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

METABOLITES 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., 1960Metabolites: 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: 0-497-00719-3 1. Metabolites-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 metabolites. 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 METABOLITES............................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Metabolites.................................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 67 The National Library of Medicine: PubMed ................................................................................ 88 CHAPTER 2. NUTRITION AND METABOLITES................................................................................ 133 Overview.................................................................................................................................... 133 Finding Nutrition Studies on Metabolites................................................................................. 133 Federal Resources on Nutrition ................................................................................................. 137 Additional Web Resources ......................................................................................................... 138 CHAPTER 3. ALTERNATIVE MEDICINE AND METABOLITES ......................................................... 141 Overview.................................................................................................................................... 141 National Center for Complementary and Alternative Medicine................................................ 141 Additional Web Resources ......................................................................................................... 155 General References ..................................................................................................................... 161 CHAPTER 4. DISSERTATIONS ON METABOLITES ........................................................................... 163 Overview.................................................................................................................................... 163 Dissertations on Metabolites...................................................................................................... 163 Keeping Current ........................................................................................................................ 166 CHAPTER 5. PATENTS ON METABOLITES ...................................................................................... 167 Overview.................................................................................................................................... 167 Patents on Metabolites............................................................................................................... 167 Patent Applications on Metabolites ........................................................................................... 188 Keeping Current ........................................................................................................................ 214 CHAPTER 6. BOOKS ON METABOLITES .......................................................................................... 215 Overview.................................................................................................................................... 215 Book Summaries: Federal Agencies............................................................................................ 215 Book Summaries: Online Booksellers......................................................................................... 216 Chapters on Metabolites............................................................................................................. 220 Directories.................................................................................................................................. 223 CHAPTER 7. PERIODICALS AND NEWS ON METABOLITES ............................................................ 225 Overview.................................................................................................................................... 225 News Services and Press Releases.............................................................................................. 225 Academic Periodicals covering Metabolites ............................................................................... 227 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 229 Overview.................................................................................................................................... 229 U.S. Pharmacopeia..................................................................................................................... 229 Commercial Databases ............................................................................................................... 231 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 235 Overview.................................................................................................................................... 235 NIH Guidelines.......................................................................................................................... 235 NIH Databases........................................................................................................................... 237 Other Commercial Databases..................................................................................................... 239 APPENDIX B. PATIENT RESOURCES ............................................................................................... 241 Overview.................................................................................................................................... 241 Patient Guideline Sources.......................................................................................................... 241 Finding Associations.................................................................................................................. 243 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 245 Overview.................................................................................................................................... 245

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Preparation................................................................................................................................. 245 Finding a Local Medical Library................................................................................................ 245 Medical Libraries in the U.S. and Canada ................................................................................. 245 ONLINE GLOSSARIES................................................................................................................ 251 Online Dictionary Directories ................................................................................................... 251 METABOLITES DICTIONARY.................................................................................................. 253 INDEX .............................................................................................................................................. 359

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

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

Decreased Lumbar Cerebrospinal Fluid Levels of Monoamine Metabolites in Vascular Dementia Source: International Psychogeriatrics. 8(3): 425-436. 1996. Summary: This journal article describes a study that investigated lumbar cerebrospinal fluid (CSF) levels of monoamine metabolites in 56 patients with vascular dementia (VAD). The patients, aged 56 to 89 years, were from the neuropsychiatric ward of Molndal Hospital, University of Goteborg, Sweden. Using a standardized protocol, levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were measured in the patients with VAD, and 57 healthy controls, aged 51 to 85 years. The VAD group had significantly lower HVA, 5-HIAA, and HMPG concentrations than the control group. However, there was wide variation in values in both groups and

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considerable overlap between groups. The monoamine metabolite levels were not associated with degree of dementia in the patients with VAD. The authors conclude that the low CSF levels of monoamine metabolites in patients with VAD do not appear to be disease specific, but may be attributable to subcortical white matter changes or to a decreased production of monoamines, which are dependent on oxygen for their synthesis. 1 figure, 4 tables, 44 references.

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

Project Title: ACYLCOA PHARMACOKINETICS

FORMATION--COVALENT

BINDING,

Principal Investigator & Institution: Benet, Leslie Z.; Professor; Biopharmaceutical Sciences; University of California San Francisco 3333 California Street, Suite 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2002; Project Start 01-APR-1986; Project End 31-MAR-2004 Summary: The overall goal of the research described in this renewal is to investigate the hypothesis that acyl-CoA thioester metabolites of carboxylic acid-containing drugs are reactive acylating species that, in addition to, but possibly more important than, reactive acyl glucuronides, contribute to the covalent binding of acidic drugs to proteins and which may be responsible for, among other toxicities, untoward allergic side-effects. This hypothesis will be focused on by a range of in vitro and in vivo studies, as directed by the following specific aims: 1) To evaluate the chemical reactivity of acyl-CoA thioester derivatives with biological nucleophiles and compare such reactivity with that of their respective acyl glucuronides; 2) To evaluate the effect of enzyme inducers and inhibitors, with respect to acyl glucuronidation and acyl-CoA formation, on the covalent binding of selected carboxylic acids to protein; 3) To quantitatively determine and compare the levels of drug-protein acylation, acyl glucuronidation and acyl-CoA formation of selected carboxylic acid drugs in vivo in selected tissues; 4) To develop improved methodology for the analysis of acyl-CoA thioester derivatives from biological samples; 5) To determine the effect of alpha-fluoro-substitution of carboxylic 2

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

Studies

5

acid drugs on xenobiotic acyl-CoA formation and protein acylation; 6) To assess the enantioselectivity of covalent binding of chiral NSAIDs to protein and their metabolism to reactive acylating derivatives in vivo and in vitro, 7) To identify the hepatic protein targets for reactive metabolites of diclofenac, resulting from either glucuronide or CoAthioester intermediates, using 2D-PAGE and mass spectrometry; 8) To investigate the role of the enzymes of fatty acylation on the selective acylation of cellular proteins by acidic drugs through their acyl-CoA thioester derivatives; 9) To determine if drugprotein conjugates formed by the reaction of xenobiotic-acyl-CoA thioester derivatives with protein are antigenic. This application proposes studies designed to: (a) characterize the chemical reactivity of acyl-CoA thioester metabolites of a number of acidic drugs, (b) compare this reactivity with corresponding acyl glucuronide metabolites, (c) elucidate the mechanisms by which protein acylation may occur for carboxylic acid-containing drugs through the CoA thioester pathway, as well as define the chemical structure of these products and (d) evaluate the immunotoxic potential of these thioester metabolites. In addition, since activation of endogenous fatty acids to their corresponding high-energy acyl-CoA thioester derivatives is an important enzymatic step required prior to the utilization of fatty acids for many cellular reactions, the findings of this work should provide important insights beyond immunotoxicity questions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AMINE N-OXYGENATION BY FMO3 AND FMO4 Principal Investigator & Institution: Cashman, John R.; Senior Scientist; Human Biomolecular Research Institute 5310 Eastgate Mall San Diego, Ca 921212804 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): Variation in neurotransmitter transporters, receptors and abnormal levels of neurotransmitters potentially are involved in neurological diseases including schizophrenia, bipolar affective disorder, autism, affective disorder, late onset Alzheimer's disease, Parkinson's disease and others. Fundamental information characterizing human neurotransmitter metabolism associated with neurodegenerative diseases could provide new approaches to understanding the pathology and developing new therapeutics. Our central hypothesis is that lack of detoxication of endogenous or xenobiotic amines underlies the pathological condition of some CNS diseases. The human flavin-containing monooxygenase (FMO) is one of the major human enzyme systems that contribute to the detoxication of endogenous, environmental and dietary nitrogen-containing substances. The overall goal of our work is to understand the details of FMO-mediated N-oxygenation of amines and hydroxylamines. Accumulation of hydroxylamines in the CNS may lead to cytotoxicity or apoptosis. To test this, fundamental information about human brain FMO N-oxygenation is required. The overall goal will be accomplished by addressing five Specific Aims including: Aim 1: cDNA-express the major forms of human brain FMO; Aim 2: Chemically synthesize amine metabolites of human brain FMO; Aim 3: Determine the kinetics and mechanism of human brain FMO amine N-oxygenation; Aim 4: Test the effects of human brain FMO amine metabolites on neuronal cell function including cytotoxicity and apoptosis, and Aim 5: Investigate the mechanism of amine metabolites on human neurotransmitter function. The significance is that fundamental biochemical information will result in new insight about the way endogenous and xenobiotic and dietary amines are metabolized in human brain. Such fundamental information will be useful in the development of safer drugs, the prevention of adverse drug reactions and the protection of humans from disease.

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

Project Title: ANALYTICAL CHEMISTRY CORE Principal Investigator & Institution: Wishnok, John S.; Senior Research Scientist; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 07-APR-1993; Project End 31-MAY-2007 Summary: (provided by applicant): This Core operates as a service, a developmental laboratory, and a resource for the Program Project. Both the overall objectives and the specific aims of the Core laboratories follow primarily from those of the individual projects; e.g., development of methods for identification or quantitation of carcinogennucleic acid adducts, carcinogen-protein adducts, and carcinogen metabolites and/or their conjugates. This includes continued evaluation of capillary HPLC-LIF for quantitation of protein or DNA damage and continued development of capillary HPLC and nanoelectrospray/microelectrospray tandem MS techniques to characterize and quantitate modified proteins or DNA. Development or adaptation of methods to quantitate DNA or protein adducts or urinary levels of PhIP or 2-amino-3,8dimethylimidazo-[4,5-f]quinoxaline (MeIQx) or their metabolites during previous funding periods, for example, was in direct response to the needs of epidemiological studies that evolved into Project 1 in this proposal. Many of the methods listed below were adapted or developed by the Core in this context and some methods, such as quantitation of aromatic amine-hemoglobin adducts by NICI GC-MS have in some cases become the methods of choice for other laboratories that carry out related investigations. The specific aims of the various research projects involve quantitation in urine, physiological fluids or tissue, of DNA and protein adducts of several carcinogens including aflatoxin and aromatic amines and related compounds (e.g., alkylated anilines) and quantitation of urinary excretion of the food-related carcinogen, PhIP, and its metabolites or conjugates. Literature methods are often based on pure or in vitro samples, so methods are developed for the isolation or concentration of low levels of these compounds in complex biological mixtures using, for example, solid-phase extractions or affinity chromatography. Where necessary, for example with tandem MS methods for analyses of modified oligonucleotides, the developmental work is done in the Core laboratories. Specific objectives for additional analyses or techniques include: (1) development and applications of ultrasensitive MS methods for nucleobase and deoxyribonucleoside adducts; (2) development and applications of HPLC-LIF methods for quantitation of derivatized adducts; and (3) transfer of HPLC-LIF technology to the Johns Hopkins University (Project 1 and Core). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRANSPORT

ANALYTICAL

METHODS

FOR

INVESTIGATING

PEPTIDE

Principal Investigator & Institution: Lunte, Susan M.; Professor; Pharmaceutical Chemistry; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2002; Project Start 18-MAR-2002; Project End 31-JAN-2007 Summary: (Adapted from applicant's abstract): The overall goal of this application is to develop methods for the investigation of the neurotransmitter and neuromodulator properties of substance P (SP) and its metabolites in vivo. Substance P is an important neuropeptide that has been shown to be involved pain perception, inflammation, and a number of disease states including depression and Alzheimer's. Substance P is released in both the brain and peripheral tissue. It is metabolized by a number of different

Studies

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peptidase enzymes in the brain. Many of its metabolites have also been shown to be neurochemically and/or physiologically active. Recently, we have shown that SP can be transported across the blood-brain barrier (BBB) using an in vitro model of the BBB. Substance P was shown to undergo enzymatic degradation at this barrier to smaller peptides that can also permeate the BBB. In this proposal, methods for monitoring the release, transport, and metabolism of substance P in both central and peripheral tissue will be developed. These methods will then be used to investigate the role of the bloodbrain barrier in the distribution of substance P and its metabolites between the brain and peripheral tissue in healthy and diseased animals. In addition, the development of separation-based sensors based on microdialysis and microchip CEEC for measuring the activity of nitric oxide synthase and the production of NO will be explored. Nitric oxide is known to change the permeability of the blood-brain barrier. The effect of substance P on the expression of the inducible form of nitric oxide synthase (INOS) and the release of NO at this barrier will also be investigated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERACTIONS

ANGIOTENSINS,

PROSTAGLANDINS-ADRENERGIC

Principal Investigator & Institution: Malik, Kafait U.; Professor; Pharmacology; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2002; Project Start 01-SEP-1977; Project End 31-AUG-2007 Summary: (provided by the applicant): Our long-term goal is to investigate the mechanism of interaction of the adrenergic nervous system, angiotensin II (Ang II) and eicosanoids in the regulation of cardiovascular function and in the development of hypertension. Over the past grant period, we have shown that norepinephrine (NE)and Ang II stimulate calcium/calmodulin dependent protein kinase II (CaMKII) phosphorylate cytosolic phospholipase A2 (cPLA2) and release AA in vascular smooth muscle cells (VSMC); AA metabolltes formed via cytochrome P450 (CYP45O) and lipoxygenase (LO) activate phosphoilpase D (PLD), amplify cPLA2 activity and contribute to VSMC hyperplasia and/or hypertropby and hypertension. This proposal is an extension of these studies and will test the hypotheses that: 1) Phosphorylation of cPLA2 at Ser-515 by CaMKII is responsible for its activation, translocation to the nuclear envelope and AA release in response to NE- and Ang II. 2) Translocation of cPLA2 to the nuclear envelope is dependent upon vimentin phosphorylation and actin filament organization, which is maintained by phosphorylation of heat shock protein 27 (HSP27) by ERK1/2. 3) AA metabolites derived via CYP45O and LO by transactivating epidermal growth factor receptor (EGFR) and/or NAD(P)H oxidase, activate ERK1/2, which causes further phosphorylation of cPLA2 at Ser505/727, and of PLD2 at a Tyrresidue(s), and promotes VSMC proliferation and/or hypertrophy. The specific alms of the proposal are: I. Signaling Mechanisms Involved in NE-induced cPLA2 and PLD Activation and their Functional Significance. Aim 1. To determine if NE-stimulated CaMKII, by phosphorylating cPLA2 on Ser-515, promotes AA release, Ras/ERK1/2 and PLD activation and VSMC proliferation. Aim 2. To investigate the contribution of CaMKII, Ras-ERK1/2, actin, vimentin and heat shock protein (HSP27) to NE-induced cPLA2 translocation to the nuclear envelope and the underlying mechanism involved Aim 3. To examine the contribution of epidermal growth factor receptor (EGFR) transactivation and NAD(P)H oxidase to AA metabolite-induced activation of RasERK1/2 and PLD2, amplification of cPLA2 activity and VSMC proliferation in response to NE. Aim 4. To elucidate the mechanism of PLD activation by tyrosine phosphorylation caused by cPLA2 derived AA metabolites via ERK1/2 and p38 MAPK

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in response to NE. II. Signaling Mechanisms Involved in Ang II-Induced cPLA2 and PLD Activation and their Functional Significance. We will also investigate the effects of Ang II on the above signaling mechanisms in VSMC using an approach similar to that described for NE. We will include Ang II and NE in the same protocols. These studies should further our understanding of the cellular mechanisms involved in NE-and Ang II- induced cPLA2 activation and AA release and the mechanism by which AA metabolites cause PLD activation, amplification of cPLA2 activity and VSMC proliferation and hypertrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTINEOPLASTIC V LEUKEMOGENIC EPIPODOPHYLLOTOXIN EFFECTS Principal Investigator & Institution: Felix, Carolyn A.; Associate Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 191044399 Timing: Fiscal Year 2003; Project Start 16-FEB-1999; Project End 31-JUL-2008 Summary: (provided by applicant): The objective of this work is to understand the nature of the DNA damage leading to MLL translocations in leukemias following anticancer treatment with DNA topoisomerase II inhibitors. The CYP3A4 promoter is polymorphic and CYP3A4 genotype confers susceptibility. CYP3A4 converts etoposide to etoposide catechol; the catechol is readily oxidized to a quinone. These metabolites are genotoxins. MLL joins with one of many partner genes to form the translocations. The genomic breakpoint junction sequences contain evidence of DNA damage and repair. Several genomic breakpoint junction sequences indicate precise or near-precise interchromosomal DNA recombinations, but the cloning of additional breakpoints is essential to discern the damage spectrum. Etoposide and its metabolites induce DNA topoisomerase II cleavage at the translocation breakpoints in MLL and in its partner genes in vitro. We propose that etoposide and its metabolites can stimulate a series of different DNA lesions, which are repaired to form the breakpoint junctions, and that the heterogeneity in genomic breakpoint junction sequences reflects heterogeneity in the damage and its resolution. The DNA lesions to be tested include the direct induction of DNA topoisomerase II cleavage by etoposide parent drug, induction of DNA topoisomerase II cleavage from DNA adduct formation by etoposide quinone or reactive oxygen species, replication fork collisions with DNA topoisomerase II covalent complexes and DNA topoisomerase II-independent damage. Aim 1 will examine the spectrum and quantify the relative importance of DNA adducts from etoposide metabolites in an MLL bcr DNA substrate using mass spectrometry. Aim 2 will investigate the induction of functional DNA topoisomerase II covalent complexes in MLL and in the genome by etoposide and etoposide metabolites in human CD34+ hematopoietic progenitor cells using DNA arrays. To answer whether, how often and to what degree precise recombinations, exonucleolytic nibbling, large deletions, insertions, inversions, duplications and nonhomologous end-joining have occurred in creation of the breakpoint junctions, Aim 3 will characterize the genomic sequences of both derivative chromosomes in the leukemias in patients. Solving the mechanism of leukemogenesis of the DNA topoisomerase II inhibitors is highly relevant to the targeted prevention of this usually fatal complication of anticancer treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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•

