226 Implant radiation, 210, 211, 212, 227, 238 In situ, 53, 210 In Situ Hybridization, 53, 210 In vitro, 32, 38, 40, 56, 92, 136, 142, 210 In vivo, 14, 18, 19, 26, 32, 38, 40, 47, 136, 141, 142, 210, 216 Incontinence, 203, 210, 229 Induction, 54, 189, 210, 212, 225 Infant, Newborn, 186, 210 Infarction, 198, 210, 215 Infection, 185, 190, 194, 202, 209, 210, 213, 214, 220, 221, 233, 238 Infertility, 192, 210 Infusion, 36, 45, 210

244

Methylphenidate

Ingestion, 142, 147, 149, 209, 210, 223 Inhalation, 135, 136, 147, 210, 223 Initiation, 31, 210 Innervation, 20, 21, 68, 210 Inotropic, 200, 210 Insight, 24, 57, 60, 211 Insomnia, 135, 145, 147, 154, 211, 230, 236 Insulator, 211, 217 Insulin, 20, 95, 211 Insulin-dependent diabetes mellitus, 20, 211 Insulin-like, 95, 211 Interindividual, 53, 211 Intermittent, 138, 211, 213 Internal radiation, 211, 212, 227, 238 Interpersonal Relations, 39, 211 Interstitial, 192, 204, 211, 212, 228, 238 Intervention Studies, 33, 42, 211 Intestinal, 54, 193, 211 Intestine, 191, 192, 211, 212 Intoxication, 87, 113, 211, 238 Intracellular, 60, 193, 210, 211, 219, 227, 230 Intraocular, 196, 211 Intravenous, 37, 74, 84, 88, 89, 93, 94, 100, 116, 210, 211 Intrinsic, 56, 65, 186, 211 Invasive, 211, 214 Involuntary, 3, 205, 211, 217, 228, 232, 235 Ion Channels, 190, 211, 234 Ionization, 45, 95, 101, 211 Ions, 60, 185, 200, 202, 209, 211, 216, 231 Irradiation, 15, 212, 238 K Kb, 168, 212 Ketamine, 142, 212, 222 Kinetic, 94, 146, 212 L Labile, 150, 196, 212 Lactation, 212, 220, 225 Large Intestine, 211, 212, 228, 231 Latent, 48, 212 Laxative, 212, 216 Learning Disorders, 91, 212 Lesion, 52, 212, 213, 230, 234 Leukemia, 212 Levo, 200, 212, 225 Levodopa, 36, 200, 212 Ligament, 212, 225 Ligands, 5, 212 Limbic, 187, 212, 224 Limbic System, 187, 212, 224

Linkage, 46, 213 Linkage Disequilibrium, 46, 213 Lipid, 195, 211, 213, 217 Lithium, 70, 88, 117, 189, 213 Liver, 174, 191, 205, 213, 216, 228, 229 Liver scan, 213, 229 Localization, 47, 56, 209, 213 Localized, 28, 199, 202, 205, 210, 213, 216, 223 Locomotion, 14, 213, 223 Locomotor, 18, 19, 49, 52, 54, 58, 64, 116, 117, 213 Locus Coeruleus, 25, 50, 213 Longitudinal study, 119, 213 Long-Term Care, 26, 213 Loop, 137, 149, 213 Lutein Cells, 213, 225 Lymph, 203, 213 Lymphoblasts, 185, 214 Lymphocyte, 185, 189, 214 Lymphocyte Count, 185, 214 Lymphoid, 188, 214 M Magnetic Resonance Imaging, 29, 34, 36, 50, 66, 214, 229 Maintenance therapy, 141, 214 Malaise, 201, 214 Malignant, 9, 36, 101, 185, 214, 217, 227 Mania, 39, 78, 209, 214 Manic, 108, 189, 191, 213, 214, 226 Manifest, 135, 214 Mean blood pressure, 9, 214 Medial, 50, 214, 220 Mediate, 18, 24, 37, 40, 200, 214 Mediator, 62, 200, 214, 230 Medicament, 141, 214 MEDLINE, 169, 214 Megaloblastic, 205, 214 Meiosis, 214, 233 Melanin, 213, 214, 222, 236 Melanocytes, 214 Melanoma, 93, 214 Memory, 6, 14, 15, 19, 23, 28, 30, 33, 63, 98, 150, 154, 155, 188, 198, 215 Memory Disorders, 154, 155, 215 Meninges, 194, 198, 215 Menopause, 145, 215 Menstruation, 187, 215 Mental Disorders, 60, 144, 195, 215, 226 Mental Health, iv, 4, 13, 58, 168, 170, 174, 215, 226 Mental Processes, 200, 215, 226

