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

LIVER

ENZYMES 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., 1960Liver Enzymes: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84592-1 1. Liver Enzymes-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 liver enzymes. 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 LIVER ENZYMES ........................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Liver Enzymes............................................................................... 4 The National Library of Medicine: PubMed ................................................................................ 18 CHAPTER 2. ALTERNATIVE MEDICINE AND LIVER ENZYMES ........................................................ 55 Overview...................................................................................................................................... 55 National Center for Complementary and Alternative Medicine.................................................. 55 Additional Web Resources ........................................................................................................... 55 General References ....................................................................................................................... 57 CHAPTER 3. DISSERTATIONS ON LIVER ENZYMES .......................................................................... 59 Overview...................................................................................................................................... 59 Dissertations on Liver Enzymes .................................................................................................. 59 Keeping Current .......................................................................................................................... 59 CHAPTER 4. BOOKS ON LIVER ENZYMES ........................................................................................ 61 Overview...................................................................................................................................... 61 Book Summaries: Federal Agencies.............................................................................................. 61 Chapters on Liver Enzymes ......................................................................................................... 62 CHAPTER 5. MULTIMEDIA ON LIVER ENZYMES ............................................................................. 67 Overview...................................................................................................................................... 67 Video Recordings ......................................................................................................................... 67 CHAPTER 6. PERIODICALS AND NEWS ON LIVER ENZYMES........................................................... 69 Overview...................................................................................................................................... 69 News Services and Press Releases................................................................................................ 69 Academic Periodicals covering Liver Enzymes............................................................................ 71 APPENDIX A. PHYSICIAN RESOURCES ............................................................................................ 75 Overview...................................................................................................................................... 75 NIH Guidelines............................................................................................................................ 75 NIH Databases............................................................................................................................. 77 Other Commercial Databases....................................................................................................... 79 APPENDIX B. PATIENT RESOURCES ................................................................................................. 81 Overview...................................................................................................................................... 81 Patient Guideline Sources............................................................................................................ 81 Finding Associations.................................................................................................................... 96 APPENDIX C. FINDING MEDICAL LIBRARIES .................................................................................. 99 Overview...................................................................................................................................... 99 Preparation................................................................................................................................... 99 Finding a Local Medical Library.................................................................................................. 99 Medical Libraries in the U.S. and Canada ................................................................................... 99 ONLINE GLOSSARIES................................................................................................................ 105 Online Dictionary Directories ................................................................................................... 105 LIVER ENZYMES DICTIONARY .............................................................................................. 107 INDEX .............................................................................................................................................. 165

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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 liver enzymes 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 liver enzymes, 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 liver enzymes, 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 liver enzymes. 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 liver enzymes, 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 liver enzymes. 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 LIVER ENZYMES Overview In this chapter, we will show you how to locate peer-reviewed references and studies on liver enzymes.

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

Abnormal Liver Enzyme Levels: The Spectrum of Causes Source: Postgraduate Medicine. 93(2): 113-116. February 1, 1993. Summary: Elevated levels of one or more liver enzymes are commonly found in asymptomatic patients. Such findings may be important, because minimal elevation may be the only manifestation of significant hepatobiliary disease. This article discusses the significance of liver enzyme abnormalities in asymptomatic patients and presents a rational approach to evaluation. Specific topics include aminotransferases; gammaglutamyl transpeptidase; and the clinical approach. 2 tables. 18 references. (AA-M).

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Mildly Elevated Liver Enzymes: Significance and Diagnostic Strategies. (editorial) Source: Liver Update: Function and Disease. 5(1): 1-2. Spring 1991.

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Contact: Available from American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, NJ 07009. (800) 223-0179 or (201) 256-2550. Summary: This article discusses the significance of and diagnostic strategies for mildly elevated liver enzymes. Although there is no standard definition of what constitutes mild elevation of liver enzymes, the author proposes a working definition in multiples of the upper limits of normal for each individual enzyme test: aspartate and alanine aminotransferases; alkaline phosphatase; and gamma-glutamyltransferase. •

HELLP Syndrome: Hemolysis, Elevated Liver Enzymes, and Low Platelets Source: JAMA. Journal of the American Medical Association. 280(6): 559-562. August 12, 1998. Summary: This article presents a detailed case study and discussion of HELLP syndrome, which consists of hemolysis, elevated liver enzymes, and low platelets. The HELLP syndrome is one of the hypertensive disorders of pregnancy, which also include preeclampsia and eclampsia. The multi-organ dysfunction in HELLP can lead to acute tubular necrosis and renal failure. Preeclampsia is associated with glomerular endotheliosis, whose pathologic hallmark is a thickening of the basement membranes; a similar renal lesion may account for the proteinuria in HELLP. With proper supportive care, most patients fully recover kidney function. The author emphasizes that all physicians should know that a cardinal symptom of the HELLP syndrome is right upper quadrant pain. Clinicians examining pregnant women in a primary care or subspecialty setting should have a low threshold for ordering a complete blood count, urinalysis, and liver function tests, even if the patients complaints are nonspecific. Finally, pregnant women need regular, accurate blood pressure measurement. A blood pressure of 140 over 90 mm Hg, normal in most nonpregnant patients, may indicate serious disease in pregnant women. 28 references.