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Project Title: APPROACHES TO CHARACTERIZATION OF ANTIINFECTIVE AGENTS Principal Investigator & Institution: Hamann, Mark T.; Associate Professor; Pharmacognosy; University of Mississippi P.O. Box 907 University, Ms 386770907 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: The primary focus of this project is the isolation and characterization of new chemotypes for the treatment of infectious diseases. This includes research involving the development of instrumentation for the rapid and thorough analysis of bioactive organic compounds in complex biological mixtures. Our goal is to integrate the most powerful tools available for the purification and structure determination of organic materials into a single system while being able to recover nearly 95 percent of the purified sample for biological evaluation. The most promising metabolites will be studied for structure-activity relationships (SAR) using semi-synthesis, microbial transformations and molecular modeling. Natural product research during the last few decades has yielded thousands of novel organic compounds from the marine environment. The bioassays guiding these isolations typically have been antimicrobial, antitumor, antiviral or antiinflammatory. Little has been done to explore the oceans for compounds with activity against HIV, AIDS OI, TB and other infectious diseases. Additionally, because of the limits associated with the conventional self-contained underwater breathing apparatus (SCUBA), the majority of the compounds characterized from the marine environment are the results of shallow water collections (-30m). Dr. Michael Boyd, of the Laboratory of Drug Discovery Research and Development at the National Cancer Institute indicates that mass screening has proved to be the most effective means of discovering entirely new chemotypes not even suspected to have relevant biochemical properties. The objective of this proposed research program is to collect and screen marine samples for possible treatments of HIV and AIDS OI from depths and locations in the ocean which have remained unexplored. The active component(s) of those extracts showing promising activity will be isolated using preparative and semi-preparative high pressure liquid chromatography (HPLC) interfaced with NMR and FTMS. The chemical structures of the biologically active secondary metabolites will be determined with the use of LC-NMR-FTMS and 2D NMR. Methods for providing sufficient quantities for in vivo testing via synthesis, semisynthesis or reisolation will be addressed for promising compounds. SAR studies will be conducted utilizing chemical and microbial transformations of biologically active secondary metabolites combined with molecular modeling studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BENZENE METABOLITES AND HEMATOTOXICITY Principal Investigator & Institution: Monks, Terrence J.; Professor and Chair; Div/Pharmoacology & Toxicology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: (Adapted from applicant's abstract): Benzene, a major industrial chemical and environmental pollutant, causes a variety of hematological disorders in man, including aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia. While it is clear that benzene must be metabolized to cause its acute hematotoxic effects, no single metabolite of benzene reproduces these effects in vivo. Coadministration of hydroquinone (HQ) and phenol (PHE), however, does lead to bone marrow suppression in rodents. A pharmacokinetic interaction between these two

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benzene metabolites results in increased concentrations of both metabolites in bone marrow. Peroxidase and/or phenoxy-radical mediated oxidation of HQ then initiates redox cycling and formation of the reactive electrophile, 1,4-benzoquinone, which is considered the ultimate hematotoxic metabolite of benzene. However, 1,4benzoquinone readily undergoes glutathione (GSH) conjugation to form 2-(glutathion-Syl)hydroquinone, 2,5-bis-(glutathion-S-yl)hydroquinone, 2,6-bis-(glutathion-Syl)hydroquinone, and 2,3,5-tris-(glutathion-S-yl)hydroquinone. Preliminary data indicate that these GSH conjugates are present in the bone marrow of rats and mice following coadministration of hydroquinone and phenol. Moreover, the majority of HQGSH conjugates present in bone marrow are formed in situ and are metabolized to more reactive thiol conjugates via a previously unidentified mercapturic acid pathway. Because these quinol-thioether metabolites have enhanced capability to both redox cycle and arylate tissue macromolecules, we hypothesize that quinol-thioether metabolites contribute to benzene-mediated hematotoxicity and that the mechanism(s) likely involve the production of reactive oxygen species and/or interaction with proteins that specifically recognize GSH/cysteine and GSH/cysteine containing molecules. Such metabolite specific interactions interfere with growth- and differentiation-related signaling. We therefore propose to (i) assess the acute hematotoxicity of HQ-GSH conjugates in rodent hematopoietic tissue, (ii) determine changes in the production and/or function of hematopoietic growth factors in response to HQ-GSH conjugates, (iii) test the hypothesis that metabolite-induced changes in gamma-glutamyl transpeptidase activity (GGT), dipeptidase activity, cysteine transport, and GSH concentrations, precipitate sphingolipid turnover, the generation of ceramide and the induction of apoptosis, and (iv) test the hypothesis that specific proteins involved in the synthesis (GST), transport (GS-X pump), and metabolism (GGT, dipeptidases) of the peptidyl leukotrienes are targets of HQ-GSH conjugates and interfere with granulocytic cell differentiation. Because benzene reduces the number of myeloid stem cells in bone marrow and induces incomplete granulocytic differentiation, our studies will provide a comprehensive understanding of the mechanisms by which reactive polyphenolic metabolites of benzene cause perturbations in growth- and differentiation-related signaling and how such changes culminate in benzene-mediated hematotoxicity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOACTIVATION OF DIETARY PHENOLS BY HEMOPROTEINS Principal Investigator & Institution: Thompson, John A.; Professor; Pharmaceutical Sciences; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 30-SEP-1994; Project End 31-JUL-2003 Summary: The long-term goal of this research is to elucidate the underlying mechanisms by which phenolic compounds present in the human diet influence tumorigenesis. Ongoing studies demonstrates that the oxidative metabolism of alkylphenols by cytochromes P450 lead, in many cases, to the formation of quinoid products capable of covalent binding and/or free radical generation in cells. We now propose to extend this work to investigate the involvement of such reactive metabolites in tumor promotion utilizing the most thoroughly characterized model for probing mechanistic aspects of promotion in the lung. This system involves the enhancement of lung tumor development by chronic administration of the food additive butylated hydroxytoluene (BHT) to carcinogen-initiated mice. It has been demonstrated that metabolism of BHT in the target organ is necessary for promotion and it is known that BHT is converted to

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reactive quinoid metabolites in lung. These findings lead to the hypothesis that promotion depends upon two successive P450 catalyzed oxidations to the ultimate promoting species, a strongly electrophilic quione methide which alkylates one or more critical proteins leading to a disruption of growth control mechanisms. The following specific aims are proposed: (1) Determine the role of metabolism in the differential responsiveness of promotion- sensitive (B+) and promotion-resistant (B-) mice to the lung tumor promoter BHT. Conversion of BHT to a quinone methide and other reactive metabolites, as well as the detoxification of reactive metabolites, will be examined in lung tissues and cells from B+ and B- mice. (2) Investigate alkylation targets of a BHTderived quinone methide in lung cells that directly or indirectly impair cell-cell signaling. Protein alkylation by a highly reactive quinone methide metabolite of BHT will be examined in cells isolated from the lungs of B= and B- mice, and in tumorigenic and non-tumorigenic cell lines derived from murine lung. Alkylation patterns will be compared by radiochemical and immunochemical methods and selected adducts identified by mass spectrometry and microsequencing. (3) Examine biochemical consequences and oxidative damage in lung cells exposed to reactive metabolites of BHT. Isolated cells from B+ and B- mice and cell lines will be treated with reactive quinoid metabolites of BHT to investigate cytotoxicity, oxidative damage, inhibition of mitochondrial function, and inhibition of enzymes involved in detoxification. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOLOGICALLY ACTIVE MICROBIAL METABOLITES Principal Investigator & Institution: Floss, Heinz G.; Professor; Chemistry; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-DEC-1987; Project End 31-DEC-2003 Summary: The primary focus in the continuation of our studies on the biosynthesis of antibiotics and other microbial metabolites will be on three Actinomycete antibiotics which contain mC7N units of different biosynthetic origin. These are rifamycin, an antitubercular drug whose semisynthetic derivatives, like rifampicin, are widely used clinically, asukamycin, a member of a family of compounds which have shown, inter alia, inhibition of protein prenylation and of interleukin-1beta converting enzyme, and validamycin, a commercial agent against phytopathogenic fungi but also the precursor for the synthesis of the clinical antidiabetic drug, voglibose. In all three cases the object is to define the biosynthetic pathway and its genetic control, and to unravel key biochemical reaction mechanisms involved in these biosyntheses by a combination of molecular biological and biochemical approaches, and to lay the foundation for the generation of modified bioactive structures through genetic engineering. A secondary focus is on the elucidation, at the genetic, enzymatic and mechanistic level, of the mode of formation of the 2,6-dideoxyhexose moieties of the unusual macrolide antibiotic, chlorothricin, and of the formation and mode of attachment of the 2,6-dideoxy- and 2,3,6- trideoxyhexose moieties of the benzoisochromane quinone antibiotic, granaticin. These studies will help provide the knowledge base and the tools to modify the structures of various bioactive natural products by the attachment of different sugar moieties. Thirdly we will complete ongoing studies on the biosynthesis of phenazine antibiotics, the saphenamycins and esmeraldins, with the aim of identifying unequivocally the structure of the monomeric shikimate pathway derivative which undergoes dimerization to the general precursor, phenazine-1,6-dicarboxylic acid, and on the thiopeptide antibiotics, nosiheptide and thiostrepton, aimed at cloning the correct peptide synthases encoding their formation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOMARKERS OF AGING IN THE SERA METABOLOME Principal Investigator & Institution: Kristal, Bruce S.; Assistant Research Scientist; Winifred Masterson Burke Med Res Inst Medical Research Institute White Plains, Ny 10605 Timing: Fiscal Year 2004; Project Start 15-AUG-2004; Project End 31-JUL-2006 Summary: provided by applicant): The identification of valid, robust biomarkers of aging and age-related processes has been an elusive goal. Dietary restriction (DR, long term, low calorie diets) has established efficacy in increasing longevity and decreasing morbidity in rodents. We have now identified 93 components of the sera metabolome that define a DR serotype - i.e., a metabolic serotype or biomarker profile that reflects caloric intake. Megavariate pattern recognition analysis has identified metabolic profiles in both male and female rats that distinguish ad libitum fed and DR rats (100% accuracy in training sets, mean >90% in test sets). Profiles are robust across the lifespan (6,12,18,24, and 30 months). Profiles reflect duration of DR (fasted, 1, 2, 4, 8 weeks) and extent of restriction (10,20,30, 40% DR, r2 = 0.88 for N = 90). Profiles also distinguish long- and short-lived strains of mice, suggesting that at the profile, at least in part, reflects the physiological benefits of DR in addition to the decreased food intake. Most metabolites (>70%) cross species to humans, suggesting that the HPLC-based technique used identifies broadly conserved metabolites. We now propose to use our existing bioinformatics platform to reexamine our existing rat sera metabolomics data (>600 rats, -600,000 data-points) to identify biomarkers and metabolic profiles reflective of the aging process. This work extends our ongoing work into a new direction: a metabolome-based approach to aspects of aging. The work will be completed in the context of 4 focused Aims: Aim 1. To determine the extent to which previously identified biomarkers of DR are also biomarkers of aging Aim 2. To determine the extent to metabolites in major metabolic pathways (e.g., purines, tyrosine metabolites, tryptophan metabolites, antioxidants, neurotransmitters) are also biomarkers of aging Aim 3. To identify previously unstudied metabolites that are modulated by the aging process The markers studied in Aims 1-3 have complementary advantages for future studies: (a) likely correlation of biomarkers of aging and those of physiological deterioration captured by DR; (b) the broad literature on compounds in major pathways, and; (c) the potential to open new vistas with previously undefined markers Aim 4. To use the biomarkers above to build metabolic profiles of the aging process Profiles will be examined/generated using megavariate approaches available in the laboratory (e.g., 1 and 2-D clustering, heat maps, self-organizing maps, principal components analysis, partial least squares, partial least squares projection to latent structures discriminant analysis, ere). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BIOMARKERS FARMWORKERS

OF

PESTICIDE

TOXICITY

AMONG

TEEN

Principal Investigator & Institution: Mccauley, Linda A.; Professor and Associate Dean for Researc; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-DEC-2003 Summary: (provided by applicant): Each year, thousands of migrant farm workers migrate to the Pacific Northwest to harvest berry crops. A great number of these laborers are adolescents--some traveling alone and others working alongside their families in the agricultural fields. These adolescents are exposed to pesticide spray (drift) and residues in the soil and on foliage. However, little scientific evidence is

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available to determine acceptable levels of pesticide exposure in this vulnerable population. Pesticides are thought to pose a considerably higher biological risk to children than to adults, but little is known about the extent or magnitude of this vulnerability. The potential of neurotoxicity related to chronic low-dose pesticide exposure in children is a major public health concern. Also, there may be risk factors that influence the occupational exposures of youth agricultural workers, and the period of rapid development during adolescence may introduce added risk in areas such as DNA damage related to pesticide exposure. Our interdisciplinary research team will use a cross-sectional, repeated measures design to compare adolescent farmworkers to their adult counterparts and to non-agricultural referent groups in order to: 1) determine differences in exposure to agricultural chemicals with urinary biomarkers of pesticide metabolites, 2) examine the relationship between urinary pesticide metabolites and neurobehavioral performance, and 3) determine age-related differences in pesticideinduced markers of DNA damage and oxidative stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOSENSORS FOR METABOLIC ENGINEERING Principal Investigator & Institution: Keasling, Jay D.; Chemical Engineering; University of California Berkeley Berkeley, Ca 947205940 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2007 Summary: (provided by applicant): The study of metabolism has made great strides elucidating the metabolic pathways that sustain life in the cell. This investigation has produced a complex map of metabolites and enzymes that describe the chemical transformations that are possible in an organism. With the sequencing of entire genomes it is possible to foresee the conclusion of this phase of study such that the function of each gene product encoded in a genome will be described and every metabolite will be cataloged. At that point, we will have a static view of the chemistry possible in an exquisitely dynamic organism. To gain insight into the dynamic structure of metabolism, new tools must be developed to measure transient levels of metabolites in a living cell. The research proposed here will develop tools for the real-time monitoring of intra-cellular metabolites in vivo using native and engineering biosensors founded on transcriptional regulators. Although the tools developed here will be of value for the study of metabolism in general, we will focus our research on the development of biosensors for the purpose of directing the evolution of metabolism. The identification of chemical compounds has traditionally relied on expensive and cumbersome analytical instruments that require considerable expertise to operate. The data generated by these machines must be interpreted by a trained scientist to accurately determine the presence or absence of a specific compound in a complex sample. Microorganisms face a similar problem as they must constantly sample their chemical environme nt to identify the most efficient source of carbon, nitrogen and other cellular building materials. Microbes accomplish this task through a multitude of biological sensing systems (biosensors) that determine which metabolic pathway should be expressed at any given time. Exploiting these sensor-actuator systems to detect target compounds will not only provide the tools for the next phase of metabolism study, but will also deliver methodology to direct the metabolic machinery of the cell to make target compounds. These systems also may be used to detect toxic chemicals in the environment such as groundwater contamination or chemical warfare agents. We propose the development of chemical sensor/actuator systems to detect target analytes. We will demonstrate the utility of these biosensors as tools for metabolic engineering, as well as develop methodogy applicable for building any desired biosensor. To demonstrate that a biosensor can be used to direct the

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evolution of a metabolic pathway, we will first use a native transcriptional regulator to report on the relative concentrations of intracellular target compounds and we will use this regulator to direct the evolution of a biosynthetic pathway to make more of the target compound. Next, we will develop a selection cassette for the evolution of new transcriptional regulators with desired properties. Finally, we will use the selection cassette to evolve new transcriptional regulators to detect specific target molecules. Accordingly, the specific tasks of this proposal are (1) to use the endogenous transcriptional activator PrpR to direct the evolution of a propionate production pathway, (2) to build a reporter/selection (RS) cassette for the evolution of new biosensors, and (3) to evolve new DitR-based biosensors that sense different target compounds. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOSYNTHESIS OF MICROBIAL POLYKETIDES Principal Investigator & Institution: Cane, David E.; Vernon K. Krieble Professor of Chemistry; Chemistry; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2002; Project Start 01-AUG-1977; Project End 31-JUL-2005 Summary: Ongoing studies of the ensymology of complex polyketide natural product biosynthesis will be continued and extended, with focus on the macrolide antibiotics erythromycin (1), methymycin (2), and tylosin (3), as well as the antitumor metabolite epothilone (4). Each of these metabolites is assembled by exceptionably large, multifunctional, modular proteins known as polyketide synthases (PKSs) that are closely related to fatty acid synthases, both biochemically and genetically. In addition, epothilone synthase contains additional catalytic activities belonging to the class of nonribosomal peptide synthetases (NRPSs). A combination of chemical, enzymological, and molecular genetic techniques this being used to elucidate the molecular basis for the programming of the complex series of reactions responsible for polyketide chain elongation. The emphasis in this work is on the elucidation of the mechanisms of multistep, enzyme-catalyzed transformations leading to formation of biologically important metabolites. It is expected that the results of these studies will be broadly applicable not only to the understanding of polyketide and other natural product biosynthetic processes in general, but will provide fundamental insights into how catalysis and molecular recognition control both product specificity and molecular diversity in Nature. 1) Deoxyerythronolide B synthase (DEBS) is a modular PKS that catalyzes the formation of 6-deoxyerythronolide B (5), the parent aglycone of erythromycin A. Individual modules of the DEBS protein, responsible for catalysis of a single round of polyketide chain elongation and functional group modification, can be expressed in E. coli. These modules will be used to study the biochemical basis for the specificity and selectivity of individual catalytic domains, particularly the ketosynthase (KS) domains that mediate the key polyketide chain-building decarboxylative condensation reaction. 2) The methymycin and tylosin PKSs have intriguing similarities and differences to the well-studied DEBS system. Individual modules of the methymycin/picromycin and tylactone PKSs will be expressed in E. coli in order to investigate their biochemical function and substrate specificity. 3) The EpoA protein, the loading module for the epothilone hybrid PKS/NRPS, will be expressed in E. coli in order to study the EpoAcatalyzed conversion of malonyl-CoA to acetyl-S-EpoA, the substrate for the NRPS module EpoB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BRAIN H2D MRS: IMPLEMATION AND INITIAL APPLICATIONS Principal Investigator & Institution: Wang, Zhiyue J.; Assistant Professor; Radiology; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant) The long-term objective is to apply 2D 1H magnetic resonance spectroscopy (MRS) techniques in studies of pediatric neurological disorders. 1H MRS is valuable for evaluating neurological brain diseases. However, there are limitations in current clinical 1H MRS examinations. Most peaks are crowded in a narrow aliphatic spectral window, and numerous low concentration metabolites are overshadowed by a few metabolites present in higher levels, and much valuable information is lost. Most metabolites have coupled spins, and 2D MRS separates the peaks in a second frequency dimension, greatly increasing the information content of the data. Application of 2D MRS in clinical examinations will enhance the abilities for diagnoses and patient management, and improve the understanding of disease processes. The specific aims are: (1) to implement 2D spin-echo double-quantum MRS pulse sequences for in vivo measurement of brain metabolites in 1.5T clinical scanners: (1a) to implement a localized pulse sequence optimized for GABA measurement; (1b) to implement localized pulse sequences for general detection of metabolites; (1c) to implement whole-brain measurement pulse sequences for general detection of metabolites. (2) to assign and evaluate peaks detected in the normal brain: (2a) to acquire spectra from metabolite solutions; (2b) to acquire brain spectra and baselines due to macromolecules in a group of adult normal volunteers; (2c) to assign the in vivo peaks and measure metabolite levels, and to determine optimal pulse sequences for studies of Aim 3; (2d) to acquire age-matched control spectra from normal children. (3) to explore the utility of the 2D MRS techniques in patients between the ages of 7 and 11 years: (3a) to study the effects of the ketogenic diet (KD) on brain GABA levels in seizure patients; (3b) to measure the brain?s level of branched chain amino-acids (BCAA) and keto-acids (BCKA) in maple syrup urine disease (MSUD); (3c) to test the hypothesis that low levels of brain galactitol are present even under a lactose restrictive diet; (3d) to study unassigned, unusual spectral peaks found in routine clinical MRS examinations. A localized 1D double-quantum filtered MRS pulse sequence will be modified into several 2D double quantum MRS pulses for localized and whole brain measurement. Different pulse parameters will be used for different types of spin systems. A frequency selective coherent transfer pulse will be used for optimal detection of GABA, and a broadband coherent transfer pulse will be used for all other 2D pulse sequences. The measurement procedures will be applied to normal subjects first. MRS measured GABA level before and after initiation of KD therapy will be compared in seizure patients and correlated with response. The MRS measurement of BCAAs and BCKAs will be conducted during metabolic crisis and in normal conditions in MSUD and correlated with clinical condition and serum BCAA and urine BCKA. In galactosemia, 2D MRS will be used to look for low levels of galactitol, and the MRS results will be correlated with the urine galactitol levels. 2D MRS will also be used to characterize unusual peaks found in clinical practice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BRAIN SPECTROSCOPY