245

Mental Retardation, 26, 83, 85, 111, 215 Meperidine, 9, 215 Mesencephalic, 213, 215, 228 Mesolimbic, 23, 53, 189, 215, 237 Meta-Analysis, 68, 77, 90, 215 Metabolite, 45, 86, 94, 143, 215 Methamphetamine, 18, 23, 47, 57, 63, 65, 143, 147, 148, 215 MI, 123, 183, 215 Microbe, 215, 235 Microbiology, 185, 190, 215 Microdialysis, 5, 47, 50, 216 Microglia, 190, 216 Microorganism, 216, 238 Mineral Oil, 4, 216 Minocycline, 137, 216 Mitosis, 189, 216 Modeling, 19, 48, 216 Modification, 94, 111, 187, 206, 216, 226 Molecular Structure, 216, 236 Molecule, 140, 143, 189, 191, 196, 200, 201, 203, 204, 209, 216, 227 Monitor, 10, 14, 216, 219 Monoamine, 45, 47, 56, 65, 187, 199, 216 Monoamine Oxidase, 187, 199, 216 Monoclonal, 212, 216, 227, 238 Monotherapy, 61, 217 Morphine, 9, 143, 189, 193, 196, 215, 217, 220 Morphology, 24, 217 Motility, 217, 230 Motion Sickness, 217, 229 Motor Activity, 38, 79, 217 Mucosa, 133, 217, 225 Multiple sclerosis, 57, 217 Mutagenesis, 65, 217 Mutagens, 217 Mydriatic, 217, 229 Myelin, 217 Myocardium, 215, 217 N Nalbuphine, 9, 217 Narcolepsy, 102, 134, 199, 203, 217 Narcosis, 217 Narcotic, 112, 193, 205, 209, 215, 217, 220, 225, 236 Nausea, 189, 201, 217, 220, 236 Necrosis, 189, 210, 215, 217, 230 Neonatal, 51, 117, 217 Neoplasms, 185, 217, 227 Nerve Endings, 207, 218 Networks, 28, 218

Neural, 5, 20, 25, 28, 32, 50, 53, 63, 65, 102, 186, 199, 216, 218, 231 Neuroanatomy, 26, 29, 64, 66, 213, 218 Neurobehavioral Manifestations, 199, 218 Neurodegenerative Diseases, 57, 218 Neuronal, 5, 24, 25, 27, 28, 39, 53, 59, 63, 65, 122, 195, 217, 218 Neuropeptides, 155, 218 Neurophysiology, 58, 67, 72, 76, 114, 218 Neuropsychological Tests, 26, 29, 91, 218 Neuropsychology, 50, 218 Neurosciences, 58, 70, 98, 101, 107, 218 Neurosurgery, 6, 94, 218 Neurotoxic, 23, 57, 218 Neurotoxicity, 63, 218 Neurotoxin, 64, 218 Neurotransmitter, 14, 30, 38, 46, 60, 64, 185, 187, 192, 200, 207, 211, 218, 219, 233, 234 Neutrons, 186, 212, 219, 227 Nicotine, 22, 23, 28, 37, 82, 143, 219 Nitric Oxide, 63, 219 Nitrogen, 86, 186, 205, 219, 236 Norepinephrine, 5, 25, 40, 47, 64, 186, 199, 200, 203, 207, 218, 219, 230 Nuclear, 35, 110, 191, 202, 204, 206, 213, 217, 219, 234 Nuclei, 10, 186, 187, 202, 206, 213, 214, 216, 219, 223, 225 Nucleic acid, 142, 143, 206, 210, 217, 219 Nucleus, 5, 48, 59, 64, 189, 195, 198, 204, 206, 213, 214, 219, 224, 225, 234, 237 Nucleus Accumbens, 5, 48, 59, 64, 219, 237 O Ointments, 201, 219 Oncology, 57, 91, 93, 99, 103, 104, 219 On-line, 35, 183, 219 Opacity, 199, 220 Opiate, 12, 217, 220 Opium, 143, 217, 220 Opportunistic Infections, 185, 220 Optic Chiasm, 209, 220 Orofacial, 94, 220 Osmosis, 220 Osmotic, 4, 81, 83, 116, 136, 138, 220 Outpatient, 8, 38, 39, 220 Overdose, 45, 85, 137, 149, 220 Ovum, 206, 220, 224, 225 Oxycodone, 8, 143, 220 Oxytocin, 24, 220 P Paired-Associate Learning, 43, 220