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Abnormal Liver Enzyme Levels: Evaluation in Asymptomatic Patients Source: Postgraduate Medicine. 89(4): 137-141. March 1991. Summary: When serum levels of liver enzymes are found to be elevated and continue to be elevated on follow-up testing, significant disease may be present even if the patient has no symptoms. Physicians who are aware of possible causes of such elevations have the opportunity to identify certain disorders in the very early, presymptomatic stages. This article describes disorders of hepatic origin and some mimics that may cause abnormal enzyme levels and outlines the steps to narrow and confirm diagnosis. Patients with persistently abnormal alkaline phosphatase levels may have extrahepatic biliary tract disease or a chronic cholestatic disorder. The author recommends a careful history and thorough physical examination, appropriate timing of follow-up blood tests, and timely referral for percutaneous liver biopsy or endoscopic retrograde cholangiopancreatography. 2 tables. 17 references. (AA-M).

Federally Funded Research on Liver Enzymes The U.S. Government supports a variety of research studies relating to liver enzymes. These studies are tracked by the Office of Extramural Research at the National Institutes of

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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 liver enzymes. 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 liver enzymes. The following is typical of the type of information found when searching the CRISP database for liver enzymes: •

Project Title: ALCOHOL IN ISRAEL: GENETIC AND ENVIRONMENTAL EFFECTS Principal Investigator & Institution: Hasin, Deborah S.; Associate Professor; New York State Psychiatric Institute 1051 Riverside Dr New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Alcohol dependence and heavy drinking are complex traits caused by genetic and environmental factors. A powerful design to study etiology would therefore address both types of factors jointly, but this has seldom been done. Polymorphisms in alcohol metabolizing genes encode liver enzymes that differ in their kinetic properties, including ADH2*2, which has a protective effect against heavy drinking and alcohol dependence. Elevated ADH2*2 prevalence in Jews facilitates its study in Jewish samples. Three large, distinct Jewish population groups in Israel offer the opportunity to study ADH2 and other alcohol metabolizing genes under different conditions. (1) Between late 1989 and 1994, many highly assimilated, urban Russian Ashkenazis migrated to Israel due to sharply increased Soviet anti-Semitism amid socially chaotic conditions. In Israel, they formed a consolidated ethnic group whose lifetime drinking histories reflect the high Russian per capita alcohol consumption. (2) Other Israeli Ashkenazis have much lower lifetime drinking histories, reflecting Israel's much lower per capita alcohol consumption. The lifetime histories of these two Ashkenazi groups allow study of ADH2*2 and other alcohol metabolizing genes under contrasting environmental conditions. (3) Israeli Sephardics offer a third important contrast. They differ from Ashkenazis in some social and genetic respects, and also have much lower lifetime drinking than the Russian immigrants. This is a unique research opportunity to study variation in gene-phenotype associations under different conditions. The relationship of ADH2 to lifetime peak alcohol consumption and lifetime DSM-IV alcohol dependence severity will be studied in 850 Russian immigrants arriving 1989-1994, 850 other Ashkenazis, and 850 Sephardics in Israel. The ADH2*2-alcohol phenotype associations are predicted to be weakest in the Russians due to Russian cultural influences promoting drinking even among those with the protective form of the gene. Gene effects are predicted to be intermediate in other Ashkenazis and strongest in Sephardics. ADH3 and promoters of ADH4 and ALDH2 will also be studied. Psychiatric comorbidity, religiosity and trauma will be assessed and controlled. Unrelated microsatellite markers will be tested for population stratification, which will be adjusted for if found. The sample will be drawn from the Israel Population Register.