RESPONSE

TO

HAART

MEASURED

WITH

MR

Principal Investigator & Institution: Taylor, Michael J.; Psychiatry; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006

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Metabolites

Summary: (provided by applicant): The goal of the proposed project is to systematically study biochemical markers of cerebral response to highly active antiretroviral treatment (HAART) in people with HIV associated cognitive impairment using proton (1 H) magnetic resonance spectroscopy (MRS). Metabolic findings will also be related to virological studies and indices of neuropsychological impairment. The specific aims of the proposed study are 1) to evaluate brain metabolites before and after treatment with HAART regimens in individuals with HIV-associated neurocognitive disorders (dementia and minor cognitive-motor disorder); 2) To relate changes in brain metabolites with alterations in CSF and plasma HIV RNA as a result of treatment; and, 3) To evaluate the effect of altering treatment strategies in those individuals who fail HAART treatment and initiate a new regimen after structured treatment interruption. It is hypothesized that concentrations of N-acetyl aspartate (NAA) will be lower, and concentrations of myo-lnositol and Choline will be higher in HIV+ participants with cognitive impairment than in those without cognitive impairment, and that these changes will become more normal in participants whose treatments are effective in reducing viral load in the CNS. It is also hypothesized that changes in NAP, myolnositol, and Choline from baseline in response to HAART treatment will be related to changes in neurocognitive functioning. The study will be linked to an already funded 5year research program at the San Diego HIV Neurobehavioral Research Center entitled "HIV Neurocognitive Disorders: CSF HIV RNA and Chemokines" (Ronald J. Ellis, PI). The study will compare individuals who are prescribed antiretroviral drug treatment regimens based on drug resistance phenotyping of plasma, or both plasma and CSF virus. These drug resistance assays will be used to select ARV agents to maximally suppress CSF virus. The proposed study will evaluate brain metabolites in 64 neurocognitively impaired HIV infected individuals, compared to 40 HIV infected individuals without neurocognitive impairment. All participants will undergo MRS scans at baseline, four weeks post-treatment, and 12 weeks post-treatment. Their HW RNA level will also be assessed at the same intervals through the parent study, and they will receive comprehensive neuropsychological evaluations at baseline and 12 weeks post-treatment. The proposed study may provide evidence for the utility of monitoring cerebral metabolites with MRS during treatment and may yield predictors of success or failure in treating HIV associated cognitive dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CARCINOGENIC ANTIESTROGENS

METABOLITES

FORMED

FROM

Principal Investigator & Institution: Bolton, Judy L.; Professor; Medicinal Chem & Pharmacognosy; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 08-JAN-1999; Project End 31-DEC-2002 Summary: Tamoxifen remains the endocrine therapy of choice in the treatment of all stages of hormone-dependent breast cancer. In addition, large-scale clinical trials are in progress to determine the potential of tamoxifen to act as a chemopreventive agent in women considered at high risk for developing breast cancer. However, several studies have raised concern over the safety of chronic treatment with this drug. Alternate antiestrogens including droloxifene, toremifene, and idoxifene, may not be genotoxic probably because of different routes of metabolism which could lead to a decrease in amount and/or type of ultimate carcinogen(s). The central hypothesis of this project is that the formation of reactive intermediates is an important mechanism of carcinogenesis and/or cytotoxicity for certain antiestrogens. For example, tamoxifen can

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be metabolized to at least three electrophilic metabolites of very different reactivity: quinone methides, carbocations, and o-quinones. The following specific aims are proposed: 1. Role of quinone methides, carbocations, and/or o-quinones in the carcinogenic and cytotoxic effects of antiestrogens. The carcinogenic potential of the proximate carcinogens from tamoxifen, droloxifene, toremifene, and idoxifene will be studied in C3H1 OT1/2 cells and their tumor promoting ability examined in JB6 cells. The biochemical effects of the antiestrogens and their metabolites will be investigated in human breast and endometrial cancer cell lines. 2. Investigate the effect of reactive metabolite structure on electrophilic and/or redox reactivity. The substituent effects on the electrophilicity/redox ability of the antiestrogen reactive intermediates will be investigated by measuring their ability to alkylate/oxidize DNA. Redox active metabolites will be tested by monitoring changes in reduced cofactors and by determining the formation of reactive oxygen species. 3. Determine if the antagonist/agonist activity of antiestrogen metabolites correlates with the extent of DNA damage in estrogen receptor positive cell lines. The Ishikawa cell system will be used to determine the estrogenic antiestrogenic and/or toxic effects of the proximate hydroxylated metabolites and the ultimate reactive intermediates. Cellular DNA from estrogen receptor positive and negative cells lines will be isolated after treatment with the test compound. The DNA will be hydrolyzed to deoxynucleosides (identified from Aim 2) and examined for covalent adducts and oxidative damage. These studies will greatly assist in the design of estrogen antagonists that maintain beneficial properties without generating genotoxic metabolites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

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 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

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Metabolites

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: CHOLINERGIC INSECTICIDE TOXICOLOGY Principal Investigator & Institution: Casida, John E.; Professor of Entomology; Environmntl Sci Policy & Mgmt; University of California Berkeley Berkeley, Ca 947205940 Timing: Fiscal Year 2003; Project Start 01-JUN-1998; Project End 31-JUL-2007 Summary: (provided by applicant): Neonicotinoids are the most important new class of insecticides of the last three decades, already accounting for about 10% of the world insecticide market and with major human exposure. They have the same nicotinic acetylcholine receptor (nAChR) target as nicotine but are much more potent and selective for insects. The long term objective is to define the mechanisms of selective toxicity for the major neonicotinoids, imidacloprid, thiacloprid, thiamethoxam and acetamiprid. The first specific aim is to establish the unique neonicotinoid and nicotinoid structural features for nAChR specificity and selective toxicity. The negatively-charged tip is proposed to confer potency and selectivity for insect nAChRs, prompting us to synthesize structural probes with this feature. The preferred conformation and configuration will be determined by X-ray crystallography and NMR and related to potency. Quantum mechanics studies will establish the electrostatic potential surface, molecular charge distribution and binding energy. The same approaches will be used to characterize the analogous nicotinoids selective for mammalian nAChRs. The second aim is to characterize nAChR subtypes, subunits and subsites that determine selective action. One goal is to establish the role(s) of alpha4beta2, alpha3beta2(and/or beta4) alpha5, or alpha7 and alpha1Gamma alpha1deltabeta1 subtypes in binding neonicotinoids and their metabolites relative to functional assays and selective toxicity. Drosophila nAChR and vertebrate nAChR subtypes are solubilized, purified by neonicotinoid- or nicotinoid-affinity chromatography, and labeled with potent azidoneonicotinoid and azidonicotinoid photoaffinity probes designed in this laboratory. The labeled subunits will be identified with particular attention to the proposed cationic subsite(s) in insects and pi-electronrich subsite(s) in vertebrates. Molecular modeling of the detailed binding site architecture will then relate the structure of the Drosophila D-alpha subunits and the acetylcholine binding protein to the findings on photoaffinity labeling. The third aim is

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to define neonicotinoid metabolic activation and detoxification relative to selective toxicity. Metabolites of imidacloprid, thiacloprid, thiamethoxam and acetamiprid will be characterized and synthesized for receptor, toxicity and functional assays to clarify selective metabolic activation versus detoxification. Toxicokinetic studies with mice will relate the brain levels of neonicotinoids and their desnitro and descyano metabolites (toxic iminium derivatives) to the poisoning signs. Continuing investigations will define human cytochrome P450 isozyme specificity in metabolism of neonicotinoids and characterize human microsomal "neonicotinoid nitroimine reductase" that generates unique hydrazone and triazolone derivatives of imidacloprid. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CITRUS/CANCER ASSOCIATION IN MEDITERRANEAN DIET Principal Investigator & Institution: Hakim, Iman A.; None; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 01-FEB-1998; Project End 31-JAN-2004 Summary: (Applicant's Description) The goal of this proposal is to improve understanding of diet-cancer associations, by developing a dietary assessment technique which would allow accurate reporting of previous and recent citrus (and hence dlimonene) consumption. While the Mediterranean diet is associated with lower cancer rates, food preparation techniques in the Mediterranean area include more use of citrus peel than do U.S. preparation styles, possibly resulting in higher levels of d-limonene intake. In animal models, d-limonene in the diet has resulted in tumor regression. The objectives of this project are to develop and validate a supplement to the Arizona Food Frequency Questionnaire, and to further knowledge of the interrelationship of citrus consumption, dietary d-limonene and human plasma levels of d-limonene and/or its main metabolites, perillic acid and dihydroperillic acid. The first aim of this project is to assess levels of consumption of d-limonene by (1) assessing the limonene content of different types of foods prepared with high amounts of citrus pulp and/or peel to supplement food composition database, (2) developing and validating a dietary questionnaire to assess citrus peel, pulp, and juice consumption, which can be converted to mg d-limonene per day, (3) and applying the developed questionnaire into ongoing edipemiologic research at the Arizona Cancer Center. The second aim is to prepare for future clinical trials by (1) determining the acceptability of citrus as dietary supplements for cancer primary prevention trials, (2) assessing plasma levels of d-limonene and its metabolites in subjects after one month of high citrus consumption, and (3) determining whether d-limonene or its metabolites can serve as a biomarker for compliance with dietary citrus peel consumption intervention. This proposal for research will be the major component of a 5 year Academic Investigator Award in which cancer prevention and epidemiology will be the focus. These studies along with continued course work in advanced epidemiology and biostatistics, and experience in teaching will provide the experience and expertise needed to function as a successful, independent cancer investigator in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CO-CARCINOGENIC ACTIVITY OF NITROSAMINE METABOLITES Principal Investigator & Institution: Peterson, Lisa A.; Associate Professor; Environ & Occupational Health; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 05-MAY-1993; Project End 31-MAR-2007

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Summary: (provided by applicant): The mechanism of tumor induction by unsymmetric nitrosamines is poorly understood. Alpha-hydroxylation activates these carcinogens to DNA alkylating agents by generating a metabolite that decomposes to an aldehyde and a diazohydroxide. The diazohydroxide, presumably via a diazonium ion, alkylates DNA. Unsymmetric nitrosamines have two activation pathways that lead to two different types of DNA adducts. Interactions between these two pathways likely contribute to the carcinogenic activity of the nitrosamine. In addition, the aldehyde metabolites are themselves chemically reactive and may contribute to the toxicological properties of nitrosamines. Interactions between the various reactive nitrosamine metabolites will be explored with 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK). This tobacco-specific nitrosamine selectively induces lung tumors in laboratory animals and is a possible human carcinogen. NNK is activated to either a methylating agent or a pyridyloxobutylating agent. Experimental data support a carcinogenic mechanism for this compound in which the formation and persistence of O6methylguanine (O6-mG) is important for the initiation of tumorigenesis by NNK. Pyridyloxobutylating agents and NNK-derived aldehydes, formaldehyde and 4-oxo-1(3-pyridyl)-1-butanone, are capable of interfering the repair of O6-mG by O6alkylguanine-DNA alkyltransferase (AGT). In vivo levels of the AGT substrate pyridyloxobutyl DNA adduct, O6-[4-oxo-4-(3-pyridyl)butyl] - guanine, are insufficient to explain the extent of O6-mG persistence in NNK-treated mice. Therefore, there appears to be other mechanisms by which nitrosamine metabolites interfere with O6mG repair. The objective of this application is to explore the mechanisms by which nitrosamine metabolites can reduce the repair of O6-mG by AGT. The central hypothesis is that nitrosamine metabolites can inactivate DNA repair pathways, leading to increased persistence of promutagenic adducts. These mechanisms differ from a mechanism involving competition between O6-alkylguanine adducts for repair by AGT. We plan to test our central hypothesis by pursuing the following specific aims: 1) Determine the importance of direct alkylation of AGT by diazohydroxides on AGT depletion; 2) Determine the contribution of aldehydes to the depletion of AGT following nitrosamine exposure; 3) Determine the effect of nitrosamine metabolites on the degradation rate of inactivated AGT; 4) Determine the ability of nitrosamine metabolites to influence the rate of AGT protein synthesis. The results of our studies will lead to a better understanding of mechanisms of lung cancer induction. In addition, this mechanism is likely applicable to other unsymmetric nitrosamines as well as carcinogenic mixtures such as tobacco smoke, a known human carcinogen. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COORDINATE REGULATION OF SPHINGOLIPID PRODUCTION Principal Investigator & Institution: Holleran, Walter M.; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-JUL-2008 Summary: The epidermis is faced with the daunting task of generating a permeability barrier that allows survival of mammals in a xeric, terrestrial environment. To accomplish this goal, the epidermis generates the stratum corneum (SC), with its highlyhydrophobic, lipid-enriched extracellular matrix, organized into lamellar bilayers. To generate these unique protective structures, keratinocytes must synthesize extensive quantities of cholesterol and sphingolipids, along with free fatty acids (FA), and deliver an approximately equimolar ratio of these barrier lipids to the SC. These three key lipids, and/or their immediate precursors, are removed from the intracellular, membrane-lipid pool by sequestration within an epidermis-specific, secretory organelle,

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the lamellar body, and delivered to the SC interstices coincident with terminal differentiation. Coordinate regulation of the synthesis of these lipid classes, and their subsequent sequestration into lamellar bodies, not only sustains a flow of lipids in an appropriate equimolar ratio to meet permeability barrier requirements, but also quickly funnels newly-synthesized ceramides (Cer) into glucosylceramides (GIcCer), thereby avoiding premature, Cer-induced apoptosis. It is our hypothesis that epidermal lipid synthesis is co-regulated and co-ordinated with both cholesterol and FA production: e.g., as cholesterol and FA synthesis increase in response to barrier requirements, nuclear hormone receptor-activating oxysterol and free fatty acid metabolites will be generated, which in turn up-regulate Cer and GIcCer synthesis. Conversely, when cholesterol and FA synthesis declines, fewer lipid metabolites will be generated and NHR-dependent activation of SPT and GCS also will decline. We propose first, to identify those NHR agonists that regulate Cer and GIcCer synthesis in relation to differentiation, and then to determine the basis, as well as the receptor-mediated requirement for such regulation (Aim 1). After identifying the most-potent NHR activators, we will determine how SPT and GCS are regulated by these agents at a molecular level (Aim 2). Finally, we will assess how Cer/GIcCer production are coregulated with cholesterol and FA synthesis, to generate the equimolar mixture required for the barrier (Aim 3). Since the formation of the epidermal barrier lipids, and subsequent generation of the extracellular lamellae, are late steps in epidermal differentiation, the proposed studies will result in significant new information regarding the coordinate regulation of barrier lipid generation and epidermal homeostasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--BIOANALYTICAL Principal Investigator & Institution: Blair, Ian A.; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-AUG-2002; Project End 31-JUL-2007 Summary: The Bioanalytical Core will serve all projects in this Program. It will consist of an Analytical component (directed by Dr. Blair-Center for Cancer Pharmacology, University of Pennsylvania), and a Synthetic component (directed by Dr. Harvey-The Ben May Institute, University of Chicago). The major roles of the Analytical component are: 1) to assess the purity of PAHmetabolites used by all Project Investigators (Projects 1-3), and this is pertinent to the use of anti- and syn-diol epoxides which hydrolyze to tetraols; 2) to quantitate PAH-metabolites formed in cell culture experiments, once structural validation of the analyte has been achieved; 3) to quantitate concentrations of PAH-o-quinones used in cell culture experiments, once structural validation of the analyte has been achieved; 4) to quantitate covalent modifications to DNA by PAHmetabolites and reactive oxygen species in Project 1 once methods development and validation has been achieved in Project 2; and 5) with support from the Administrative Core A to act as a liaison between the NCI Chemical Carcinogen Reference Standard Repository and Project Investigators to maintain stocks of individual PAH-metabolites and PAH-synthons. The analytical component will be reliant on a PAH-Database and a Program Database maintained in the Administrative Core-A these will monitor stocks of PAH-metabolites and perform statistical analysis of PAH-DNA adducts. The Analytical component of Core B contains a triple-quadruple mass spectrometer and an ion-trap mass spectrometer. The Synthetic component of Core B will develop efficient synthetic strategies to: 1) the major stable benzo[a]pyrene diol-epoxide (BPDE) adducts [(+) and ()-anti-BPDE-N6-dAdo (trans-isomers); (+) and (-)-anti-BPDE-N6 dAdo (cis-isomers), (+) and (-) anti-BPDE-N2-dGuo (trans-isomers) (+)-and (-)-anti-BPDE-N2-dGuo