246

Methylphenidate

Palliative, 103, 220, 235 Pancreas, 191, 211, 220, 236 Panic, 209, 220 Panic Disorder, 209, 220 Parasympathomimetic, 189, 221 Parietal, 28, 32, 221 Parietal Lobe, 221 Parkinsonism, 189, 212, 221 Paroxetine, 36, 221 Parturition, 221, 225 Patch, 158, 221 Pathologic, 189, 198, 209, 221, 237 Pathologic Processes, 189, 221 Pathophysiology, 21, 27, 32, 221 Patient Compliance, 141, 147, 149, 221 Pelvic, 221, 225 Pemoline, 9, 57, 117, 144, 154, 155, 221 Penicillin, 188, 221 Peptide, 187, 221, 223, 225 Perception, 14, 79, 221, 229 Peripheral Nervous System, 203, 218, 221, 224, 233 Personality Disorders, 39, 48, 221 Petroleum, 206, 216, 221 PH, 89, 92, 221 Pharmaceutical Solutions, 201, 221 Pharmacodynamic, 9, 28, 54, 137, 149, 222 Pharmacokinetic, 10, 28, 45, 104, 137, 145, 146, 149, 222 Pharmacologic, 10, 43, 54, 57, 63, 141, 154, 207, 222, 236 Pharmacotherapy, 32, 53, 61, 66, 71, 77, 85, 91, 222 Phencyclidine, 24, 143, 222 Phenotype, 14, 20, 31, 32, 33, 62, 64, 222 Phenyl, 52, 134, 215, 222 Phenylalanine, 222, 236 Phospholipids, 205, 222 Phosphorus, 12, 193, 222 Phosphorylation, 46, 222 Physical Examination, 10, 222 Physiologic, 186, 200, 207, 215, 222, 227 Physiology, 18, 21, 26, 39, 52, 185, 202, 218, 222 Physostigmine, 155, 222 Pigment, 214, 222 Pilot study, 38, 44, 71, 81, 91, 93, 98, 99, 120, 222 Plants, 186, 190, 195, 207, 217, 219, 223, 236, 237