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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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In-person interviews will include well-tested measures from U.S. and international studies. Genotyping will be done at Indiana and Columbia Universities. Preliminary studies support the hypotheses and feasibility of the methods. The larger significance of the study is to improve understanding of how genes relate to heavy drinking and alcohol dependence and how different environmental conditions may impact on these relationships Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALCOHOL, INOS UPREGULATION, LEAKY GUT & LIVER DISEASE Principal Investigator & Institution: Keshavarzian, Ali; Professor of Pharmacology & Molecular Bi; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): Clinically significant alcoholic (A) liver damage (LD), secondary to a hepatic necroinflammatory cascade (HNIC), occurs only in a subset of alcoholics. Hence, factors other than ethanol (E) must be involved. Hypothesis: The key cofactor for ALD is a breakdown of gut barrier integrity ("leaky gut") due to chronic E use, which allows intestinal endotoxin to reach the liver & initiate a HNIC; this leakiness is due to cytoskeletal instability caused by oxidation of cytoskeletal proteins which is elicited by E-induced gut iNOS upregulation & nitric oxide (NO) overproduction. We found: 1} in man, gut leakiness in alcoholics with LD but not in those without LD or in nonalcoholics with LD; 2} in rats, E-induced leaky gut is associated with LD; reversal of gut leakiness attenuates LD; 3} in intestinal monolayers, E-induced iNOS upregulation causes cytoskeletal & barrier disruption. We will continue to use this successful translational approach (monolayers, rats & man) to test our current hypotheses. Aims: (1) To see if, in a larger sample, a leaky gut: a) occurs only in alcoholics with LD & precedes cirrhosis b) persists during abstinence & after liver transplant for ALD, c) correlates quantitatively with LD severity, d) is associated with NO overproduction & HNIC, e) is more pronounced in females. We predict that gut leakiness (excess urinary lactulose, mannitol & sucralose levels after oral sugar load): i) is seen only in alcoholics with LD, precedes cirrhosis; ii) correlates with severity of LD (clinical parameters, liver enzymes); iii) is associated with NO overproduction (gut mucosal NO), serum endotoxin & HNIC (high neopterin/cytokines). (2) To see if, in rats, prevention of E-induced leaky gut also prevents E-induced LD & if a hyperactive, NO pathway is involved. We predict that in E-fed rats with LD: i) leaky gut, endotoxemia, HNIC, upregulation of intestinal iNOS, NO overproduction & oxidation of actin & tubulin occurs; ii) preventing gut leakiness (by oats, iNOS inhibitors or Arginine) prevents LD. (3) To see, using monolayers of wild type ((inhibitors) & transfected cells, if E-induced iNOS upregulation & its consequences (assessed by cytoskeletal oxidation/disarray & barrier disruption) are mediated by NF-kappaB activation. We predict i) E activates NF-kappaB by degrading IkappaBalpha; ii) preventing NF-kappaB activation prevents E-induced iNOS upregulation & its consequences. Significance: Showing that ALD requires a leaky gut, & that NO & cytoskeletal pathways are involved, could 1) identify drinkers at risk for LD (sugar test); 2) lead to therapies to prevent LD in those drinkers unable to abstain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMBINED TREATMENT FOR COCAINE-ALCOHOL DEPENDENCE Principal Investigator & Institution: Schmitz, Joy M.; Professor; Psychiatry and Behavioral Scis; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225

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Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Treatment seeking patients who are cocaine and alcohol dependent have poor prognosis. While there are no uniquely effective medications, combined pharmaco- and psychotherapy may prove efficacious. Naltrexone (NTX), approved for alcohol dependence, may block cocaine-alcohol rewarding effects at higher doses (> 50 mg/d) but psychotherapeutic context is critical. Our preliminary work indicates potential utility of NTX when combined with Relapse Prevention (RP) therapy and Contingency Management Procedures (CMP). We propose a large, double-blind, placebo-controlled, full factorial study to examine the role of RP + CMP combined with NTX for treatment of cocaine-alcohol dependence. Cocaine-alcohol dependent outpatients (N = 140) will be randomly assigned to NTX 100 mg/d or placebo combined with one of two psychotherapy conditions (RP or RP + CMP). Standardized consent and intake procedures will be followed by a single-blind baseline placebo week and then a 12 week trial with twice weekly visits. Manual-guided RP therapy will be delivered weekly in 60-minute individual sessions. CMP will reinforce abstinence based on cocaine-negative urine screens and negative breath alcohol test results. Medication adherence will be monitored with riboflavin and pill counts. Followup assessments will be conducted at 3, 6, 9, and 12 months after treatment termination. Primary efficacy variables will be measures of substance use (i.e., urine screens, TimeLine Follow-Back methods, collateral informants, change in liver enzymes) and retention (i.e., number of sessions attended, time to dropout). Secondary variables will include addiction severity and adverse event measures. A third set of variables will be tested as possible predictors of therapeutic outcomes. These include measures of motivation, self-efficacy, medication compliance, serum 6-beta naltrexol levels, craving, family history of alcohol problems, and severity of dependence. Power is sufficient to test the main hypothesis that NTX 100 mg/d with RP + CMP will reduce cocaine and alcohol use. Secondarily we will: (1) examine outcome variability as a function of individual differences on a range of potential predictors; (2) evaluate relative reinforcement of cocaine and alcohol using an innovative multiple choice measurement strategy; and (3) examine the relationship between cocaine and alcohol use during treatment and follow-up. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIPHTHERIA FUSION PROTEIN THERAPY OF AML Principal Investigator & Institution: Frankel, Arthur E.; Professor of Medicine; Cancer Biology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 12-DEC-1997; Project End 31-DEC-2006 Summary: Ten thousand people in the U.S. develop acute myeloid leukemia (AML) each year. While many patients achieve remissions with combination chemotherapy, most relapse and die with drug resistant disease. We have produced a diphtheria fusion protein (DT388GMCSF) consisting of the catalytic and translocation domains of diphtheria toxin fused to human granulocyte-macrophage colony- stimulating factor. We initiated a phase I single-arm, inter-patient dose escalation clinical trial of five daily intravenous infusions for patients with relapsed or refractory AML. To date, we have observed dose- related transient elevations in liver enzymes and circulating inflammatory cytokines. Half of the patients were found to have pre- treatment antibodies to DT388GMCSF >2mu g/mL associated with reductions in the peak blood concentrations of DT388GMCSF. Clinical remissions have been observed at the higher dose levels. In the next funding period, we propose to better define the potential role for DT388GMCSF in the care of AML patients. We will complete the on- going phase I