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Metabolites

(cisisomers)], major radical-cation BP depurination adducts [N7- and C8-guanine and N7-adenine adducts of BP], and the stable and depurinating adducts of BP-2 7,8-dione [N -dGuo, N6-dAdo, N7-guanine and N7-adenine]. These reference standards will be used in Projects 1 and 2 to identify unknowns; and 2) to develop synthetic strategies to the stable and depurinating adducts of BA-3,4- dione [N2-dGuo, N6-dAdo, N7-guanine and N7-adenine] and the stable and depurinating adducts of DMBA-3,4-dione [N2dGuo, N6-dAdo, N7-guanine and N7- adenine] for their detection in cell culture paradigms in collaboration with Project 1. Via Core A, we will inform the Repository of the availability of novel PAH-DNA adducts for distribution to the PAH-research community. This will establish a symbiotic relationship between Core B and the Repository. Thus, Core B is a vital component to the success of all Projects of the PPG and may impact PAH-DNA adduct research in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CHEMICAL ANALYSIS Principal Investigator & Institution: Knize, Mark G.; University of Calif-Lawrnc Lvrmr Nat Lab Lawrence Livermore National Lab Livermore, Ca 945509234 Timing: Fiscal Year 2002; Project Start 19-APR-2002; Project End 31-JAN-2007 Summary: (provided by applicant): The Chemical Analysis Core Facility will support experiments by instrumental analysis of foods and urine samples and by supplying heterocyclic amine chemicals to the other Projects. Food analysis for heterocyclic amines is a longstanding area of expertise, and will be used to support cooking experiments to understand heterocyclic amine formation and devise practical ways to reduce or eliminate them. Other food samples will be analyzed in support of studies of an at-risk population of African-American men. Analysis of human urine samples will be undertaken for three purposes: 1) to determine the uptake of PhIP and the total amount of metabolites to support experiments in dietary intervention to reduce exposure, and 2) to determine individual metabolic phenotype and the relationship of the metabolism of PhIP with other phenotypic endpoints, and 3) to determine the relative amounts of PhIP metabolites in individuals participating in a prostate cancer study. Methods used will be solid-phase extraction and analysis by LC/MS/MS detection. The human feeding procedures, urine and blood sample collection, and inventory and storage will also be part of this core?s function. The heterocyclic amine chemicals will be purchased and synthesized, and supplies maintained for distribution to users in the Exposure Reduction and Prevention, Carcinogenesis of Cooked Food Mutagens, Metabolic Susceptibility to Cooked Food Carcinogens, and HA Macromolecular Adducts as Biomarkers groups in support of their specific experiments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--CHEMICAL AND ANALYTICAL Principal Investigator & Institution: Ball, Louise M.; Professor and Director; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: The Chemistry and Analytical Core will provide support for the individual research projects. The Core consists of two components: the Synthesis Laboratory and the Mass Spectrometry Facility. The Synthesis Laboratory will be responsible for providing, on a continuing basis, specific compounds for which need has been established by the Program Projects. Compounds synthesized by the Core will be used as standards in quantitation, for in vitro formation of DNA and protein adducts for in

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vivo dosing protocols. The availability of standards multiply labeled with stable isotopes from the Synthesis Laboratory will crucial to the development of isotope dilution methods for ultra-trace analysis of metabolites and DNA and protein adducts by the Mass Spectrometry Facility. Specific classes of compounds for which synthetic needs have been established are: Project 1, tricyclic nucleobases, deoxynucleosides and deoxynucleotides; protein adducts of malondialdehyde and 4-hydroxynon-2-enal; cysteine contual basis for dosing protocols; Projects 3 and 8, S-phenyl-d5-cysteine and mercapturic acid; Project 4, fungal metabolites of PAH and Project 5, 13C-labeled PAH phenoles. Synthesis Laboratory will also be available for consultation on questions involving structural characterizations, and application of spectroscopic techniques to problems of quantitation and characterization. Other areas where Core expertise may be useful to Program Projects are in the application of structure-activity relationships to direct efforts in isolation and characterization of products of metabolism or nonenzymatic decay. The Core has access to 500 and 500 MHz NMR spectrometers with multinuclear and variable temperature capability. Core personnel are trained operators, proficient in all aspects of data acquisition, work-up and interpretation, and will fill the NMR needs of program projects. Additional techniques of physical characterization accessible through the Core are circular dichroism X-ray crystallography, EPR and FTIR. The Mass Spectrometry Facility will provide support for Program Projects when mass spectrometry requirements are beyond the capacity of equipment belonging to Program Projects or when extensive methods development is necessary. The Mass Spectrometry Facility performs characterization and ultra-trace analysis on a routine basis by a variety of mass spectrometric techniques, and is also involved in developmental work. Major objectives of the Mass Spectrometry Facility will be to develop on-line sample clean-up and analyte pre-concentration procedures and to apply HPLC/MS/MS techniques to characterization of DNA adducts, protein adducts and PAH metabolites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MASS SPECTROMETRY Principal Investigator & Institution: Borgerding, Anthony J.; University of North Dakota 264 Centennial Drive Grand Forks, Nd 58202 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2007 Summary: This core facility will support the research of the COBRE investigators. Specifically, high resolution LC/MS/MS instrumentation housed in the facility will be used in Project 2 (Porter) for identification of proinflammatory arachidonic acid metabolites generated by CGRP stimulated THP-1 cells, and to quantitate the amount of prostaglandin compounds hypothesized to be produced from an increased expression of COX-2. These measurements will benefit studies of the characterization of the neuroinflammatory CGRP receptor. In Project 3 (Picklo), MS will be utilized in studies of the mechanism of HNE metabolism in CNS tissue. High resolution LC/MS will be used to identify and quantitate HNE metabolites, and MALDI/TOF will be used to identify novel detoxification enzymes. Project 4 (Murphy) will utilize the mass spectrometry core facility to fulfill analysis requirements for two specific aims. These aims address phospholipid head group flux and turnover in neuronal, astroglial, and stably transfected HEK-293 cell lines. LC/MS and GC/MS will be used to measure labeled and unlabeled phospholipids to study the kinetics of compound incorporation. The core facility will consist of three instruments. One instrument will be a highresolution tandem mass spectrometer (MS/MS, QQTOF geometry) with an ESI source and a liquid chromatography interface. In addition, we will acquire a MALDI/Time of Flight (TOF) instrument and a gas chromatography 1 ion trap system. The combination

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Metabolites

of these instruments will result in a facility capable of providing molecular weight and structural information for all of the wide variety of samples that will be generated in this COBRE. The facility responsibilities (training users and helping with data analysis, operation and maintenance, assuring that the standard operating procedures are followed) will be divided between between the facility director and a research technician. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MASS SPECTROMETRY Principal Investigator & Institution: Deinzer, Max L.; Professor; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: The broad objective of this Mass Spectrometry Core is to provide high- end mass spectroscopy techniques to support the biomedical and non- biomedical projects in this Superfund Basic Research Program and to develop and apply a new, highly specific and sensitive mass spectroscopy technique to detect and quantify environmental compounds and their metabolites. These compounds will include tetrachloroethene, 1,1,2- trichloroethene, cis-1,2-dichloroethene, vinyl chloride, chloroacetaldehyde and chloroform. The development of this new instrument will require the construction of a gas chromatograph electron monochromater-time-of flight-mass spectrometer (GC-EMTOF-MS) to analyze negative ions using the EM for the production of monoenergetic beams of ionizing electrons in combination with pulsed extraction. To support the other biomedical and non-biomedical projects in this application, we will develop and apply mass spectrometric methods to analyze adducts formed between proteins and hydrocarbon solvent metabolites. We will develop mass spectrometric methods for analyzing protein and peptides resulting from reaction with 2,5-hexanedione, and analogs, 3-methyl-2,5-hexanedione, 3,4-dimethyl-2,5-hexanedione, 3-4- diethyl-2,5hexanedione, 2,9-dimethyl-4,7, decanedione and 1,2- diacetylbenzene. The effects of gamma-diketone hydrocarbon adducts on the thermal stability of neurofilament protein structures will be a assessed by hydrogen-deuterium exchange (H/D) exchange and equilibrium thermal denaturation studies in conjunction with electrospray mass spectroscopy. The effects of hydrocarbon adducts on the conformation of neurofilament protein subunits will be determined by kinetic H/D exchange experiments, together with electrospray mas spectrometry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--SPECIALIZED ASSAY Principal Investigator & Institution: Kulkarni, Rohit N.; Assistant Professor; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 30-SEP-1986; Project End 31-MAR-2007 Summary: (provided by applicant): The Core currently provides radioimmunoassay (RIA), immunogenetic, and other basic biochemical assays performed in support of the studies carried out on the General Clinical Research Section (GCRC), as well as animal studies taking place in the laboratories of individual investigators. Over the last 5 years there has been a tremendous increase in the number of rodent mouse models created to study various aspects of types 1 and Type 2 diabetes, their complications and obesity. At the Joslin Diabetes Center there are currently at least about 68 rodent models that are being studied and 17 more are in various stages of being created. This has resulted in the obvious need for the measurement of rodent hormones and metabolites on a large scale.

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Assays are currently performed by individual laboratories using different kits and are not cost-effective. It is proposed to expand the current Core at Joslin to undertake measurement of the multiple hormones, metabolites and other markers of diabetes required by these animal studies. The new Specialized Assay Core (stated as Core here onwards) will be responsive to the varied requirements of investigators by providing an assay service and back-up support for experiments involving humans and animals. Furthermore, the facility will also provide advice and consultation, and if necessary develop and perform additional assays for novel hormones, metabolites and markers when required by the investigators. In a large institution such as the Joslin, there are often multiple investigators measuring similar parameters as part of their basic research or for clinical protocols. In the operation of any central assay Core, greater efficiency is created by planning and integrating facilities and personnel. This results from sharing antibodies, reagents and equipment, allows more economic use of expensive or limited materials, and provides for more focused training of junior investigators. It is proposed that all the human insulin assays (accruing from GCRC and other studies) will be performed at the BIDMC assay Core, which is equipped to handle the current number of human insulin assays performed at the Joslin. The BIDMC unit is the Core laboratory of the NIH-funded GCRC and will be able to assay human samples for insulin and thereby provide for a single center for both Joslin and BIDMC investigators. Consequently, this will free up a portion of the current time available for the technician to take on more of the DERC-related insulin assays and if time permits to focus on setting up, maintaining and running the additional different assays in the proposed Specialized Assay Core. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETECTING CRACK AND OTHER COCAINE USE WITH FASTPATCHES Principal Investigator & Institution: Liberty, Hilary J.; Principal Investigator; Social Sciences Innovations Corporation 71 W 23Rd St, 8Th Fl New York, Ny 10010 Timing: Fiscal Year 2004; Project Start 15-SEP-2000; Project End 31-JAN-2006 Summary: (provided by applicant): PharmChem Inc. has developed a new sweat patch product, the FastPatch TM, which reduces minimum wear times to detect cocaine and most other drugs of abuse from the full day typically required with standard sweat patches (Liberty et al., 1999a) to 20 or 30 minutes through mild heating (Liberty, 2003). Additionally, there is an increasing need and growing market for the detection of crack use distinct from other cocaine. Recent research (Martin et al., 1989) has identified unique pyrolytic metabolites of crack, anhydroecgo-nine methylester (AEME) and ecgonidine (ECD) through GC/MS. It is likely that a low-cost EIA procedure for detection of crack use will be available within a year, increasing the market potential for detection using a Fastpatch (tm). During Phase I, 180 subjects wore two FastPatch prototypes (one on each hand) and only one patch per subject was needed to obtain sufficient sweat eluate for GC/MS. This finding has positive market potential. Cocaine use was detected in sweat of 92.4 percent of subjects, comparable to 91 percent with EMIT urinalysis in a high prevalence sample. Crack metabolites were successfully detected in 54 percent of subjects. While there were no significant differences in detection rates between 15, 20, and 30 min. wear periods, all wear periods successfully detected substantial cocaine/crack use, and a shorter 10 min. condition will be tested. This finding has positive market potential. During Phase II, these changes will occur: Fast patches will be worn in moderate and low prevalence samples, a shorter wear period will be added, more biological tests will be included (e.g., standard sweat patches and GC/MS of urine), testing for more drugs (heroin and marijuana), data

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collection will expand to include both a residential drug treatment program and a workplace, low-prevalence sample, the latter a venue with positive market potential. The FastPatch avoids problems with urinalysis such as violations of privacy, dilution or substitution of specimens, possibility of disease transmission, and transport of noxious fluids. Advantages over the standard sweat patch include a longer window of detection (2-3 wks. versus 2-3 days) and a shorter minimum period of wear needed to detect most drugs (10-20 m n. versus 24 hrs.). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DHEA--PPAR DEPENDENT & INDEPENDENT MECHANISMS OF ACTION Principal Investigator & Institution: Prough, Russell A.; Professor; Biochem and Molecular Biology; University of Louisville Jouett Hall, Belknap Campus Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 15-MAR-1999; Project End 31-DEC-2002 Summary: The proposed studies will evaluate the mechanisms by which dehydroepiandrosterone (DHEA) and its metabolites alter the metabolic activation of and block early steps in the promotion phase of chemical carcinogenesis and toxicity. Currently, DHEA, a potent peroxisome proliferator (PP) is being used in a number of human trials to enhance immune function and ameliorate several metabolic disorders, but humans appear to be a species which is not highly responsive to PP. Our preliminary results, correlated with the literature, suggest that DHEA and its metabolite function in both Peroxisome Proliferator Activated Receptor Alpha (PPARalpha)dependent and independent pathways. Our goals to characterize the PPARalphaindependent actions of DHEA or one of its metabolites are encapsulated in four specific aims: 1. Establish whether metabolites of DHEA serve as proximal inducers of peroxisome proliferation on other processes specific for DHEA action using cell-based reporter assays. The metabolites of DHEA formed by rat, hamster and human liver microsomes will be characterized by GC/MS and the enzymology of their formation deducted using specific inhibitors. Cell-based reporter assays with PPARalpha expression constructs and fatty acyl-CoA oxidase reporter constructs will test their role is ligand/activators for PPARalpha. 2. Characterize the properties of DHEA or any active metabolites involving PPARalpha or the non-classical glucorticoid induction mechanism described by Guzelian and Kasper. Our preliminary data suggests that CYP2Bl and CYP3A are induced by DHEA in vivo, but not by other peroxisome proliferators. Since the CYP4 enzyme subfamily are not good catalysts of PAH metabolism, CYP2Bl and 3A23 must account for enhanced metabolism possibly due to the non-classical mechanism of induction. The effects of DHEA in rat and human hepatocytes will address this possibility; PPARalpha knock-out mice will be used to dissect PPARalpha-dependent and independent pathways of regulation. 3. Utilize the technique of Differential Display to elucidate gene products induced or suppressed by DHEA in rats in vivo or cultured human hepatocytes, relative to other PP. The technique of Differential Display will be utilized to observe genes whose expression is altered (induced or repressed) by DHEA, but not by a prototype PP, nafenopin. This will allow us to ascertain large differences in mechanism between DHEA and other PP, in addition to regulation of CYP2B, CYP3A and CYP2C11 expression and related human genes. 4. The goal of Aim 4 is to characterize the PPARalpha-independent molecular regulation of P450s and other genes. Genes which we show are not regulated through PPAR will be studied by preparing reporter constructs with 5'-flanking regions of those genes to evaluate PPAR- independent pathways of DHEA action.

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

Project Title: DIETARY SOY/ISOFLAVONES AND URINARY ESTROGEN METABOLITES Principal Investigator & Institution: Tseng, Marilyn M.; Associate Member; Fox Chase Cancer Center Philadelphia, Pa 191112434 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Research on potential cancer-protective effects of soy and isoflavones has led to an increase in the availability and consumption of soy products in the US. Yet conflicting scientific evidence raises the concern that high levels of intake might actually increase breast cancer risk. Whether current levels of soy and soy isoflavone intake are sufficiently high to affect breast cancer risk is unknown largely because of a lack of convenient, current, and validated methods of assessing intake. The objectives of the proposed study are to (1) evaluate the validity of overnight urine samples as a method of assessing soy isoflavone intake, and (2) examine associations between soy/isoflavone intake and urinary estrogen metabolites. Participants will be drawn from a program at Fox Chase Cancer Center for women at high breast or ovarian cancer risk. The study will include 50 women with either very high or low soy intake based on questionnaire data. Participants will complete a soyfood questionnaire and provide four 24-hour urine specimens over a one month period, with overnight samples collected in separate containers. Urines will be analyzed for isoflavones, primarily daidzein and genistein, and for estrogen metabolites including 2-, 4-, and 16alphahydroxy estrogens. Isoflavone levels in overnight urine samples will be evaluated for validity by examining their correlations with isoflavone levels in 24-hour urine specimens. We will use multiple linear regression to examine associations of soy/isoflavone intake with urinary estrogen metabolites. The proposed research will provide useful information towards assessment of soy/isoflavone intake in a non-Asian sample. It is also an opportunity to add to limited knowledge on soy/isoflavone intake and its association with urinary estrogen metabolites as markers of breast cancer risk. Findings from this research will contribute information towards a soy supplementation trial to evaluate modification of soy/isoflavone intake as a means of reducing risk of breast cancer, a disease for which few preventive measures are available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISRUPTION OF ESTROGENIC RESPONSES BY PCB-PAH MIXTURES Principal Investigator & Institution: Arcaro, Kathleen F.; Research Assistant Professor; Veterinary and Animal Sciences; University of Massachusetts Amherst 408 Goodell Building Amherst, Ma 01003 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: There is widespread concern that exposure to chemicals in the environment may be related to the observed increase in the incidence of breast cancer. Among the chemicals of concern are polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs), which have the potential to disrupt estrogenic responses. It is difficult to predict the health effects of exposure to complex mixtures of these chemicals because individual congeners of PCBs and PAHs can be either estrogenic or antiestrogenic and act through a variety of mechanisms potentially leading to additive, antagonistic or synergistic effects. Furthermore, the microbial reductive dechlorination of PCBs and the metabolic transformation of both PCBs and PAHs within the body, may

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substantially alter the activity of these mixtures. It is hypothesized that reductive dechlorination of PCBs increases the estrogenic activity of the resulting mixture, and that metabolism of PCBs and PAHs further alters the estrogenic and anti-estrogenic activity of these mixtures. Thus, the objective of this proposal is to determine how mixtures of PCBs and PAHs may interact and modulate estrogenic activity in human cells. Specifically we will: 1) Determine the estrogenic and anti-estrogenic activity of relevant complex mixtures of PCBs and PAHs. Extracts from sediment samples and mixtures reflecting the composition of PCBs and PAHs detected in human tissue, food and water will be tested in human breast cancer cells for their estrogenic and antiestrogenic activity. 2) Determine how mixtures of PCBs and PAHs alter estrogenic activity and assess whether knowledge of the activity of the individual components is sufficient to predict the activity of the mixture. Mechanisms to be investigated include, estrogen receptor (ER) binding, regulation of ER level, metabolism of 17-estradiol metabolism of PCBs and PAHs in breast cancer cells. The nature of the interactions will be explored using full dose-response curves and probit analysis. 3) Determine the extent to which the estrogenic and anti-estrogenic activity of a mixture is altered by metabolism in human liver microsomes, and identify the major active metabolites. Metabolites generated from incubations in human liver microsomes, and identify the major active metabolites. Metabolites generated from incubations in human liver microsomes will be tested for their estrogenic and anti-estrogenic activity in human breast cancer cells. Knowledge gained from these studies will provide insight into the relationship between exposure to environmental estrogens and health risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DNA METABOLITES