Plasma, 14, 45, 50, 53, 54, 65, 75, 76, 78, 86, 95, 96, 101, 105, 111, 140, 188, 208, 223, 230 Plasma cells, 188, 223 Plasticity, 21, 63, 223 Platelet Aggregation, 188, 219, 223 Platelets, 219, 223 Platinum, 213, 223 Pleomorphic, 219, 223 Pneumonia, 197, 223 Poisoning, 189, 204, 211, 217, 223 Polymorphic, 54, 199, 223 Polymorphism, 24, 32, 46, 223 Polypeptide, 187, 223, 225, 238 Pons, 192, 206, 223, 228 Posterior, 187, 194, 201, 220, 223 Postherpetic Neuralgia, 187, 223 Postoperative, 8, 215, 223 Postprandial, 4, 223 Postsynaptic, 26, 65, 223, 234 Postural, 223, 232 Potentiate, 223, 224 Practicability, 224, 236 Practice Guidelines, 170, 224 Precipitating Factors, 194, 208, 224 Precipitation, 87, 224 Preclinical, 10, 66, 224 Precursor, 31, 121, 185, 195, 200, 201, 203, 212, 219, 222, 224, 236 Prefrontal Cortex, 6, 14, 50, 51, 224 Premedication, 224, 229 Prenatal, 15, 27, 42, 48, 202, 224 Prescription drug abuse, 93, 224 Presynaptic, 26, 46, 64, 190, 218, 224, 234 Presynaptic Terminals, 190, 218, 224, 234 Prevalence, 43, 57, 91, 100, 106, 224 Probe, 24, 51, 159, 216, 224 Problem Solving, 6, 224 Progesterone, 224, 225 Progression, 31, 188, 225 Progressive, 8, 198, 201, 217, 218, 225, 228 Projection, 21, 68, 219, 224, 225, 228, 237 Prolactin, 87, 192, 225 Promoter, 24, 225 Prone, 33, 225 Prophase, 225, 233 Propoxyphene, 8, 225 Prospective study, 213, 225 Prostate, 57, 191, 225, 236 Protein C, 60, 187, 225 Protein S, 191, 206, 225, 234

247

Proteins, 46, 63, 187, 189, 195, 196, 206, 216, 219, 221, 223, 225, 227, 230 Proteolytic, 196, 225 Protocol, 16, 35, 225 Protons, 186, 209, 225, 227 Proxy, 17, 225 Psychiatric, 7, 12, 14, 27, 29, 39, 40, 41, 42, 43, 46, 47, 48, 58, 67, 100, 102, 122, 215, 225 Psychic, 215, 226, 229 Psychoactive, 25, 52, 55, 65, 226, 238 Psychology, 7, 23, 24, 26, 27, 32, 42, 72, 82, 98, 100, 110, 117, 120, 121, 200, 218, 226 Psychomotor, 9, 37, 38, 58, 63, 78, 226 Psychopathology, 59, 67, 226 Psychophysiology, 102, 104, 113, 123, 218, 226 Psychosis, 85, 154, 189, 226 Psychotherapy, 196, 226 Psychotomimetic, 187, 199, 226 Psychotropic, 9, 58, 134, 148, 226 Public Health, 11, 42, 62, 67, 106, 170, 226 Public Policy, 169, 226 Publishing, 3, 68, 154, 226 Pulmonary, 84, 192, 226, 237 Pulmonary Artery, 192, 226, 237 Pulmonary hypertension, 84, 226 Pulse, 74, 149, 216, 226 Q Quality of Life, 6, 16, 35, 57, 145, 226 Quaternary, 227, 229 R Race, 132, 135, 138, 139, 145, 150, 200, 227 Racemic, 132, 135, 138, 139, 145, 150, 200, 227 Raclopride, 17, 21, 35, 227 Radiation, 18, 57, 204, 206, 211, 212, 227, 229, 238 Radiation therapy, 57, 204, 211, 212, 227, 238 Radioactive, 17, 192, 207, 209, 210, 211, 212, 213, 219, 227, 229, 238 Radiolabeled, 212, 227, 238 Radiopharmaceuticals, 17, 227 Radiotherapy, 192, 212, 227, 238 Randomized, 10, 15, 34, 35, 36, 37, 57, 67, 69, 70, 72, 82, 84, 107, 202, 227 Randomized clinical trial, 15, 38, 227 Rationalize, 19, 227 Reality Testing, 226, 227 Receptors, Serotonin, 227, 230 Recovery of Function, 65, 227