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study and expand the cohort of patients at the maximal tolerated dose to better estimate the preliminary response rate and side effects. Further, we propose three areas of laboratory studies to be carried out to facilitate our understanding of the molecular pharmacology of DT388GMCSF in these patients. In Specific Aim 1, the molecular mechanism for the liver damage and cytokine release will be investigated. The amount and types of cytokines released into the blood will be measured. Patient cytokine gene polymorphisms will be determined. A rat model will be used to determine whether the cytokines induce the liver injury. Methods of prevention of the cytokine release and liver injury in the rat will be tested. If successful, such measures may be tested in patients. In Specific Aim 2, anti- DT388GMCSF antibody formation and DT388GMCSF serum levels will continue to be measured and correlated with toxicity and response. In Specific Aim 3, pre-treatment blast proliferation sensitivity to DT388GMCSF will be measured and correlated with clinical response. These studies should lead to the design of pivotal phase II clinical trials to determine the role of this therapeutic in AML management. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FATTY LIVER DISEASE AND HEPATIC ENERGY HOMOSTATIS IN SH* Principal Investigator & Institution: Diehl, Anna M.; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 15-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Obesity is associated with insulin resistance, diabetes mellitus, hypertension, and dyslipidemia; less well known is its association with non-alcoholic fatty liver disease (NAFLD). The prevalence of NAFLD is 14-21 percent in some populations, is more common in those who are diabetic or over age 45, and can lead to fibrosis and cirrhosis. Recent evidence indicates that NAFLD is a consequence of disordered hepatic energy homeostasis. Several emerging lines of evidence suggest the overall hypothesis that disordered hepatic energy homeostasis and subsequent NAFLD may play a central role in mediating the adverse metabolic effects of obesity and may influence the success of weight loss interventions. Unfortunately, prior clinical studies have been limited. We, therefore, have the following specific hypotheses: 1) NAFLD and disordered hepatic energy homeostasis will be common in SHOW participants; 2) NAFLD will be associated with disordered energy homeostasis, AfricanAmerican race and male gender; 3) disordered hepatic energy homeostasis will be associated with a proinflammatory state, and adaptive decreases in normal energy requirements; 4) those with disordered hepatic energy homeostasis will have a weaker response to the SHOW intervention compared to those with normal hepatic energy homeostasis; and 5) the SHOW intervention will improve NAFLD and hepatic energy homeostasis in those with little or no defect in hepatic energy homeostasis but worsen it in those with moderate to severe defects. To test these hypotheses we propose a single center ancillary study to the SHOW trial. The study sample for the ancillary study would be the 313 SHOW participants enrolled at Johns Hopkins. We will measure symptoms of hunger and fatigue (0, 6, 12 mo.) and collect additional data including liver enzymes (0, 6, 12 mo.), MRI Spectroscopy (0, 12 mo.), and ketone bodies, insulin levels, and proinflammatory cytokines (0, 12 mo.) The main outcomes will be the prevalence, correlation, and 1-year progression of NAFLD and disordered hepatic energy homeostasis. Our secondary outcomes will be weight change, physical activity, dietary intake, and symptoms of hunger and fatigue in those with and without NAFLD and disordered hepatic energy homeostasis. If our hypotheses are confirmed, this study

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will establish blood and other clinical markers of NAFLD and disordered hepatic energy homeostasis, which will facilitate population based research; advance our understanding of the pathophysiology of NAFLD; establish disordered hepatic energy homeostasis as a biologic modifier of behavioral approaches to weight loss; and determine whether weight loss improves NAFLD or poses unsuspected risks. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATITIS C INFECTION & DIABETES IN INJECTION DRUG USERS Principal Investigator & Institution: Mehta, Shruti H.; Epidemiology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-APR-2002 Summary: Proposed is a two-phase study to examine the association between hepatitis C virus (HCV) infection and subsequent development of type 2 diabetes mellitus. Recent evidence from the third National Health and Nutrition Examination Survey and other studies suggest such an association. Given the high prevalence of HCV infection (approximately 90 percent) in injection drug users (IDUs), this study has tremendous health implications for IDUs. Phase I involves a case-cohort study to determine whether there is an independent causal association between HCV infection and type 2 diabetes in a large cohort of community-based men and women. We will enroll 436 incident diabetes cases and 872 age- matched controls from the Atherosclerosis Risk in Communities (ARIC) study and will assess the presence of HCV antibody from frozen serum samples taken prior to the onset of diabetes. In Phase II, we will test a subset (n=210) of anti-HCV positive individuals from a large cohort of IDUs (AIDS Link to Intravenous Experiences) in Baltimore, Maryland for diabetes. Cases of type 2 diabetes will be compared to age-matched controls for differences in HCV viral characteristics such as HCV RNA, liver enzymes and HCV genotype in an attempt to elucidate the mechanism of this proposed association. The results of this study will drive future epidemiological and physiological research into the role of liver disease in the pathogenesis of diabetes as well as potential diabetes prevention programs in populations such as IDUS who bear most of the burden of the hepatitis C virus epidemic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIV, DRUG USE AND HEPATITIS C PATHOGENESIS Principal Investigator & Institution: Thomas, David L.; Associate Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: (Applicant's Abstract) The purpose of this investigation is to evaluate the effect of HIV infection, drug use and other factors on the progression of hepatitis C. The observation of heterogenous outcomes after hepatitis C virus (HCV) infection suggests the hypothesis that viral, genetic, and environmental factors affect disease progression. To examine the relative importance of multiple factors, in a representative setting and with appropriate power, a series of integrated experiments have been designed for specimens from a large cohort (ALIVE) of injecting drug users (IDUs) who have been followed semiannually since 1988. The study population is 1,265 HCV-infected IDUs, including 378 coinfected with HIV at enrollment. By prospectively assessing liver enzymes and actively ascertaining clinical evidence of hepatic failure or death on all participants and evaluating liver biopsies randomly obtained from 210 individuals, an