AND

HEMOGLOBIN

ADDUCTS

OF

BUTENEDIOL

Principal Investigator & Institution: Powley, Mark W.; Environmental Sciences & Engr; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-JAN-2005 Summary: (provided by applicant): The main purpose or the proposed research is to determine the formation of potentially mutagenic metabolites in the 1,3-butadiene (BD) metabolic pathway leading to MI, a major urinary metabolite in humans. To understand this pathway, tissues from female mice and rats exposed to 3-butene-1,2-diol (BD-diol) will be used. BD-diol is the hypothesized immediate precursor of two potentially mutagenic metabolites, hydroxymethylvinylketone (HMVK) and 3,4-epoxy-1,2butanediol (EB-diol), and is also a precursor to MI. The first hypothesis to be tested is that HMVK, but not EB-diol, is formed in B-diol exposed animals in an exposuredependent manner and therefore contributes to mutagenicity observed in animals exposed to BD-diol and BD. The second hypothesis is that a hemoglobin adduct of HMVK can serve as a biomarker of BD-diol and BD exposure. In testing these hypotheses we will accomplish several aims. The first specific aim is to develop methods to measure promutagenic adducts formed by HMVK, specifically 1,N2propanodeoxyguanosine adducts, in BD-diol exposed animals. Another specific aim is to develop methods to measure the hemoglobin adduct of HMVK in the exposed animals. The third specific aim is to measure DNA and hemoglobin adducts of EB-diol. The results of these experiments will demonstrate the formation and possible contribution to mutagenicity, of HMVK and EB-diol following metabolism of BD-diol. The final specific aim is to measure the HMVK adducts in BD exposed animals and humans. The proposed research will help explain a critical, but not fully understood, BD

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metabolic pathway. This will improve our understanding of BD metabolism as a whole and ultimately increase our ability to accurately assess the risk of BD to humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL DYSFUNCTION IN INSULIN RESISTANCE Principal Investigator & Institution: Busija, David W.; Professor; Physiology and Pharmacology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2003; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): The insulin resistant (IR) syndrome is associated with an increased incidence of hypertension and cardiovascular (CV) disease. Data from the applicant's laboratory suggests that endothelial dysfunction may be the mechanism that links IR to CV disease. Previous studies show impaired endothelium-dependent relaxation in small mesenteric and coronary arteries from IR rats. This dysfunction appears to be secondary to a defect in endothetium-derived hyperpolarizing factor (EDHF). These data support the existence of a situation where the EDHF dilator component is selectively impaired and provides a model to assess mechanisms leading to impaired EDHF function. Moreover, it provides us a model to assess compensatory responses of other endothelium derived relaxing factors to an EDHF deficit. The overall hypothesis to be examined is that impairment of endothelium-dependent dilator capacity occurs during IR. Specific hypotheses to be tested are (1) Endothelium dependent relaxation is impaired in small mesenteric arteries to physiologic as well as pharmacologic stimuli. (2) Restoration of normal endothelium function occurs after cessation of fructose-rich diet. (3) Endothelial dysfunction associated with IR is due to a decreased production of EDHF. (4) Decreased substrate availability and/or abnormally low levels of cytochrome P450 (CYP) isoforms account for decreased EDHF production. (5) Endothelial dysfunction associated with IR is due to decreased sensitivity of potassium channels on vascular smooth muscle to EDHF. (6) The NO and prostacyclin systems do not compensate for this loss of dilator capacity. To test these hypotheses, two specific aims will be addressed. Specific aim 1. Characterize the nature of impaired vascular function in insulin resistance. First, we will assess whether IR induced impairment of endothelium-dependent relaxation is stimulus dependent. Second, we will explore the vascular effects of insulin in the setting of IR. And third, we will determine the vascular characteristics of reversal of endothelium dysfunction after cessation of fructose feeding. Specific aim 2. Determination of the mechanism of impaired endothelium-dependent dilation in insulin resistance. First, we will investigate the effect of lR on dilator responses to exogenous arachidonic acid. Second, we will explore the effects of IR on synthesis of bioactive metabolites of arachidonic acid. Third, we will examine the relationship between endothelial function and levels of CYP and NO synthase protein. Fourth, we will determine the effect of application of exogenous arachidonic acid metabolites (epoxyeicosatrienoic acids) on vascular tone. These data will determine mechanisms of endothelial dysfunction in IR. Moreover, the specific role of EDHF and mechanisms for its dysfunction will be determined. This project employs physiologic, cellular, and molecular biology techniques to address the proposed questions. Findings from this project may provide important information that can be used to design treatments to prevent the cardiovascular complications of IR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ESTROGEN METABOLITES EFFECTS ON BONE Principal Investigator & Institution: Turner, Russell T.; Professor; Mayo Clinic Coll of Medicine, Rochester 200 1St St Sw Rochester, Mn 55905

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Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: A serious obstacle to the rational design of innovative approaches for preventing and/or treating osteoporosis is the idiopathic nature of postmenopausal bone loss. Menopause is the most important risk factor for osteoporosis. However, not all postmenopausal women develop osteoporotic fractures indicating that cessation of the menstrual cycle is insufficient to fully account for the disorder. Our working hypothesis is that the denovo production and metabolism of estrogens are among the most important factors influencing the rate of postmenopausal bone loss. Estrone (E1) and its metabolites, 16alpha-Hydroxyl estrone ( (16alpha-OHE1) and 2-hydroxyesterone (2-OHE1), are the most abundant estrogens in postmenopausal women. 16alpha-OHE1 has been recently shown to be a negative risk factor (reduced risk) for postmenopausal bone loss, whereas 2-OHE1 has been positive risk factor (increased risk). 2-OHE1 does not have estrogenic activity in ovariectomized (OVX'd) rats. In contrast, 16alpha-OHE1 appears to be a tissue selective estrogen agonist with a profile of activity similar to the anti-breast drug tamoxifen; 16alpha-OHE1 is a much more effective estrogen agonist on bone and liver than on reproductive tissues. These observations suggest that differences in the skeletal activities on 2-OHE1 and 16-alpha-OHE1 are responsible for the observed association between bone mass and circulating levels of these metabolites in postmenopausal women. We propose to test this hypothesis in ovary intact and OVX'd rats. The specific aims are to determine the dose response effects of 2-OHE1 and 16alpha-OHE1 on the expression of immediate response genes in bone and other estrogen target tissues; and establish the long-term effects of the estrone metabolites on bone architecture, turnover and strength. The proposed research will characterize the probably cellular mechanisms of action. The results of these studies are likely to be relevant to women because of the similarity between postmenopausal bone loss and OVX-induced bone loss in rats, as well as the previous success the rat model has enjoyed for predicting the response of the human skeleton to estrogen agonists and markers to predict the rate of postmenopausal bone loss; 2) manipulation of estrone metabolism by changes in diet or by pharmacological intervention may be a valuable tool for reducing bone loss; and 3) analogs of 16alpha-OHE1 may be useful for prevention and treatment of postmenopausal osteoporosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN METABOLITES, RELATED GENES AND BREAST CANCER Principal Investigator & Institution: Shore, Roy E.; Professor of Medicine; Environmental Medicine; New York University School of Medicine 550 1St Ave New York, Ny 10016 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The NYU Women's Health Study (NYUWHS) cohort has played a leading role in elucidating the associations of estrogens and androgens with breast cancer, based on blood samples that were obtained prospectively in 1985-91 from over 14,000 healthy women of ages 35-65. We now team up with another cohort from the Northern Sweden Health and Disease Study in Umea to address questions about the roles of estrogen metabolites in breast cancer. The proposed grant period would extend the NYUWHS follow-up to about 19 years on average and would permit the accrual of nearly 1,000 incident breast cancer cases, while the Umea study will have over 600 cases. The follow-up and cancer case ascertainment rates have been high in both studies. The study will investigate how much levels of estrogen metabolites which can be both estrogenic and genotoxic - affect breast cancer risk, and the degree to which functional polymorphisms in estrogen metabolism genes are predictive of

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estrogen metabolite levels and of breast cancer risk. We hypothesize that: Circulating levels of 16alpha-hydroxyestrone are positively associated with breast cancer risk, and the 2-hydroxyestrone to 16alpha-hydroxyestrone ratio is negatively associated with breast cancer; Genetic polymorphisms associated with altered activity of enzymes catalyzing 16alpha-hydroxylation (CYP3A4 and CYP3A5) and 4-hydroxylation (CYP1B1) are associated with breast cancer risk. Functional polymorphisms in the sulfotransferase and glucuronidase genes that diminish estrogen conjugation activity are associated with increased breast cancer risk. Over the last five years, the NYUWHS cohort has been the basis for investigations, with a series of collaborators, of numerous risk factors for various cancers (breast, colorectal, endometrial, ovarian) e.g., IGF-I and its binding proteins; organochlorines; serum carotenoids, phytoestrogens, folate and homocysteine; polymorphisms in luteinizing hormone and DNA repair genes. The availability of serum specimens, DNA, and lifestyle and dietary data collected prospectively, combined with the extended followup and increasing numbers of cancers, will allow the study to continue to foster the investigation of various biological risk factors for a range of cancers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXPLORING MICROBIAL DIVERSITY FOR NOVEL NATURAL PRODUCTS Principal Investigator & Institution: Olson, Julie B.; Biological Sciences; University of Alabama in Tuscaloosa Tuscaloosa, Al 35487 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2006 Summary: (provided by applicant): The combination of the discovery, development, and exploitation of antibiotics was one of the most significant advances in medicine in the 20th century. Virtually all current antibiotics with clinical utility were identified during the so-called 'golden' period of discovery between the 1940's and 1960's and their implementation produced impressive reductions in the burden of disease caused by bacterial infections. Unfortunately, the widespread emergence of acquired resistance to antibiotics in bacteria over the last three decades now constitutes a serious threat to global public health. Thus, there is an important demand for the discovery and development of new classes of antibiotics to add our current arsenal and an urgent need for new drug discovery strategies. Natural products have historically been the single most productive source of drug leads, including antibiotics, yet screening of these secondary metabolites has recently fallen out of favor. For microbial-produced natural products, this is largely the result of the extremely high (99%) rediscovery rate, which occurs as a result of isolation, and testing of the same organisms again and again. This high rediscovery rate supports recent work suggesting that less than 1% of microbial diversity has been cultured and studied experimentally, and that the remaining 99% is not readily amenable to laboratory cultivation. Using this generally accepted theme as a starting point, novel media, media supplements, and cultivation conditions will be utilized to isolate microorganisms from a variety of natural, under-explored environments in Alabama. Microbial cultivations will be combined with fermentation and genetic screening to identify organisms that are capable of producing secondary metabolites. These studies are aimed at increasing our understanding of the problems associated with the isolation of microorganisms from natural environments and of the conditions required to increase production of secondary metabolites. The specific aims of the proposed project include: 1) to determine what approaches are necessary to increase the percentage of microorganisms isolated from natural environments; 2) to determine what growth factors/additions/manipulations will initiate production of

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secondary metabolites in fermentation broths; and 3) to determine which organisms possess biosynthetic pathways for the production of potentially useful secondary metabolites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC POLYMORPHISMS IN THE EPOXYGENASE PATHWAY IN HYPERTENSION Principal Investigator & Institution: Dreisbach, Albert W.; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 31-AUG-2007 Summary: Vasoactive arachidonic acid metabolites of the cytochrome P450 (CYP) epoxygenase pathway, the epoxides, have been implicated in animal and human studies of hypertension. The epoxide 11-12 epieicosatrienoic acid (11,12-EET), the putative endothelium derived hyperpolarizing factor (EDHF)is formed by the enzymes CYP2C9, CYP2C8, and converted to its corresponding dihydroxy metabolite (DHET) by soluble epoxide hydrolase (sEH). CYP2C9 and CYP2C8 and sEH exhibit a high prevalence of genetic polymorphisms which may lead to altered levels of epoxides and reduced formation of EDRH in hypertensive patients. The perturbed vasoactive epoxide profile produced by genetic polymorphisms in this pathway may play a mechanistic role in a subgroup of patients with hypertension. Specific Aim 1: We propose to determine the prevalence of CYP2C9fC8 and sEH polymorphisms in hypertensive populations including both African Americans and Caucasians and compare these to the prevalence of these polymorphisms in race matched healthy control subjects. Specific Aim 2: We will also measure levels of EETs and DHETs in plasma and urine of patients with hypertension compared to race matched healthy controls for the various genotypes of CYP2C8/C9 and sEH. Specific Aim 3: We will determine whether in vivo CYP2C9 activity as measured by plasma S/R warfarin ratio, correlates with plasma and urine concentrations of eicosanoid metabolites for the various CYP2C9 genotypes in these same groups. Specific Aim 4: We will determine brachial artery reactivity via ultrasound in each of these same genotypic subgroups in race matched hypertensives and controls. The results from these studies will lead to new insights into the role of polymorphisms of the P450 epoxygenase system in cardiovascular regulation. The studies may demonstrate a role of these polymorphisms in some hypertensive populations, but in any case will provide increased understanding of the role of EETs and DHETs in vascular reactivity and blood pressure regulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HCG ISOFORM MARKERS OF TROPHOBLASTIC MALIGNANCIES Principal Investigator & Institution: Birken, Steven; Senior Research Scientist; Obstetrics and Gynecology; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): HCG is the main tumor marker for both gestational and non-gestational trophoblastic disease. After a pregnancy with partial or complete hydatidiform mole, some patients develop malignant gestational trophoblastic disease. Patients may display unexplained elevation of circulating hCG with no evidence of clinical disease and are treated solely because of their hCG marker. Other patients under treatment develop resistance to therapy or relapse as detected by the hCG marker. We propose to assess the utility of several new immunoassays for hCG isoforms, recently developed in our laboratory, as improved hCG-related tumor markers. New markers

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may help to identify the subpopulation of women who will require chemotherapy from those who will undergo spontaneous remission after a premalignant molar pregnancy. The new markers may also improve therapeutic care for both gestational and nongestational trophoblastic disease patients, including testicular cancers. These markers are based on four differentiating immunoassay systems to: 1.carbohydrate-related variants of hCG. 2. "nicked" forms of hCG. 3. isoforms both "nicked" and hyperglycosylated. 4. hCG and hLH beta core fragments. Most of these hCG isoforms have been shown to be structurally altered in malignancies but no assay measurement systems existed previously to quantify these isoforms. The hCG isoforms produced by healthy individuals (from pituitary) must be clearly differentiated from those isoforms produced by malignant tissues. The detection of carbohydrate-variant hCG isoforms are based on the antibody B152 (developed to choriocarcinoma-secreted hCG isoforms) which detects a differentially O-glycosylated form of hCG produced very early in pregnancy as well as in various malignancies. HCG-secreting cancers have also been reported to produce "nicked" hCG isoforms with peptide bond cleavages within the beta subunit. These will be measured by assay system (B151) in conjunction with a rapid chromatographic procedure. Choriocarcinoma and other trophoblastic cancers produce isoforms, which are both "nicked", and hyperglycosylated. These are detected by a B151 capture B152 detection assay. Systems to specifically measure urinary hCG and urinary hLH metabolites have also been developed so that hCG-related metabolites can be distinguished from normal hLH metabolites in postmenopausal women. Structural analyses will be performed to correlate isoform structures with assay measurements. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HUMAN METABOLISM OF ANTI-ABUSE MEDICATIONS Principal Investigator & Institution: Moody, David E.; Associate Director; Pharmacology and Toxicology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-AUG-1997; Project End 31-JUL-2006 Summary: (provided by applicant): Buprenorphine is a partial mu agonist under consideration by the FDA for use in opioid substitution therapy. It will join methadone and I-alpha-acetylmethadol (LAAM) as medications available at treatment centers. Buprenorphine is also being considered for private physician dispersal; which will greatly expand access to substitution therapy. All three of these drugs are cytochrome P450 (P450) 3A4 substrates. Drug interactions are a major cause of serious adverse drug effects and P450 3A4 is a major site of drug interactions. Many known drug interactions with methadone are due to its metabolism by P450 3A4. The proposal funded during the last period (R01 DA 10100-02) tested the hypothesis that the 3A4 inhibitor, ketoconazole, would inhibit the metabolism of LAAM to its more active metabolites, norLAAM and dinorLAAM, and thereby diminish its therapeutic effect. Data from that study demonstrate both in vitro and in vivo evidence of significant drug interactions providing support for this hypothesis. Since buprenorphine is nearing market launch, and few studies exist on its potential for serious drug interactions, we now hypothesize that determination of enzymes involved in the in vitro hepatic metabolism of buprenorphine will allow prediction of in vivo drug interactions of clinical significance. While testing this hypothesis, the fact that buprenorphine and its metabolite, norbuprenorphine, are extensively glucuronidated, and preliminary data that suggest other metabolites are produced by P450s must be taken into consideration. Therefore, to test this hypothesis we will: 1) extend our current liquid chromatographic-tandem mass spectrometric (LC-MSMS) method for buprenorphine and norbuprenorphine to include their glururonides; 2) use LC-MSMS to identify metabolites of buprenorphine generated

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in human liver microsomes (HLM) and cDNA-expressed P450s; 3) determine the quantitative involvement of specific P450s in these pathways using kinetic analyses, specific inhibitors, specific antibodies and correlational analysis in HILM and cDNAexpressed P450s; determine the qualitative involvement of specific UDP-glucuronosyl transferases (UGTs) using HILM and cDNA-expressed UGTs; and 4) determine the in vitro induction of buprenorphine phase I and phase II metabolism in primary cultures of human hepatocytes. We anticipate these studies will provide the evidence to support clinical studies to more thoroughly test our hypothesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION OF BIOACTIVE CRANBERRY METABOLITES Principal Investigator & Institution: Howell, Amy B.; Center for Blueberry and Cranberry Research; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2004; Project Start 05-JAN-2004; Project End 31-DEC-2005 Summary: (provided by applicant): Cranberries have been clinically studied to assess their potential role in prevention of urinary tract infections. The results have been generally favorable, but many of the studies have been criticized for design flaws. One vital component at issue is participant adherence to study dosage, which has been particularly difficult to assess due to the lack of a reliable compliance marker. A quantifiable urinary metabolite(s) would be an ideal compliance marker for clinical trials, as the level could be associated with a biologically effective dosage of cranberry. Proanthocyanidins have been identified as the potential active compounds in cranberry, preventing the in vitro adhesion of P-fimbriated uropathogenic bacteria to uroepithelial cells, and producing an anti-adhesion effect in mouse urine following ingestion. However, the proanthocyanidin urinary metabolites have never been elucidated. The objectives of this proposal are to utilize bioassay-directed fractionation to isolate and identify the molecular structures of the active urinary metabolites and to determine the scope of the bacterial anti-adhesive properties of these metabolites. The long-term goal is to identify and quantify the levels of the active urinary metabolites so they can be utilized as markers for measuring compliance in clinical research. Urine will be collected over time from swine that have been fed defined quantities of standardized cranberry powder. Bioassay-directed fractionation of urine will be performed to identify active compounds. Assays will measure the ability of the fractions and subsequent pure compounds to prevent the adhesion of P-fimbriated E. coli. The structures of the active compounds will be identified by a range of spectroscopic techniques, including HPLC/API MS, LC/MS/MS, NMR and MALDI/TOF. The scope of activity of the metabolites will be measured by testing their anti-adhesion ability against a range of uropathogenic E. coli bacteria with known virulence factors. This will establish their utility for use as a broad-spectrum marker for measuring compliance to cranberry protocols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMPACT OF GENDER DIFFERENCES IN MORPHINE METABOLITES Principal Investigator & Institution: Kern, Steven E.; Pharmaceutics and Pharmaceutl Chem; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2004; Project Start 01-AUG-2004; Project End 31-JUL-2006 Summary: (provided by applicant): Gender differences in pain and analgesia produced from opioid analgesics have been well documented in both animal and human clinical