Rectal, 3, 228 Rectum, 189, 192, 205, 206, 210, 212, 225, 228 Recurrence, 191, 228 Red Nucleus, 228, 237 Refer, 1, 196, 200, 203, 205, 213, 219, 226, 228, 236 Reflex, 59, 228 Refraction, 228, 231 Refractory, 113, 117, 228 Regimen, 9, 49, 88, 136, 201, 221, 222, 228 Reliability, 27, 228 Remission, 191, 214, 228 Renal failure, 9, 228 Respiration, 216, 228 Response rate, 8, 35, 228 Reticular, 122, 228 Reticular Formation, 122, 228 Retina, 220, 228, 229 Retrospective, 7, 108, 228 Rhinitis, 203, 228 Riboflavin, 10, 228 Ribose, 185, 229 Risk factor, 91, 194, 225, 229 S Saline, 35, 229 Satiation, 20, 229 Scans, 12, 35, 51, 229 Schizoid, 229, 238 Schizophrenia, 5, 14, 16, 45, 56, 59, 67, 73, 96, 215, 229, 237, 238 Schizotypal Personality Disorder, 229, 238 Sclerosis, 217, 229 Scopolamine, 90, 143, 229 Screening, 10, 35, 143, 195, 229 Scrotum, 85, 229, 234 Secobarbital, 113, 229 Secretion, 87, 192, 211, 212, 216, 229, 230 Secretory, 229, 234 Sedative, 190, 196, 209, 229 Seizures, 67, 75, 109, 229 Selenium, 144, 230 Semen, 225, 230 Semisynthetic, 192, 216, 220, 230 Senile, 155, 230 Sensitization, 49, 52, 58, 63, 117, 230 Sensor, 142, 143, 230 Sequela, 199, 230 Sequester, 230, 234 Serologic, 209, 230 Serum, 10, 25, 86, 87, 95, 109, 188, 196, 230 Sex Characteristics, 186, 230

248

Methylphenidate

Shock, 230, 236 Sibutramine, 65, 230 Signs and Symptoms, 135, 228, 230 Skull, 198, 231, 234 Small intestine, 201, 208, 211, 231 Smoking Cessation, 193, 231 Smooth muscle, 188, 193, 217, 231, 233 Social Behavior, 100, 136, 154, 231 Social Environment, 226, 231 Sodium, 61, 114, 231, 237 Sodium Channels, 231, 237 Solvent, 191, 204, 220, 221, 231 Soma, 231 Somatic, 72, 186, 212, 214, 216, 221, 224, 231 Spatial disorientation, 200, 231 Specialist, 175, 231 Species, 203, 214, 216, 227, 231, 232, 237, 238 Specificity, 15, 47, 66, 143, 186, 231 Spectroscopic, 24, 231 Spectrum, 14, 21, 39, 216, 231 Sperm, 195, 231, 234 Sphincters, 205, 231 Spike, 50, 146, 232 Spinal cord, 190, 192, 194, 195, 215, 218, 221, 228, 232, 233 Sporadic, 218, 232 Stabilization, 46, 232 Stabilizer, 61, 232 Staging, 229, 232 Standardize, 34, 232 Staphylococcus, 216, 232 Startle Reaction, 59, 232 Steady state, 141, 232 Stereotyped Behavior, 85, 232 Sterility, 18, 210, 232 Steroids, 143, 198, 232 Stimulus, 7, 9, 11, 27, 47, 55, 59, 62, 80, 122, 201, 204, 210, 211, 228, 232, 235 Stomach, 206, 208, 217, 231, 232 Stool, 3, 210, 212, 232 Street Drugs, 11, 232 Stress, 24, 26, 193, 217, 232 Stria, 26, 232 Striatum, 5, 21, 24, 45, 64, 68, 145, 219, 232 Stroke, 9, 95, 168, 193, 232 Structure-Activity Relationship, 11, 52, 233 Stupor, 217, 233 Subarachnoid, 206, 207, 233 Subclinical, 210, 229, 233