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estimated 50 cases of progressive HCV infection will be identified. The effect of HIV infection, drug use, viral heterogeneity, and genetic factors on HCV natural history will be evaluated. Prospective and nested case control analysis will be used to compare the occurrence of putative cofactors among the 50 cases and controls, matched for confounders such as the duration of drug use. After 4 years of rigorous follow-up and reassessment with liver biopsy, the relationship of hepatic histology, liver enzymes, HCV viral load and the clinical expression of disease also will be evaluated. The investigators have experience with all research methods, including assessment of HCV viral load, genotype and quasispecies distribution; HLA haplotype and gene marker characterization; liver biopsy procurement and evaluation; and analytic techniques. Success at minimal expense is likely because the study will utilize a large HCV-infected cohort, an established research setting, eight years of existing data, experienced lab personnel, and superb collaborators. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPERINSULINEMIA AND THE PATHOGENESIS OF NASH Principal Investigator & Institution: Neuschwander-Tetri, Brent A.; Internal Medicine; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 20-MAY-2002; Project End 30-APR-2007 Summary: Non-alcoholic fatty liver disease (NAFL or NAFLD) and its subset, nonalcoholic steatohepatitis (NASH) are increasingly recognized as common forms of liver disease. In the absence of concomitant cellular injury, fatty liver is a benign condition that may cause elevated liver enzymes, fatigue and abdominal pain. MASH is identified by the presence of fat in the liver plus hepatocellular injury, inflammation and varying degrees of liver fibrosis. It afflicts up to 3% of adults n the United States and one third of these people may be at risk for developing cirrhosis. NASH also affects children, although its prevalence in the pediatric population is less well defined. Currently 2% of liver transplants performed in the United States are performed because of known diagnosis of NASH. Insulin resistance, with its major associated diseases of obesity and Type 2 diabetes, is emerging as a major coexisting condition. This application proposes two clinical studies to be performed in the context of a cooperative clinical research network to achieve the long-term goals of establishing the role of hyperinsulinemia in the pathogenesis of NASH and identifying rational and effect strategies to prevent and cure NASH. These goals will be addressed by specific aims of this proposal that seek to better understand the prevalence of NASH in hyperinsulinemic patients and establish whether reducing insulin levels pharmacologically improves the necroinflammatory changes associated with NASH. Two clinical studies are proposed. The first study establishes the prevalence of NASH in patients with hyprinsulinemia and imaging evidence of fatty liver. A secondary goal of the prevalence study is to establish racial differences in the risk for developing NASH because NASH may be underrepresented or underdiagnosed in African Americans. Enrollment will include adequate African Americans to allow subgroup analysis. The second proposed study is to a 48 week treatment trail of patients with NASH using the PPAR-gamma ligand rosiglitazone and, if needed to control hyperinsulinemia, metformin. Liver biopsies of patients recruited from all Clinical Centers will be compared to liver biopsies of patients treated with the standard recommendation of weight reduction. The primary endpoint will be improvement in the liver biopsy necroinflammatory score. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPID CONJUGATES OF XENOBIOTICS Principal Investigator & Institution: Ansari, Ghulam A.; Professor; Pathology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 01-MAY-1988; Project End 31-MAY-2005 Summary: To understand the mechanism(s) responsible for toxicity of xenobiotics capable of forming fatty acid (FA) conjugates, the investigators characterized rat liver FA ethyl ester synthetase (FAEES) isozymes that conjugate xenobiotics to FAs. The studies indicate that pancreatic and plasma FAEES are structurally and functionally different from those they characterized in the liver. Therefore, in Aim 1, they will purify and characterize FAEES from pancreas and plasma and establish their interrelationships to each other and to the liver enzymes by comparing structural and functional properties. These relationships will be further characterized using inhibitors (e.g., tri-otolyphosphate) and inducers (e.g., phenobarbital) of FAESS. In Aim 2, the relative formation of FA conjugates will be examined in hepatoma cell lines expressing different levels of enzymes involved in the conventional oxidative metabolism of the model compounds methanol and aniline. In Aim 3, the formation, kinetics and enzymology of FA conjugation of biologically important functional compounds will be investigated in vivo and in vitro and in cell culture. Finally, in Aim 4, the mechanism of toxicity of FA conjugates of methanol (FA methyl esters) and aniline (fatty acid anilides) will be evaluated in vivo. The mechanism by which FA methyl esters inhibit Kupffer cell function (phagocytosis) will be thoroughly investigated by studying their metabolism and effect on energy production. Similarly, the pancreatic toxicity of FA methyl esters will be evaluated, along with the evaluation of FA anilides to induce autoimmunity, and associate mechanisms. The project may provide a clear understanding of the formation of FA conjugates of xenobiotics, the enzymes involved in this process and the mechanism(s) by which such conjugates exert their toxicity. This information may be important in devising approaches to prevent the toxicities mediated by FA conjugates. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIVER TRIGLYCERIDE METABOLISM IN NASH Principal Investigator & Institution: Parks, Elizabeth J.; Food Science and Nutrition; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (adapted from the application) Non-alcoholic steatohepatitis (NASH) is a disease of emerging clinical significance. The risk factors for NASH include female gender, non-insulin dependent diabetes, obesity and hyperlipidemia. In NASH, the fat that accumulates in the liver is primarily triglyceride (TG) and three sources potentially contribute to this lipid are fatty acids (FA) derived from the diet, those originating in the adipose tissue (FFA in the plasma), and FA newly synthesized in the liver via process called de novo lipogenesis. The origin of the fat that accumulates in the liver has not been extensively investigated previously due to the technical challenges of studying de novo lipogenesis and the limitations of using radioactive isotopes in humans. Recent advances in gas chromatography/mass spectrometry and stable (non-radioactive) isotope methodology now make it possible to study hepatic TG metabolism in vivo. The hypothesis to be tested is that de novo lipogenesis contributes substantially to hepatic TG found in NASH. Further, it is hypothesized that plasma-derived FFA will contribute quantitatively less to the fat stored in hepatocytes and more to the TG that is exported from the liver in lipoproteins. Patients with persistently elevated liver enzymes of uncertain etiology, who are being considered for liver biopsy, will undergo a 5-day,