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studies. Many of these studies have characterized factors that contribute to genderspecific pharmacodynamic differences in response to painful stimuli and alteration of the response with opioid analgesics. However pharmacokinetic factors, which may also contribute to this difference, have not been studied to the same detail. There are many reports identifying endogenous and exogenous compounds that interact with morphine by altering its metabolism, but understanding the resulting impact on analgesia is complicated by temporal delays in the pharmacokinetic effects. Using a computercontrolled, pharmacokinetically driven infusion of morphine, we have developed a study method for assessing the interaction of a parent drug with its active metabolites that takes advantage of the temporal lag that occurs in metabolite formation. In this exploratory R21 proposal, we will use pharmacokinetics to fix the concentration of one agonist agent, morphine, so that the impact of its active and inactive metabolites, whose concentrations we cannot control, can be rationally assessed. By conducting these studies in subjects where gonadal steroid hormones are held stable by oral contraceptives and in subjects where they cyclically fluctuate, we will begin to discern the difference between the pharmacokinetic and pharmacodynamic influences that gonadal steroid hormones have on analgesia produced by morphine. The results of this project will determine gender differences and important pharmacokinetic and pharmacodynamic covariates to aid in appropriate dosing strategies for the most widely prescribed opioid analgesic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IN VITRO GLYCORANDOMIZATION OF NATURAL PRODUCTS Principal Investigator & Institution: Thorson, Jon Scott.; Associate Professor; None; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 03-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Roughly 70 percent of current lead compounds in modern drug discovery derive directly from the natural products, many of which are glycosylated bacterial metabolites. While it is known that the sugar ligands of these pharmaceutically important metabolites often define their corresponding biological activity, efficient methods to alter these essential carbohydrate ligands are still lacking. This proposal outlines a stepwise approach to accomplish this goal while also providing invaluable mechanistic and structural information on two critical, but poorly understood, enzyme classes; namely, nucleotidylytransferases and glycosyltransferases. Specifically, the proposed studies are designed to exploit structure/function-based protein engineering to generate a promiscuous in vitro nucleotidylyltransferase/glycosyltransferase systems which will provide a library of potentially new bioactive metabolites. The model system selected includes the Salmonella rmlA-encoded alpha-D-glucose-1-phosphate thymidylyltansferase (Ep) and three glycosyltransferases, which act ponerthronolide B (EryBV, EryCIII and MegGT). Among the many advantages of the presented model, it has been shown that the MegGT-catalyzed addition of a single sugar (megosamine) to erthromycin leads to a metabolite (megalomicin) with remarkably different biological activity. Thus, the selected model promises varied biological activity from metabolites anticipated from the proposed studies. The specific goals include: 1) structural and mechanistic studies on Ep3 EryBV, EryCIII and MegGT, 2) structure-based Ep engineering for the construction of nucleotide sugar libraries and 3) the use of this library, in conjunction with EryBV, EryCIII and MegGT, to generate libraries of glycosylated erythronolides with potentially new bioactivity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INVESTIGATION OF GLUTARIC ACIDEMIA TYPE I. Principal Investigator & Institution: Koeller, David M.; Pediatrics; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Glutaric acidemia type I (GA-I) is an inherited disorder of amino acid metabolism, which in its usual form, causes a progressive extrapyramidal movement disorder and death during the first decade of life. We have recently generated a mouse model of GA-I via gene targeting in embryonic stem cells. The affected mice demonstrate many of the phenotypic features seen in GA-I patients. The goal of this proposal is to use this animal model to answer a fundamental question regarding the pathophysiology of GA-I. Specifically, is the neurologic damage the result of circulating levels of toxic metabolites, or due to the lack of glutaryl CoAdehydrogenase (GCDH) activity within individual neurons (i.e. is it a cell autonomous phenotype). The specific aim of this proposal is to test the hypothesis that expression of the GCDH cDNA in the liver of Gcdh 1" mice will normalize the circulating levels of toxic metabolites (glutaric and 3-OH glutaric acids), and prevent the development of the myelinopathy and motor deficits seen in these animals. The approach we will use is to express the Gcdh cDNA in the liver of Gcdh / animals using the albumin promoter. Current therapy of GA-I consists primarily of a protein-restricted diet, which is based on the assumption that minimizing the levels of glutaric and 3-OH glutaric acids is beneficial. The experiments in this proposal will directly test that assumption. If our hypothesis is correct, the subsequent development of therapies such as liver directed gene therapy and liver stem cell therapy could then begin. Alternatively, if it is determined that normalization of metabolite levels is insufficient to prevent neuropathology in GA-I, alternative approaches to therapy need to be developed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ION CONDUCTANCES IN THE RETINAL PIGMENT EPITHELIUM Principal Investigator & Institution: Hughes, Bret A.; Associate Professor; Ophthalmology and Visual Sciences; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JAN-1991; Project End 31-DEC-2004 Summary: The health and integrity of photoreceptors critically depend on the composition and volume of their extracellular microenvironment. Regulation of the ionic composition and volume of this so-called subretinal space is accomplished by the transport of ions, water, and metabolites across the retinal pigment epithelium (RPE), a monolayer of cells juxtaposed between the photoreceptor outer segments and the choroidal blood supply. RPE transport is the result of the coordinated activity of a diverse group of ion pumps, co-transporters , exchangers, and channels residing in the apical and basolateral membranes. With changes in retinal activity, chemical signals released by retinal cell diffuse too the RPE where transport is adjusted to compensate for alteration in the photoreceptor microenvironment. Disruption of these transport processes or their regulation may cause adverse changes in the subretinal space, contributing to retinal disease. These transport pathways are also responsible for maintaining the intracellular composition in the RPE cell, which, if disturbed, could adversely affect other key RPE functions such as vitamin A transport and metabolism. Our overall goal is to understand the mechanisms by which potassium (K+) channels participate in the regulation of the volume and ionic composition of the fluid in both the subretinal space and the RPE cytoplasm. The specific aims are: (1) To determine the

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molecular basis for the inwardly rectifying K+ (Kir) conductance of the RPE; (2) To determine the mechanism underlying the regulation of the Kir channel by intracellular ATP; (3) To understand how the Kir channel is modulated by physiological changes in intracellular pH; and (4) To test the hypothesis that volume-induced activation of another K+ channel, an M-type K+ channel, is mediated by arachidonic acid metabolites. These aims will be pursued using a combination of molecular and electrophysiological techniques to investigate K+ channel structure, function, and regulation. The outcome of these studies will be a better understanding of how these critically important transport proteins operate in the RPE to maintain a healthy photoreceptor microenvironment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LINOLEIC ACID METABOLISM AND COLON CARCINOGENESIS Principal Investigator & Institution: Shureiqi, Imad; Clinical Cancer Prevention; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: The candidate seeks to develop his career as a translational researcher in the field of cancer chemoprevention and he is now working in an environment highly conducive to such research. This proposal provides the framework for the candidate's plans to develop a multidisciplinary translational approach to chemoprevention research. Better interventions are needed to prevent the high mortality of colon cancer. Linoleic acid (LA), a common dietary polyunsaturated fatty acid, can be convertted to arachidonic acid (AA) that can in turn form mitogenic metabolites [e.g. prostaglandin, E2 (PGE2) and leukotriene B4 (LTB4)]. LA is also the substrate for 15-lipoxygenase-1 (15lox-1) in forming 13-S-hydroxyoctadecadienoic (13-S-HODE). We have found that 15lox-1 and 13-S-HODE are reduced in human colon cancers and that 13-S-HODE induces apoptosis in transformed colonic cells. In normal cells, the enzyme delta 6-desaturase (d6-d) forms gamma- linolenic acid (GLA) to start the conversion of LA to AA. Many tumor cells lack d-6-d activity and die by GLA exposure. Some evidence suggests tumor cells convert LA to AA by an alternative pathway that requires delta 5-desaturase (d-5d). The hypothesis is that a shift in linoleic metabolism from producing pro- apoptosis products [13-S-HODE and (GLA)] to the formation of mitogenic metabolites of arachidonic acid (e.g. PGE2 and LTB4) significantly contributes to colonic carcinogenesis. The specific aims are 1) to determine the activity of the alternative conversion pathway in relation to the transformation and differentiation states of colonic cells in vitro; 2) to evaluate the association between the shift in LA metabolism and the progressive steps of human colonic carcinogenesis using a clinical observational study model(by measuring the activity of LA alternative pathway and levels of related enzymes and metabolites of LA and AA [e.g. 13-S-HODE, PGE2, LTB4, d-6-d, and 15lox-1] in colonic tissues from 3 patient groups [normal, polyp, and colon cancers]); 3) to evaluate the effects of ectopic d-6-d expression on apoptosis, differentiation, and LA metabolism in transformed colonic cells in vitro; 4) to evaluate the impact of selective d5-d inhibition on LA metabolism and the survival of transformed colonic cells in-vitro; and 5) to determine the effects of selective d-5-d inhibition on colon carcinogenesis in an established short-term assay in rats. This work will set the stage for future animals and clinical studies of LA alternative pathway modulation as means of colon cancer chemoprevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPID MAPS Principal Investigator & Institution: Dennis, Edward A.; Chemistry and Biochemistry; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2003; Project Start 12-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Lipids play a central role in cellular function and disease. The scope of lipid involvement in cellular function has only recently been recognized to extend well beyond its established roles in energy metabolism and membrane structure. Lipids are an extensive group of small, amphipathic molecules that are divided into a series of classes based on structure and their biosynthetic origins. Still, all of these compounds possess many similar chemical and physical properties. Because of these similarities, the metabolic pathways that deal with lipids are complex and intertwined. Developing an integrated metabolomic system capable of characterizing the global changes in lipid metabolites ("lipidomics") is a daunting task but one that it is important to undertake in light of the significant returns produced by the global approaches of genomics and proteomics. Our consortium has developed a Lipid Metabolites And Pathways Strategy, termed LIPID MAPS that applies a global integrated approach to the study of lipidomics. The specific aim of LIPID MAPS for this grant period is to develop the requisite technology and conduct an integrated research program that will establish lipidomics as a fully functioning research field. By employing a rigorously maintained set of common biological, biochemical, and analytical technologies in each of the consortium laboratories, and by using an extensive informatics infrastructure, we will be able to integrate and analyze the large amount of data that will be generated by this large scale collaborative project. We will be able to generate "road maps" that will define how all of the lipid components of a cell move through the complex lipidomic network from biosynthesis to removal, including their important roles as second messengers. All of this information will be shared with the entire research community and should greatly aid in the development of metabolomics for other systems. In addition, LIPID MAPS should also aid in drug development since lipids play critical roles in numerous diseases, including inflammatory processes, atherosclerosis, Alzheimer's disease, cancer and stroke. Despite the clear benefits that developing a lipidomics field would produce, no large scale national or international programs for such a study exist. We believe that the experimental technologies are now in hand for establishing the field of lipidomics and that LIPID MAPS represents a viable strategy for achieving this goal. This would lead to the integration of lipids into the general focus of 21st Century biology; namely, into a fully quantitative systems-level biology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPID MEDIATORS OF SIGNAL TRANSDUCTION IN SMOOTH MUSCLE Principal Investigator & Institution: Gross, Richard W.; Professor; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JUL-1988; Project End 31-MAR-2006 Summary: (provided by the applicant): The end organ sequelae of atherosclerosis and hypertension represent the largest public health problems in industrialized populations. The importance of arachidonic acid (AA) and its metabolites in modulating vascular tone, cell growth, migration, proliferation and gene expression is well known. The rate determining step in the production of eicosanoids is the release of AA by intracellular phospholipases A2 (PLA2). Accordingly, a detailed understanding of the types and

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modes of regulation of vascular cell intracellular PLA2S are necessary to gain insight into the critical signaling mechanisms, which mediate atherosclerotic, and hypertensive disease states. We have identified the major vascular intracellular phospholipases as iPLA2B and 1PLA2Gamma The structure of iPLA2B is remarkable for: 1) the presence of ankyrin-like repeat domains in its N-terminus which likely modulate protein-protein interactions facilitating its intracellular sorting; and 2) a calmodulin binding domain in its C-terminus which regulates its activity. Accordingly, in Specific Aim 1 we will examine the functional role of the N-terminal ankyrin-like repeat domains in iPLA2B by identifying its protein binding partners. Next, we will explore the role of phosphorylation of the calmodulin binding domain to elucidate the role of protein kinases in regulating iPLA2B activity. Finally, the role of proteolytic activation of iPLA2B activity by caspase-3 and calpain-mediated cleavage will be examined. In Specific Aim 2, we will generate smooth muscle cell (SMC) specific overexpressors and mice null for IPLA2B and 1PLA2gamma in a SMC specific manner to determine the role of iPLA2s in vascular SMC tone, proliferation and migration. In Specific Aim 3, we will explore the newly identified role of AA as a modulator of endothelial cell (EC) nitric oxide production and the roles of Akt mediated activation of eNOS and iPLA2B in NO production. Finally, by exploiting chiral mechanism-based inhibitors of iPLA2B and iPLA27 we have developed, we will examine the role of intracellular phospholipases in EC responses to cyclic mechanical force. Alterations in the release of AA, generation of eicosanoid metabolites, lipid composition and cytoskeletal organization during changes in shear stress and mechanical stretch will be examined. Collectively, these studies represent a targeted, multidisciplinary approach to elucidate the roles of intracellular phospholipases in the vascular biology of the hypertensive and atherosclerotic disease states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LUMINAL LIPID EXPOSURE, GENETICS AND COLON CANCER RISK Principal Investigator & Institution: Kato, Ikuko; Pathology; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 05-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The long-term goal of the proposed study is to provide the scientific basis for public health strategies to reduce incidence of and mortality from colorectal cancer. Several lines of evidence suggest that a high fat diet increases the risk of colorectal cancer. While ecologic studies and earlier case-control studies demonstrated a strong association with high fat intake, the results from cohort studies and recent case-control studies have rather been inconsistent. These discrepancies may indicate some genetic susceptibility that modify the effects of a high fat diet. One of the major mechanistic bases for the roles of fat in colorectal carcinogenesis is intracolonic exposure to potentially carcinogenic substances which are generated from lipid and its metabolites with fecal bacterial activities. In this context fat absorption may play a key role in determining the effects of a high fat diet on colorectal cancer risk via modifying the levels of luminal exposure to potentially carcinogenic metabolites. Recently, two common genetic polymorphisms (FABP2 and Apo E) that affect intestinal fat absorption and bile acid secretion have been reported and associated with risks of cardiovascular diseases, diabetes and dementia. We hypothesize that individuals with genotypes for lower intestinal absorption, which results in more intracolonic exposure to potentially carcinogenic substances, have a higher risk of developing colorectal cancer in relation to a high fat diet. To test this hypothesis, we

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propose to conduct a population-based case-control study in Metropolitan Detroit taking an advantage of the SEER Cancer Registry. We plan to interview 2000 cases and 2000 controls for their usual diet to estimate fat and other nutrient intake and collect blood or buccal cell specimens for genotyping assays. Specific aims of the study are (1) To determine whether the genotype, FABP2 A54, Apo E2/E3 or a combination of these, is associated with risk of colorectal cancer; (2) To determine whether the effect of a high fat diet on colorectal cancer risk is more pronounced in the subjects with these genotypes; and (3) To determine if the above interactions are modified by intake of other dietary components, such as fiber, calcium and iron, which affect luminal lipid metabolism. The results from the proposed study would provide useful information for effective dietary modification in primary prevention for colorectal cancer. In addition, accumulated dietary data and biological specimens will serve as an important resource for future research on other nutrient-gene interactions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF CARDIOVASCULAR COMPLICATIONS IN AIDS Principal Investigator & Institution: Agrawal, Krishna C.; Regents Professor and Chairperson; Pharmacology; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 08-FEB-2000; Project End 31-JAN-2004 Summary: The primary long term goal of the proposed research is to investigate the mechanisms responsible for cardiovascular complications from cocaine abuse in AIDS patients. Serious cardiovascular complications due to cocaine abuse are well known; however, the molecular mechanisms have not been delineated. Cytokines play a significant role in the normal regulation of the function of endothelial cells and cardiac myocytes. There is growing evidence that the Tat protein of HIV- l can alter cellular gene expression and signal transduction pathways and can induce the formation of cytokines such as TNFalpha, and IL-1beta. Preliminary data demonstrate that TNFalpha can compromise cardiovascular function which is exacerbated in the presence of cocaine. We will therefore test the hypothesis that a combination of Tat and the cytokines (TNFalpha and IL- 1beta) with cocaine and its metabolites can produce cardiovascular complications in AIDS patients, by investigating the following specific aims: (l) to determine the effects of cocaine and its major metabolites in modulating the Ca2+, Na+ and K+ currents in isolated human cardiac myocytes in the presence and absence of TNFalpha or IL-1beta; (2) to investigate the modulatory effects of Tat protein and/or the inflammatory cytokines in the presence or absence of cocaine on integrin expression and integrin mediated events, i.e., endothelial cell migration and leucocyte adhesion to endothelial cells; (3) to assess the cardiovascular complications in mice acutely or chronically treated with cocaine and/or TNFalpha by monitoring the changes in: (a) systemic vascular resistance measured by systemic arterial pressure and cardiac output, (b) pulmonary vascular resistance determined by monitoring pulmonary arterial pressure and cardiac output, and (c) left ventricular contractility by measuring changes and the rate of change in the left ventricular pressure; and (4) to determine the role of Tat protein in modulating cardiovascular function. The tat transgenic and TNFalpha receptor knockout mouse models will be used to test the various parameters indicated under specific aim #3. The proposed studies will provide an in-depth understanding of the molecular mechanisms that may be responsible for the cocaine-induced cardiovascular complications in the presence of HIV infection. The unifying theme of the proposal is to define the role of Tat and the inflammatory cytokines in modulating the cocaine induced cardiotoxic effects that have been observed in patients with AIDS.