Subiculum, 208, 233 Substance P, 215, 229, 233 Substrate, 60, 102, 203, 233 Suppression, 30, 47, 233 Sympathetic Nervous System, 218, 233 Sympathomimetic, 187, 199, 200, 203, 215, 219, 233 Symphysis, 195, 225, 233 Symptomatic, 36, 59, 110, 135, 187, 233 Symptomatic treatment, 135, 187, 233 Symptomatology, 16, 233 Synapse, 21, 81, 108, 116, 186, 199, 224, 233, 234, 236 Synaptic, 5, 21, 65, 68, 116, 218, 219, 233, 234 Synaptic Transmission, 5, 65, 219, 233 Synaptic Vesicles, 68, 234 Syncope, 117, 234 Synergistic, 13, 225, 234, 235 Systemic, 54, 59, 65, 132, 141, 145, 164, 192, 203, 210, 212, 227, 234, 238 Systemic disease, 132, 234 Systolic, 9, 209, 214, 234 Systolic pressure, 214, 234 T Tachycardia, 30, 113, 234 Tardive, 189, 195, 234 Telecommunications, 197, 234 Telencephalon, 191, 194, 234 Temporal, 14, 73, 187, 208, 234 Teratogenic, 200, 234 Testicles, 229, 234 Tetracycline, 216, 234 Thalamic, 28, 122, 234 Thalamus, 50, 199, 213, 224, 234 Theophylline, 37, 84, 234 Therapeutics, 34, 51, 63, 74, 84, 139, 164, 216, 235 Threshold, 209, 235 Thrombin, 223, 225, 235 Thrombomodulin, 225, 235 Thrombosis, 225, 232, 235 Thyroid, 30, 235, 236 Thyroid Gland, 235 Thyroid Hormones, 30, 235, 236 Tic, 13, 44, 71, 96, 235 Time Perception, 81, 235 Token Economy, 111, 235 Tolerance, 39, 137, 144, 149, 185, 193, 235 Tomography, 32, 70, 235 Tone, 235 Tonic, 25, 235

249

Topical, 133, 140, 144, 204, 235 Toxic, iv, 47, 190, 191, 207, 219, 230, 235, 236 Toxicity, 63, 70, 94, 135, 201, 222, 232, 235 Toxicology, 8, 56, 71, 85, 94, 170, 235 Toxin, 47, 235, 236 Trace element, 205, 236 Trachea, 192, 235, 236 Tramadol, 8, 236 Transfection, 32, 191, 236 Translational, 4, 53, 236 Transmitter, 20, 68, 185, 190, 200, 211, 214, 219, 234, 236 Trauma, 6, 24, 217, 228, 236 Treatment Outcome, 43, 73, 236 Triazolam, 120, 236 Tricyclic, 91, 195, 199, 209, 236 Tryptophan, 230, 236 Tubercle, 219, 236 Tumor marker, 191, 236 Tunica, 217, 236 Tyrosine, 21, 144, 200, 236 U Unconscious, 188, 227, 236 Uremia, 228, 236 Urethra, 225, 237 Urinary, 203, 210, 229, 237 Urine, 10, 54, 71, 86, 93, 106, 191, 200, 210, 229, 237 Uterine Contraction, 220, 237 V Vagina, 199, 215, 237 Valproic Acid, 116, 237

Vascular, 191, 199, 203, 208, 210, 219, 235, 237 Vasoconstriction, 203, 237 Vasodilator, 192, 200, 237 Vegetative, 199, 237 Vein, 211, 219, 237 Venlafaxine, 109, 113, 237 Venous, 208, 225, 237 Venter, 237 Ventral, 21, 48, 64, 81, 209, 219, 223, 237 Ventral Tegmental Area, 48, 64, 237 Ventricle, 187, 194, 208, 209, 219, 226, 234, 237 Venules, 192, 193, 237 Vesicular, 56, 68, 237 Veterinary Medicine, 169, 237 Virulence, 190, 235, 237 Virus, 135, 185, 194, 206, 238 Viscera, 231, 238 Vitro, 19, 32, 238 Vivo, 19, 27, 32, 47, 238 Volition, 211, 238 W White blood cell, 185, 188, 214, 223, 238 Windpipe, 235, 238 Withdrawal, 10, 37, 55, 87, 110, 215, 238 X Xenograft, 188, 238 X-ray, 197, 206, 212, 219, 227, 229, 232, 238 X-ray therapy, 212, 238 Y Yeasts, 222, 238 Z Zymogen, 225, 238

250

Methylphenidate

251

252

Methylphenidate

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