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stable-isotope infusion of labeled FA and precursors of FA, preceding the scheduled biopsy. Liver biopsy tissue (100 mg) will be analyzed to determine its biochemical content (TG, cholesterol, phospholipid and FFA), the composition of FA within these fractions, and the enrichment of labeled FA in the tissue (the sources of these FA). Control subjects will be aged- and sex-matched individuals undergoing surgical treatment for obesity who will have an identical isotope infusion before surgery. These methods will be used to accomplish the specific aims: (1) to quantify the concentration of the various lipids in NASH liver samples and samples from obese control subjects; (2) to determine the sources of FA used for lipid synthesis, and the turnover of these lipids in NASH patients and controls; and (3) to determine whether there is a difference between NASH patients and controls with respect to the composition of FA within liver tissue. Liver samples will be graded histologically and the stage of NASH documented semi-quantitatively. Computer tomography will be used to quantify liver size and abdominal visceral fat; ultrasound will also be performed. The results of all of these measurements will be analyzed to determine their relationship with hepatic lipid content. NASH will become more clinically important in the future as the incidence of obesity and diabetes continue to rise in the United States. In combination with the clinical data obtained, an understanding of the contributions of FA sources to liver TG will aid in the development of future treatment strategies for this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LONG TERM ADMINISTRATION OF TESTOSTERONE IN ELDERLY MEN Principal Investigator & Institution: Urban, Randall J.; Professor; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: Elderly men have lower serum testosterone concentrations and less muscular strength than young men. In a short-term study (1 month), we administered testosterone to elderly men in doses designed to raise their testosterone concentrations to those found in young men. This treatment increased skeletal muscle strength and muscle protein synthesis. The goal of this project is to determine whether more prolonged testosterone administration (6 months) will show a continuation of an increase in muscle strength and net muscle protein synthesis. Moreover, it will assess the changes that occur in myofibrillar protein (actin and myosin) and muscle size. Elderly men (ages 60 and greater) will be recruited from 3 sources, the Geriatrics outpatient clinic, a registry of elderly volunteers maintained by the Geriatrics Division at the University of Texas Medical Branch, and the local population. They will be enrolled in a double-blinded, placebo controlled study in which testosterone enanthate is given by intramuscular injection every week for 1 month, then every 2 weeks for an additional 5 months. At baseline, 1 and 6 months, we will determine muscle strength, muscle protein synthesis and degradation, myofibrillar (actin and myosin) protein synthesis, amino acid transport and arterial-venous balance, mRNA concentrations of actin and myosin, and muscle strength. Muscle size will be determined by DEXA and MRI scan at baseline and 6 months. Careful assessment of the risks of testosterone administration in this age group will be done by measuring prostate size and urinary flow rates (baseline and 6 months), lipid concentrations, liver enzymes, CBC, blood pressure, and prostate specific antigen. This study will determine whether the long-term administration of testosterone in elderly men will increase muscle strength, net protein anabolism, and muscle size. If 6 month testosterone administration increases strength, then studies can be done to assess