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

Project Title: MECHANISMS OF INHIBITORY DRUG INTERACTIONS Principal Investigator & Institution: Kunze, Kent L.; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: The long-term objective of the research described in this grant proposal is to better understand metabolism-based drug-drug interactions that are underpredicted from in vitro data. This is important because underprediction of effect has negative consequences for drug therapy and the development of new drugs. It is also important because these outliers represent a significant fraction of clinically relevant drug-drug interactions. An in-depth understanding of why predictions fail should improve predictive efforts. The interactions we propose to study are drawn from the larger class of interactions that appear to arise as the result concentrative cell uptake and/or metabolites of the interactant drug. Predictive quality is degraded because the magnitude of the inhibition depends not only on the concentration of the interactant drug at the active site, but also on the activity of the enzymes involved in converting the drug to the proximate inhibitory metabolite as well as the mechanism of metabolite inhibition. The first section of this proposal investigates two potent inhibitors of P450catalyzed drug metabolism, fluvoxamine and itraconazole, who's in vivo effects are 10to 100- fold higher than predicted. Fluvoxamine causes potent and differential inhibition of at least 4 important human P450' s in vivo. Aims 1-3 will identify the sources of the underprediction for each enzyme by examining the importance of concentrative uptake as well as direct inhibitory effects of fluvoxamine, itraconazole and their major metabolites on enzyme activities in microsomal preparations and human hepatocytes. The finding that time dependent, persistent inhibition of CYP3A4 activity by itraconazole is observed in microsomes and intestinal cells further suggests that itraconazole is a mechanism-based inhibitor of this important enzyme. Aim 4 will assess if other factors, such as concentrative uptake, are required to fully explain the effect of itraconazole and, if so, to identify them. The second section of the proposal addresses the propensity of alkylamine containing drugs to elicit irreversible inhibition of enzyme activity via formation of MI complexes in vivo and in vitro. This process requires that the alkylamine undergo as many as 4 rounds of oxidation to the corresponding Cnitroso metabolite prior to the inhibitory event. This very complex type of inhibition has not been fully characterized and a deeper understanding of the underlying mechanisms is critical for meaningful and reproducible in vitro-in vivo predictions of inhibitory effect. Aims 5 and 6 of this proposal set out to fully describe the kinetics of the system and evaluate the limits and advantages of a less complex empirical approach. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISTIC STUDIES ON TEA AND CARCINOGENESIS Principal Investigator & Institution: Yang, Chung S.; Professor Ii & Chair; Chemical Biology; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2002; Project Start 01-APR-1992; Project End 31-DEC-2005 Summary: (Applicant's Abstract) The long-term goal of this project is to elucidate the mechanisms of inhibition of carcinogenesis by tea (Camellia sinensis) and to assess its usefulness in the prevention of human cancer. Previous studies have demonstrated that tea preparations inhibit carcinogenesis in animal models and that tea polyphenols inhibit cell transformation, proliferation, and related signal transduction pathways.

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Plasma and tissue levels of tea polyphenols and their metabolites in animals and humans have been determined. In this project the applicant and colleagues plan to further elucidate the mechanisms of action and identify the active components involved with the following specific aims: 1. To elucidate the mechanisms of inhibition of carcinogenesis by tea in the NNK-induced lung carcinogenesis model in A/J mice and in relevant cell lines. The applicant and colleagues will study the inhibition of cell proliferation and tumor promotion by tea and tea constituents, and relate the activity to pertinent signal transduction pathways (such as MAP-kinases and AP-1 activation) in short and long term animal experiments. In-depth mechanistic studies in cell lines, on the inhibition of AP-1 and NFkB and the upstream of protein kinase cascade, will complement the animal studies and provide basic understanding of the action of tea polyphenols in general. 2. To determine the blood, urine, and tissue levels of tea polyphenols and their metabolites in rodents and humans under different experimental conditions and to understand the factors influencing these levels. Improved methods will be developed to include the analysis of many newly identified metabolites in pharmacokinetic studies. The blood and tissue levels of these compounds will serve as a reference for evaluating the mechanisms of anti-carcinogenesis and for comparing results in mice and humans. 3. To synthesize and determine the biological activities of the metabolites identified in Aim 2 in cell lines and animal models. The applicant and colleagues will address key issues concerning the bioavailability and bioactivities of Omethyl, glucuronide, and sulfate derivatives and two ring-fission metabolites of tea catechins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: METABOLIC REGULATION OF MUSCLE BLOOD FLOW Principal Investigator & Institution: Hester, Robert L.; Physiology and Biophysics; University of Mississippi Medical Center 2500 N State St Jackson, Ms 39216 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: The blood flow to the peripheral circulation is regulated to maintain a balance between the delivery of nutrients and the metabolic demands of the tissue. Blood flow increases to a metabolically active tissue. This increased blood flow is the result of an increase in arteriolar diameter of terminal arterioles and larger upstream vessels. The terminal arterioles appear to determine distribution of flow while the upstream or "feed" vessels are more important in regulating total tissue flow. With an increase in metabolism there is the release of vasoactive metabolites from the tissue. Although vasoactive metabolites are known to affect the diameters of terminal arterioles the mechanisms by which metabolic factors regulate the diameter of upstream arterioles is uncertain. Recent studies from our lab and others have indicated an important role for the venular-arteriolar diffusion of vasoactive substances. The studies outlined in this proposal will test the following working hypothesis. In response to mismatches in blood flow and tissue metabolism, decreases in PO2 and/or increases in PCO2 and H+ are directly or indirectly sensed by the venular endothelial cells, resulting in the release of vasoactive metabolites of arachidonic acid which regulate the tone of adjacent arterioles. The proposed studies will test this hypothesis utilizing recently developed in situ microcirculatory techniques in which we are able to selectively remove the venular endothelium and assess the impact on blood flow regulation. The proposed studies will test two specific hypotheses: 1) The venular endothelium releases a metabolite of arachidonic acid that diffuses from the venule to the arteriole to cause an arteriolar dilation in response to an increase in tissue metabolic rate. 2) The venular endothelium responds to hypoxia, hypercapnia, and acidosis, directly, or indirectly to

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initiate the release of one or more vasoactive factors from the venular endothelial cells. These studies should provide new and important information relevant to our understanding the importance of venular-arteriolar diffusion of endothelial derived factors in the regulation of blood flow. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MIDARP AT HAMPTON UNIVERSITY Principal Investigator & Institution: Mclean, Hugh M.; Pharmaceutical Sciences; Hampton University Administration Bldg., Room 100 Hampton, Va 23668 Timing: Fiscal Year 2003; Project Start 15-MAR-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The proposed MIDARP Program is envisioned to be the vehicle by which biomedical research in the substance abuse arena is initiated on the campus of Hampton University. The underlying goal of the program is the unbridled development of a vigorous and sustainable biomedical research program on substance abuse. This goal will be realized via a series of planned activities that are designed to enhance the research culture by augmenting the biomedical research infrastructure, by creating faculty development programs that facilitate the training of minority faculty members and foster interdisciplinary collaboration between the School of Pharmacy and the Departments of Biology, Chemistry and Psychology and to facilitate the training of graduate and undergraduate minority students in the biomedical sciences, particularly in substance abuse research. Furthermore, the proposal seeks to elucidate the underlying biochemical mechanisms associated with the neurotoxicity occasioned by 3,4-methylenedioxy-methamphetamine ("Ecstasy," MDMA). Toward this end, five research projects have been proposed: 1. Synthesis of potential metabolites and antagonists of MDMA. 2. Induction of apoptosis in neuritic cells innervated by serotonergic and dopaminergic neurons, by metabolites of MDMA. 3. In Vitro study of the metabolism of MDMA using human hepatocytes 4. Interactions between MDMA metabolites and dopamine and serotonin transporters. 5. The impact of MDMA metabolites on a variety of brain regions and processes in rats. It is anticipated that the results garnered from the planned activities will significantly enhance the existing body of knowledge on the mechanisms involved in the deleterious effects of MDMA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MITOCHONDRIAL METABOLITES TO TREAT PARKINSON'S DISEASE Principal Investigator & Institution: Ames, Bruce N.; Professor; Children's Hospital & Res Ctr at Oakland Research Center at Oakland Oakland, Ca 946091809 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2006 Summary: Mitochondrial decay due to oxidation is an important contributor to Parkinson's disease (PD) and other neurodegenerative diseases of aging. We have previously shown that mitochondrial decay in old rats can be ameliorated by feeding them the normal mitochondrial metabolites R-alpha-lipoic acid (LA) and acetyl-Lcarnitine (ALCAR), which inhibited oxidative damage and restored much of the mitochondrial structure and function in old animals. There is evidence that some mitochondrial metabolites may protect against PD. For example, coenzyme Q10 (CoQ) has been shown to protect against PD in clinical trials in humans; and ALCAR has been shown to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity, a PD mimic in monkeys. These metabolites protect by restoring mitochondrial antioxidants and function. We hypothesize that a mixture of mitochondrial

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antioxidants/metabolites, CoQ, ALCAR and LA, could be optimized to be more effective than any single compound in preventing or treating PD. We will test our hypothesis using behavioral, biochemical, and immunohistochemical techniques on two models of PD: the chronic rotenone-exposed SK-N-MC human neuroblastoma cell model and the chronic rotenone-treated rat model. This project on PD is a new direction for our work on preventing mitochondrial decay and could lead to an effective and cost efficient prevention /therapy for PD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODIFIERS OF CARCINOGENESIS--ENVIRONMENTAL PAH MIXTURES Principal Investigator & Institution: Baird, William M.; Director, Environmental Health Sciences; Environ & Molecular Toxicology; Oregon State University Corvallis, or 973391086 Timing: Fiscal Year 2002; Project Start 01-JUN-1980; Project End 31-MAR-2006 Summary: (provided by applicant): Humans are exposed to polycyclic aromatic hydrocarbons (PAH) in complex environmental mixtures and this exposure is linked to human cancer. Determination of the total levels of PAH-DNA adducts formed by complex mixtures is insufficient to provide the information necessary to assess human risk, because specific PAH metabolites differ greatly in carcinogenic potency. The hypothesis of the proposed studies is that by assessment of how two major classes of carcinogenic PAH are activated within complex mixtures, it will be possible to predict the potential of that mixture to affect activation of carcinogenic PAH present within that mixture and allow rapid estimation of the relative carcinogenic potency of complex mixtures. This hypothesis will be evaluated by examining the effect of environmental PAH mixtures on both PAH-DNA adduct formation and PAH-induced tumor induction in mouse skin by accomplishing four specific aims: 1. To extend our recent studies on the effect of environmental PAH mixtures on the metabolic activation and DNA binding of representative examples of the two major classes of carcinogenic PAH in mouse epidermis. We will compare our recent results from a standard mixture of PAH extracted from coal tar, SRM 1597, to two extracts derived from urban dust, SAM 1649 and from diesel exhaust (SRM 1650) obtained from the NIST. In order to determine how this type of environmental PAH mixture affects the metabolic activation of carcinogenic PAH, we will conduct PAH-DNA binding and tumor initiation-promotion studies in mouse epidermis. 2. To study the DNA-binding effect of complex PAH mixtures in human cells in culture. These studies will utilize MCF-7 human mammary carcinoma cell line and human MCF-10A human mammary carcinoma cell line which we have previously characterized with respect to their ability to metabolically activate individual carcinogenic PAH including B[a]P and DB[a,l]P to DNA binding metabolites. These studies will help us to relate the effects of complex PAH mixtures on DNA binding, tumor initiation and enzyme activation in mouse skin to how these mixtures affect carcinogen activation in humans. 3. To evaluate the carcinogenic potency of the above complex environmental PAH mixtures, as well as the effect of these mixtures on the carcinogenic activity of DB[a,l]P and B[a]P in tumor initiation-promotion assays in Sencar mice. 4. To determine the mechanism by which this complex PAH mixture affects activation of hindered bay-region and unhindered bay-region carcinogenic PAH through studies of the effect of complex PAH mixtures on CYP enzymes present in mouse skin. The proposed studies will determine whether the analysis of PAH-DNA adducts formed in mouse skin will provide a rapid approach for assessment of the relative carcinogenic potential of complex environmental mixtures of PAH. This will aid

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in the development of methods for predicting the relative carcinogenic potency based upon the PAH composition of complex environmental mixtures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTI-ANALYTE APPLICATIONS

MICRO-DEVICES

FOR

BIOMEDICAL

Principal Investigator & Institution: Andrade, Joseph D.; Professor; Bioengineering; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2004 Summary: (provided by applicant): The investigators propose to develop microdevices for the specific chemical analysis of multiple metabolites in small sample volumes of biological fluids. The specificity and sensitivity is provided by specific reactions that couple analytes to bioluminescent-based enzyme reactions and produce light proportional to the analyte concentration. Bioluminescent analytical assays, in a miniaturized and stable format, can measure sub-microMolar concentrations in microliter sample volumes. The goal of the first phase (R21) is to engineer microfluidic structures, develop enzyme packaging and stabilization techniques, and optimize optical detection systems in order to measure two model analyte solutions (galactose and lactate) using bioluminescent reactions. The goal of the second phase (R33) is to implement other bioluminescent assays in the microfluidic detection system, develop specific diagnostic panels, utilize practical biofluid samples and enhance analytical accuracy and precision. The proposed Micro-Analytical System (microAS) will be convenient to operate in point-of-care (POC) and home environments. It will likely evolve to measure up to 100 different metabolites in the submicroMolar to milliMolar range from one 1-100 microL biofluid sample, and include customized comprehensive diagnostic panels for basic research, clinical research, and for personal disease and health management. These systems would provide rapid results, facilitate patient empowerment, and reduce health care costs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW ISOPHOSPHORAMIDE MUSTARD PRODRUGS Principal Investigator & Institution: Farquhar, David; Professor of Medicinal Chemistry and Pha; Experimental Therapeutics; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 03-JAN-2001; Project End 31-DEC-2005 Summary: Ifosfamide, an oxazaphosphorine with broad-spectrum clinical activity, is a key component of many front-line protocols for the treatment of both solid tumors and hematologic malignancies. Ifosfamide is not active in its own right; it requires P-450mediated oxidative metabolism in the liver to express cytotoxicity. Despite its broadspectrum activity, ifosfamide has several major shortcomings that limit its utility. Prominent among these is organ-specific toxicities, particularly, urotoxicity, nephrotoxicity and neurotoxicity. These toxicities, which are associated with the 'unwanted metabolites' of ifosfamide, principally acrolein and chloroacetaldehyde, seriously limit optimal drug administration. A second shortcoming of ifosfamide is drug resistance. Although several resistance mechanisms have been identified, elevated aldehyde dehydrogenase (ALDH) levels plays a prominent role in many murine and human tumor cell lines. A further clinical limitation of ifosfamide is that it can not be used for regional chemotherapy because of the need for hepatic activation. The goal of this proposal is to develop new prodrugs of isophosphoramide mustard (IPM), the

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active metabolite of ifosfamide, that will avoid many of the toxicities caused by the 'unwanted metabolites' of ifosfamide. In this application, two new classes of IPM prodrugs that do not require oxidative activation are proposed. The new analogs proposed may be enzymatically convert to IPM under biological conditions. Accordingly, the new analogs should not cause many of the organ toxicities that have limited the clinical application of ifosfamide. The proposed prodrugs do not generate aldehyde intermediates, and therefore, are not susceptible to ALDH-mediated detoxification. Finally, since the prodrugs are activated in all tissues, they could be useful for regional chemotherapy as well as for the systemic management of patients with cancer. The principal investigator proposes to synthesize a number of prodrugs and study their (a) biotransformations in biologic tissues, (b) cytotoxicities against tumor cell and drug-resistant variants, (c) antitumor activities against experimental tumors and human tumor xenografts in mice, (d) organ toxicities in the mouse, and (e) antitumor efficacy compared with IPM and melphalan when administered by limb perfusion in a rat sarcoma tumor model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEW METHODS FOR EVALUATING CHOLINERGIC TOXICITY Principal Investigator & Institution: Kirchhoff, Jon R.; Chemistry; University of Toledo 2801 W Bancroft St Toledo, Oh 43606 Timing: Fiscal Year 2003; Project Start 01-AUG-1998; Project End 31-JAN-2006 Summary: (provided by applicant): Cholinergic degradation has been linked to cholinergic disorders such as Alzheimer's dementia. Direct quantitation of the changes in concentrations of neurochemical marker compounds associated with neurocompromising events is a challenging task. Here, we will develop especially sensitive methodology to directly measure the changes in these neurochemical markers in response to selective cholinergic degradation. We have prepared 6hydroxycatecholine, a cholinomimetic analogue of 6-hydroxydopamine, and a number of related catechol-based chemical agents in a series for the purpose of defining conditions for the introduction of selective cholinergic presynaptic lesions in the brain. Selective cholinotoxic events will be investigated in vitro with synaptosomal preparations to establish the selectivity and relative neurotoxicity of each catechol-based chemical agent. Subsequent in vivo studies will be conducted by microdialysis sampling in cannulated rat brain to monitor the near real-time changes that occur in a living system. Conditions for the application of selective neurocompromising agents will be sought to maximize the changes in levels of choline and acetylcholine, while at the same time minimize the changes in catecholamine and tryptophan neurotransmitters relative to controls. Analytical methods based on capillary electrophoresis with microelectrochemical detection have been developed to selectively and sensitively monitor changes of trace levels of neurotransmitters and their metabolites. Capillary electrophoresis techniques permit efficient separation of mu l to nL samples of species based on their electrophoretic mobility, while electrochemical detection with specially designed microelectrode devices allow for additional selectivity and sensitive detection at the trace level. This strategy will allow sequential and time-resolved monitoring of the catechol-based chemical agents and their metabolites uptake efflux when coupled with microdialysis of tissues surrounding specific brain regions compromised with the chemical agents. The methodology will define the temporal and concentrationdependent acute and chronic selective compromise of cholinergic presynaptic sites by 6hydroxycatecholine and related quaternary ammonium catechol-based redox-affinity reagents. Thus, new methodologies to follow the chemical events in cholinotoxic states