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the functional implications of this therapy in reducing falls, increasing independence, and improving the quality of life in elderly men. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFECTION

LONGITUDINAL

COHORT

OF

NEWLY

Principal Investigator & Institution: Kaldor, John M.; Epidemiology/Clncl Res Epidemiology/Clinical Research Sydney,

ACQUIRED Natl

HCV

Centre/Hiv

Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Currently, there is no effective hepatitis C virus (HCV) vaccine. Despite introduction of harm minimization strategies in Australia since the late 1980s, incidence of HCV infection among injecting drug users is extremely high. An estimated 16,000 new HCV infections occur each year in Australia, with approximately 90% related to injecting drug use. This estimate of new HCV infections has increased from 11,000 in 1997, due largely to an increasing prevalence of injecting. Although the vast majority of people with new HCV infection are asymptomatic at the time of infection, an increasing number of cases of newly acquired HCV infection are detected through enhanced HCV surveillance in Australia. For HCV surveillance purposes newly acquired HCV infection is defined as a person with a positive HCV antibody with evidence of a negative HCV antibody in the previous 24 months, or a person with acute clinical hepatitis (e.g. jaundice) with a positive HCV antibody where other causes of acute hepatitis have been excluded. In 2000 approximately 450 cases of newly acquired HCV infection were detected through enhanced surveillance in Australia. Further cases of newly acquired HCV infection are detected through primary care clinics that regularly screen injecting drug users for HCV, and referrals to tertiary care clinics of people with acute hepatitis. We propose to establish a longitudinal cohort of current injecting drug users (injected within previous 12 months) with newly acquired HCV infection. Within this cohort we propose to offer antiviral therapy for HCV infection with a 24-week course of pegylated interferon monotherapy to those people who have evidence of HCV viraemia (HCV-RNA positive) and biochemical hepatic inflammation (elevated liver enzymes). The major objectives of the study are to examine the feasibility of interferon therapy for newly acquired HCV infection among injecting drug users. In addition, the untreated group within the longitudinal cohort will be studied to examine the natural history of early HCV infection. Both groups will continue followup for a period of three years, to examine sustainability of HCV clearance (both through natural and therapeutic means) and monitor incidence of HCV reinfection among people with evidence of HCV clearance. Drug use behavior including injecting drug use will also be closely monitored, to assess the impact of enrollment into the study and specific drug dependency and risk reduction strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MATERNAL LIVER DISEASE AND FATTY ACID OXIDATION DEFECTS Principal Investigator & Institution: Ibdah, Jamal A.; Internal Medicine; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 21-SEP-2001; Project End 31-AUG-2006 Summary: Mitochondrial trifunctional protein (TFP) catalyzes the last 3 steps in the beta-oxidation spiral of long chain fatty acids and consists of 4 alpha and 4 beta subunits. Long chain 3- hydroxyacyl Co-A dehydrogenase (LCHAD) resides in the

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alpha- subunit. Mutations in the alpha-subunit such as the prevalent G1528C mutation cause "isolated" LCHAD deficiency. Other mutations cause complete TFP deficiency (all the 3 enzymes are deficient). Recently, we have documented a fetal-maternal interaction that causes maternal liver disease in heterozygote women who carry fetuses with isolated LCHAD deficiency. This raises several questions. First, what is the mechanism of this fetal-maternal interaction? Second, what is the effect of environmental factors such as high fat diet and fasting on the development of maternal liver disease in the susceptible heterozygotes? Our hypothesis is that heterozygote women develop acute fatty liver of pregnancy (AFLP) or HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome due to accumulation of hepato-toxic fatty acid metabolites generated by either the affected fetus or the susceptible heterozygote under conditions of oxidative stress. To test this hypothesis we propose the following studies. 1) To use conventional and inducible Cre/lox P strategies to generate and characterize two knockout mice models for complete TFP deficiency (null mutation) and isolated LCHAD deficiency (G1528C mutation). Clinical, biochemical, histological, and molecular analyses will be performed. Tissue-specific and developmental stage-specific gene expression will also be characterized in these mice. Differences in the accumulated fatty acid metabolites will be correlated to the genotypes and phenotypes to elucidate the role of fatty acid metabolites in the genotype-phenotype correlations in these disorders. 2) To employ preimplantation genotyping and embryo transfer to independently study the effects of fetal and maternal genotypes on development of maternal liver disease in knockout mice. Pregnant dams will be monitored for evidence of liver disease. Fatty acid metabolites will be measured in fetal and maternal sera, fetal and maternal livers, and placentas, and will be correlated to the fetal/maternal genotypes and maternal phenotypes to identify the fatty acid metabolites that are potentially toxic to the maternal liver. 3) To conduct dietary studies in knockout mice to elucidate the effects of high fat diet and fasting on pregnant heterozygotes while carrying unaffected fetuses. Four different high fat diets will be studied to elucidate the effects of fat content, fatty acid configuration, and protein/carbohydrate contents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NALTREXONE TREATMENT OF ALCOHOL DEPENDENCE Principal Investigator & Institution: Volpicelli, Joseph R.; Associate Professor; Psychiatry; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-APR-1989; Project End 31-DEC-2002 Summary: APPLICANT'S ABSTRACT: The long range goal of this ongoing program of research is to find more effective treatments for alcohol dependence through combining medication with the appropriate psychosocial support. Naltrexone when used in conjunction with psychosocial therapy, reduces relapse to clinically significant drinking in compliant subjects. The present proposal extends our previous research by comparing the efficacy of naltrexone treatment administered in two types of primary care settings: one using simple medication management and a second using medication management with compliance enhancement techniques. In addition, we will compare these two conditions with cognitive behavioral therapy--a combination that has been successfully used to demonstrate naltrexone efficacy in prior research. This proposal has 3 specific aims: 1) To compare the effectiveness of naltrexone in 3 types of treatment settings; 2) Assess the effects of psychosocial support on medication compliance and treatment retention; and 3) To investigate the subject characteristics that may predict who is likely to benefit from additional psychosocial support versus simple medication management. To this end, 240 alcohol dependent outpatients who are, currently involved in outpatient

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alcohol rehabilitation at the University of Pennsylvania's Treatment Research Center will be randomly assigned to treatment with either naltrexone (100 mg per day) or placebo in double-blind fashion over a six-month period. Medication will be administered in three types of settings: 1) simple medication management by a research physician, 2) simple medication management plus Compliance Enhancement Techniques (CET) administered by a nurse practitioner, and 3) simple medication management plus Cognitive Behavioral Therapy (CBT) administered by a trained psychologist using the Project MATCH, CBT manual. The primary outcome measures are time to relapse to clinically significant drinking (5 or more in one day) and percent days of clinically significant drinking. Other alcohol use related measures include, alcohol craving, percent of abstinent days, and blood chemistries including liver enzymes. The outcome measures will be evaluated during the medication phase and at follow-up points 12 and 18 months after entrance into treatment. In addition, medication and treatment compliance will be evaluated during the trial. Medication compliance will be assessed by pill counts, urine screens for riboflavin and for those subjects on active medication by serum levels of naltrexone and beta-naltrexol. Treatment compliance will be evaluated by the percent of research visits attended. The results of this trial will provide important information on the clinical use of naltrexone in the treatment of alcohol dependence as alcohol dependence treatment moves into primary care settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL NON-PEPTIDE ANTAGONIST OF THE MCH RECEPTOR Principal Investigator & Institution: Schwarz, David A.; Neurocrine Biosciences, Inc. 10555 Science Center Dr San Diego, Ca 921211100 Timing: Fiscal Year 2003; Project Start 01-JAN-2001; Project End 30-APR-2005 Summary: (provided by applicant): Obesity is a rapidly advancing worldwide epidemic. Within the United States alone, 60% of the population is considered to be overweight. While new treatments for obesity have been introduced in the last decade, these drugs are only capable of reducing body weight by 10%, and patients typically gain back the lost weight following cessation of treatment. The potential for more effective therapeutics may be realized by targeting hormonal systems residing within the hypothalamus, a region of the brain critical for the appropriate regulation of food intake and energy utilization. Melanin concentrating hormone (MCH) is a prominent hormonal system originating within the lateral hypothalamus, which is responsible for initiating food intake. Genetically manipulating the expression of either the MCH ligand, or its receptor, inevitably results in alteration of body weight. Thus, mice overexpressing MCH ligand are obese, while mice lacking either the ligand or the receptor are lean. These data are consistent with the notion that blocking the interaction between MCH and its receptor will provide an effective means by which to reduce food intake in humans, and ultimately cause a loss of body weight. During the first phase of this project, we used high-throughput organic chemistry to develop multiple chemical series of potent MCH antagonists. We have also developed a number of critical in vitro and in vivo assays with which to monitor the bioavailability of these compounds, and their ability to inhibit acute food intake. In the second phase of this project, we propose to further refine these small molecules to improve their bioavailability. This will be accomplished by computer assisted drug design in conjunction with evaluation for a number of biological parameters including receptor affinity, hepatic stability, membrane permeability, and the potential for adverse reactions with liver enzymes necessary for proper drug metabolism. Compounds successfully emerging from this process will be

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further evaluated in acute and chronic feeding paradigms in order to select candidates suitable for clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESISTANCE TO ANTIVIRAL THERAPY IN CHRONIC HEPATITIS C Principal Investigator & Institution: Terrault, Norah A.; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 30-JUN-2006 Summary: (provided by applicant): An estimated 600,000 African-Americans have chronic hepatitis C virus (HCV) infection, representing 22% of the total infected population in the U.S. Prior studies suggest African-Americans with chronic HCV infection have a lower rate of response to anti-viral therapy than non-Hispanic whites. The difference is, in part, related to the predominance of genotype 1 among AfricanAmericans. Response rates appear to higher with combination interferon plus ribavirin than with interferon monotherapy. However, the studies to date have included very low numbers of African-American subjects (