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may be developed for future studies of animal models relevant to Alzheimer's dementia and for the study of underlying cholinergic contributions to mechanisms that govern consciousness and cognition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NITROAROMATICS AND BREAST CANCER Principal Investigator & Institution: El-Bayoumy, Karam E.; Director of Research; Institute for Cancer Prevention 1 Dana Rd Valhalla, Ny 105951549 Timing: Fiscal Year 2002; Project Start 01-JUL-1983; Project End 31-MAR-2005 Summary: (Provided by Applicant): The etiology of most breast cancers remains obscure. A significant portion of breast cancer incidence in the U.S. is related to environmental factors and lifestyle, including diet. An example of a class of environmental mammary carcinogens is the nitropolynuclear aromatic hydrocarbons (NO2-PAH). The National Agency for Research on Cancer listed some NO2-PAH as possibly carcinogenic to humans. However, the actual risk associated with human exposure to NO2-PAH has not been clearly defined. In order to evaluate risks, we focused our efforts on understanding the mechanistic basis for tumor induction by 6nitrochrysene (6-NC) and mono-nitropyrene (mono-NP) isomers (1-, 2- and 4-NP). Studies proposed in the present application are a logical extension of our findings. Accordingly, we formulated the following hypotheses and the Specific Aims to test them. (1) We hypothesize that 1,2-dihydroxy- 1,2-dihydro-6-nitrochrysene (l,2-DHD-6NC) or 1,2-dihydroxy-1,2-dihydroxy-6-aminochrysene (1,2-DHD-6-AC) is the proximate mammary carcinogen and 1,2-dihydroxy-1,2-dihydro-6-hydroxylamino-chrysene (1,2DHD-6-NHOH) is the ultimate carcinogenic form. To test our hypothesis, we will carry out the following: (a) synthesis of DNA adducts derived from 1,2-DHA-6-NHOH, (b) synthesis of ample materials of metabolites derived from 6-NC and comparison of their relative potency as mammary carcinogens by intramammary administration in rats, (c) determine the type and frequency of mutations in the p53 gene in rat mammary tumors. (2) We have shown that NO2-PAH derived DNA adduct formation is necessary but is not sufficient for carcinogenesis. Clearly, there are gaps in our understanding of the role of DNA adducts in mammary carcinogenesis. Thus, we will determine the relationships between: (a) the nature and levels of DNA adducts, (b) mutation frequency and spectra and (c) mammary carcinogenicity induced by 6-NC using rats harboring the lacI reporter gene. Our hypothesis is that the major DNA adduct derived from l,2-DHD-6NHOH is responsible for the type and frequency of mutations in both the lacI gene and in the p53 gene. (3) To translate our ongoing studies of NO2-PAH in rodents, we propose to pursue similar studies in cultured human mammary tissues. We propose to employ normal (MCF-1OA) and cancer cell lines (MCF-7) to determine: (a) the metabolic capacity of the target organ (human breast tissues) and (b) the form of P450 isozymes involved in the activation of these carcinogens. The proposed study will also provide an experimental approach to the identification of relevant DNA adducts detected in humans; toward this end a pilot study will be initiated to determine the possible presence of NO2-PAH-derived DNA adducts in human breast tissues. (4) The hypothesis to be tested here is that certain covalent modification of genomic DNA by ultimate carcinogenic metabolites derived from 6-NC and mono-NP represents a type of cellular damage that can be responsible for an increased expression of the tumor suppressor protein p53. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NON-COX ANGIOGENESIS

ARACHIDONIC

ACID

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Principal Investigator & Institution: Rao, Gadiparthi N.; Associate Professor; Medicine; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Inflammation that follows tissue injury is believed to be important in the initiation and progression of various diseases including, atherosclerosis, cancer, and retinopathy. Phospholipase A2s (PLA2s), a group of enzymes that breakdown phospholipids generating arachidonic acid and lysophospholipids have been implicated in inflammation. One of the major events underlying the progression of atherosclerosis is angiogenesis. Endothelial cell (EC) migration and proliferation are critical events in angiogenesis. Emerging evidence suggests that PLA2, arachidonic acid and its eicosanoid metabolites play a role in the regulation of cell migration, proliferation, and apoptosis. In addition, recent investigations using nonsteroidal anti-inflammatory drugs reveal a potential role for eicosanoids in angiogenesis. Based on this knowledge, we hypothesize that eicosanoids, particularly the lipoxygenase-monooxygenase metabolites of arachidonic acid, play an important role in angiogenesis and thereby influence the pathogenesis of atherosclerosis. To test the role of eicosanoids in angiogenesis we will address the following four specific aims: 1. To identify eicosanoids produced in human microvascular endothelial cells (HMVEC) and determine their effects on angiogenesis using in vitro and in vivo models. 2. To determine the effects of angiogenic eicosanoids on HMVEC migration and proliferation. 3. To test the role of the Jak/STAT and PI3K/Akt pathways in angiogenic eicosanoid-induced HMVEC migration and proliferation. 4. To identify the effector molecules of eicosanoid-induced angiogenesis and study the mechanisms underlying their regulation of expression in HMVEC and vascular smooth muscle cells. The results of this proposal will provide novel information on the identification of specific angiogenic eicosanoids and on elucidation of the underlying mechanisms by which these lipid molecules stimulate angiogenesis. Such knowledge, in turn, could be useful in developing therapeutics in the prevention of progression of diseases such as atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OCCURRENCE TETRAHYDROISOQUINOLINES

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Principal Investigator & Institution: Liu, Yiming; Associate Professor; Chemistry; Jackson State University Jackson, Ms 39217 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2006 Summary: (provided by applicant): Occurrence and Neurotoxicity of Tetrahydroisoquinolines The goal of this research is to identify and quantify certain MPTP-like tetrahydroisoquinoline(TIQ) enantiomers in rat brain. Further, the neurotoxicity of these TIQ enantiomers and the major metabolites will be assessed. The chirality of TIQ's neurotoxicity has been observed. For example, the two enantiomers of 6,7-dihydroxy-1, 2-dimethyl-1,2, 3, 4 -tetrahydroisoquinoline (N-methyl-salsolinol) exhibit different neurotoxicological properties: the (R)-enantiomer induces Parkinsonism in rats, but the (S)-enantiomer does not. However, the in-vivo formation and metabolism of these enantiomeric neurotoxins remain largely unknown. To carry out these studies, simultaneous quantifications of the stereoisomers at trace levels are needed. However, suitable analytical methodology is lacking. To obtain the analytical

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capability, we plan to modify the chiral GC-MS method that we have developed for the determination of salsolinol enantiomers, and also to develop a chiral method based on capillary electrochromatography -mass spectroscopy (CEC-MS). Experiments will include: a). simultaneous determination of dopamine and TIQ enantiomers including (R)-/(S)-salsolinol and N-methyl-(R)-/(S)-salsolinol in rat brain; b). quantitative studies of salsolinol metabolism using 13C labeled salsolinol enantiomers (i.e. [1,m-13C2]salsolinol); c) studies of the effects of chemical stimuli on the biosynthesis and metabolism; and d) assessment of the neurotoxicity of individual enantiomers of certain TIQs and their metabolites to rats. Our hypothesis is that racemization of the neurotoxic (R)-enantiomers of endogenous salsolinol and N-methylsalsolinol is a major pathway leading to detoxification in a healthy nervous system, and the racemization can be hindered by some chemical species such as alcohol. By studying the in-vivo enantiomeric biosynthesis, metabolism, and the neurotoxicity of MPTP-like TIQ neurotoxins, this research will contribute to our understanding of the chirality of TIQ neurotoxicity and the pathogenesis of Parkinson's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ONTOGENY OF DRUG BIOACTIVATION AND IDIOSYNCRATIC ADRS Principal Investigator & Institution: Leeder, James S.; Chief; Children's Mercy Hosp (Kansas City, Mo) 2401 Gillham Rd Kansas City, Mo 64108 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Idiosyncratic adverse drug reactions (ADRs) are relatively rare, but potentially life-threatening events in which the determinants of susceptibility (largely unknown) are thought to be unique to the individual experiencing the adverse event. They can occur throughout the age spectrum but tend to be underemphasized in the pediatric literature yet children appear to be at increased risk for certain idiosyncratic ADRs such as valproate hepatotoxicity and cutaneous reactions to lamotrigine. An important step in the development of an idiosyncratic ADR appears to be biotransformation of the implicated drug to a chemically reactive metabolite ("bioactivation") that is capable of binding to cellular macromolecules and producing cell death directly or indirectly through initiation of an immune response. Although developmental changes in drug metabolizing enzymes such as the cytochromes P450 (CYPs) and glucuronosyl transferase (UGTs) have been characterized in children, little is known about the ontogeny of drug bioactivation as children grow and develop. Using biomarkers of acetaminophen (APAP), carbamazepine (CBZ) and valproic acid (VPA) bioactivation (and detoxification) in vivo, the goals of this research program are 1. to characterize the ontogeny of the drug bioactivation biomarkers in vivo and in vitro and 2. to identify the pharmacogenetic determinants of interindividual variability in APAP, CBZ and VPA biomarker expression during growth and development. To achieve these goals, two longitudinal "bioactivation" phenotyping studies will be conducted 1. in healthy children following a single test dose of APAP (15 mg/kg as Tylenol(r) alcoholfree solution, 80mg/0.8ml) and 2. in epileptic children routinely receiving CBZ or VPA for medical management of their disease involving NICHD PPRU sites in Kansas City, MO, Shreveport, LA, and Little Rock, AR. For each study, urine is collected overnight and analyzed for the presence of parent drug, "non-toxic" metabolites and conjugated l metabolites of candidate reactive metabolites. Specific urinary metabolite ratios will be used to determine the changes in reactive metabolic "burden" that occur during growth and development with specific reference to changes in CYP activities identified in longitudinal phenotyping studies currently underway. Paired DNA samples from the

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extremes of the population distributions will be subjected to a concerted search by DNA sequencing and fragment analysis for single nucleotide polymorphisms (SNPs) that contribute to inter-individual variability in drug bioactivation. It is anticipated that the results of this program will allow critical periods of increased bioactivation and thus, potential vulnerability to idiosyncratic ADRs, to be identified for subsequent prospective investigations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PARAXANTHINE AND REPRODUCTIVE EFFECTS OF CAFFEINE Principal Investigator & Institution: Bracken, Michael B.; Professor and Head; Epidemiology and Public Health; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-AUG-1987; Project End 31-DEC-2004 Summary: (provided by applicant): Epidemiologic studies of antenatal caffeine consumption and adverse pregnancy outcomes have produced conflicting results. Most prior studies relied on self-reported caffeine consumption as a measure of caffeine exposure. However, caffeine metabolism and clearance greatly affect internal dose and, subsequently, fetal dose and consumption data may not provide a valid assessment of caffeine exposure. Because only 2.0% of caffeine is excreted as such in urine, there is considerable opportunity for error in estimating caffeine exposure using urinary caffeine levels. Paraxanthine, theophylline, and theobromine are primary metabolites of caffeine in humans and readily detected in body fluids. These metabolites may provide more reliable estimates of the biologically effective internal dose of caffeine. The specific aims of this application are: 1) to examine associations between intra-uterine growth retardation, preterm delivery, and birthweight with fetal caffeine exposure as estimated by cord blood serum paraxanthine; 2) to examine associations between serum paraxanthine, urinary caffeine, other metabolites, and self-reported caffeine intake; 3) to develop statistical models to determine the most precise predictive factors of caffeine exposure. We will link the analysis of serum caffeine metabolites with data previously collected on a large cohort of pregnant women (n=1775). Trained research assistants administered a baseline interview that included detailed questions on caffeine and decaffeinated beverage consumption, demographics, pregnancy history, medical history, tobacco and alcohol use, physical activity, use of nutritional supplements, and other reproductive risk factors. All women were asked to provide a urine sample at a baseline interview and cord blood was routinely collected and stored. In addition, women were randomly assigned to provide urine samples at 20, 28 or 36 weeks gestation. Medical records were abstracted to obtain information on obstetrical outcomes. The proposed work would conduct detailed biomarker analyses on samples collected from this cohort to provide a more complete understanding of effects of caffeine exposure on perinatal outcomes from a more accurate estimate of fetal exposure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHARMACOLOGY OF TRICHLOROETHYLENE METABOLITES Principal Investigator & Institution: Stacpoole, Peter W.; Professor of Medicine; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: This application focuses on the kinetics, metabolism and toxicology of two metabolites of trichloroethylene (TCE): dichloroacetate (DCA) and chloral hydrate

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(CH). The studies are predicated on several novel findings we made during the previous grant period that include 1) orally administered CH is catabolized to DCA in children, 2) CH and DCA alter each other's metabolism, 3) DCA is biotransformed to glyoxylate, 4) DCA inhibits maleyacetoacetate isomerase (MAAI, also known as GST- zeta), a key enzyme in tyrosine metabolism 5) MAAI inhibition by DCA may cause accumulation of intermediates in the tyrosine catabolic pathway that may be responsible for the hepatotoxicity and neurotoxicity of DCA and 6) this inhibition may also be responsible for prolonging the elimination half-life of subsequent DCA doses. The following specific aims capitalize on these discoveries: (1): Determine the in vivo kinetics and biotransformation of CH in health adults and the influence of CH and DCA on each other's metabolism and toxicity. We will examine several postulates regarding CH and DCA biotransformation in humans. [13C] CH and DCA will be administered at environmentally (mug/kg) and clinically (mg/kg) relevant doses to adults and the kinetics and metabolism of these chemicals will be studied. (2): Quantify the effect of DCA and CH on tyrosine catabolism in children and adults by measuring the plasma and urinary concentrations on tyrosine, its metabolites and the heme precursor aminolevulinate. We will test hypotheses relevant t the perturbation of the tyrosine catabolic pathway by xenobiotics, via inhibition of MAAI. Such inhibition should lead to accumulation to accumulation of potentially hepatotoxic and neurotoxic metabolites. (3): Compare and contrast the in vivo human data with similar experiments performed in intact cells. We will address hypotheses concerning CH and DCA kinetics and biotransformation and their effects on tyrosine metabolism in animals. (4): Elucidate the molecular mechanisms of DCA and CH biotransformation, and their effects of biotransformation enzymes, using cellular and subcellular fractions of rat and human liver. We will test postulates regarding early molecular events involved in DCA biotransformation and their effects of biotransformation enzymes, using cellular and subcellular fractions of rat and human liver. We will test postulates regarding early molecular events involved in DCA biotransformation and the mechanism by which DNA influences MAAI activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION OF BREAST CANCER WITH SPHINGOLIPIDS Principal Investigator & Institution: Schmelz, Eva M.; Cancer Institute; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): Breast cancer is the most common female cancer worldwide. Genetic defects clearly play a role in breast cancer etiology; however, epidemiological studies suggest a strong effect of the diet or components of the diet on the development and progression of breast cancer. The consumption of milk has been negatively correlated to the incidence of breast cancer. Sphingolipids are especially rich in milk and milk products. Sphingolipids regulate signaling pathways that have been shown to be dysregulated in cancer, mediating cell growth, differentiation, and cell death. Although the sphingolipid metabolites ceramide and sphingosine are toxic to cells at higher concentrations, no toxic side effects of even large amounts of dietary complex sphingolipids have been reported. This may be due to the limited digestion. It is these properties that make them ideal candidates for chemopreventive agents. We have shown earlier that dietary sphingolipids suppress early and late stages of chemically induced colon cancer. However, small amounts of the sphingolipid metabolites are transported into the body, and this may be sufficient to suppress breast tumor growth as suggested by epidemiological data. In the studies under this

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application, we will use cell models for early and late stages of breast cancer, i.e., MCF10A, MCF10AT1 and DCIS cells, to characterize the response of normal, untransformed breast epithelial cells to exogenous sphingolipids. A comparison of the response of transformed breast epithelial cells will identify changes in signaling pathways mediating cell growth that may be responsible for the higher sensitivity of transformed cells to sphingolipids. Moreover, we will evaluate if non-toxic concentrations of sphingolipid metabolites can enhance the effects of conventional chemopreventive and chemotherapeutic agents. These studies will establish markers for sphingolipid efficacy in suppression of breast tumor growth that can be used in future in vivo studies. We also will be able to determine which combination of sphingolipid metabolites and chemotherapeutic agents is most promising in reducing cell growth and/or inducing apoptosis in tumor cells but do not affect normal cells. The results from these studies will provide the tools to conduct in vivo studies, and hopefully will lead to the development a concept of breast cancer chemoprevention with dietary sphingolipids as a non-toxic alternative to conventional treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PRIMAQUINE-INDUCED HEMOLYTIC ANEMIA Principal Investigator & Institution: Mc Millan, David C.; Pharmacology; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-JAN-2001; Project End 31-DEC-2004 Summary: (Adapted from the Applicant's Abstract): Malaria is recognized as the most widespread parasitic infection in humans. Primaquine has been a major antimalarial drug for over 40 years due to its unique effectiveness against exoerythrocytic forms of the parasite. Its therapeutic value has grown in recent years with the development of resistance to alternate antimalarial drugs such as chloroquine and because of its utility in the treatment of Pneumocystis carinii pneumonia in AIDS patients. However, primaquine therapy has been severely limited because of its capacity to induce methemoglobinemia and hemolytic anemia, particularly in patients with glucose-6phosphate dehydrogenase deficiency. It has long been known that the hemotoxicity of primaquine is due to the action of metabolites and not the parent compound. However, the toxic specie(s) have not been identified and little is known about the mechanism underlying red cell injury. In collaborative studies with individuals at Walter Reed, we have examined the hemotoxicity of known and putative phenolic metabolites of primaquine and have observed potent and direct-acting hemotoxicity. In other studies, we have synthesized 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH) and found that this metabolite was also a direct-acting hemotoxicant. We now propose to investigate the mechanism of red cell damage induced by these metabolites and examine their metabolic formation in vitro. The hypotheses under test in this proposal are: 1) that two pathways of oxidative damage, initiated by lipid peroxidation and protein thiol oxidation, occur in the red cell; and 2) that quinone/quinoneimine metabolites act via lipid peroxidation, whereas the N-hydroxy metabolite acts via protein thiol oxidation. Three aims are presented: 1) to characterize the hemolytic response and pattern of oxidative injury induced within red cells by each type of primaquine metabolite; 2) to elucidate the oxidative metabolism of primaquine in rat and human liver microsomes and hepatocytes, and identify GYP isoforms responsible for primaquine metabolism; and 3) to identify intracellular and external cell surface alterations that correlate with phagocytosis of primaquine metabolite-damaged red cells by cultured splenic macrophages. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTECTION AGAINST BENZO{A} PYRENE TOXICITY BY OLTIPRAZ Principal Investigator & Institution: Ritter, Joseph K.; Associate Professor; Pharmacology and Toxicology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-APR-1996; Project End 31-MAY-2005 Summary: (Adopted from the Applicant's Abstract): Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants found in certain foods, cigarette smoke and combustion products of oil, coal, and gas. The prototype PAH, benzo[a}pyrene (B[a]P) is one of the most potent chemical carcinogens known in animal tumorigenesis assays. The level of hepatic glucuronidating activity towards benzo[a]pyrene phenols, quinols, and dihydrodiols, appears to represent a key risk factor underlying susceptibility to B[a]P's genotoxic effects. Evidence has been obtained that oltipraz (4-methyl-5-pyrazinyl- 1 ,2-dithiole-3-thione), an investigational cancer preventive drug, may act in part through induction of hepatic UDPglucuronosyltransferases (UGTs) with activity towards B[a]P metabolites. UGTs in the UGT1 family appear to be particularly critical. A previously identified UGT1 isoform, UGT1A7, appears highly active in the glucuronidation of B[a]P metabolites. Specific Aim 1 will directly compare the activity of recombinant UGT1A7 to other UGTIA isoforms to determine if any other of these forms are potentially relevant either in protection against B[a}P or in the response to oltipraz. The UGTs will be expressed in HEK293 cells and tested for activity in vitro against key metabolites of B[a]P and other carcinogenic PAHs. Specific Aim 2 will study whether the corresponding human UGT1A isozymes are also active. In addition, variation in human liver microsomal UGT activities towards B[a]P metabolites will be characterized in relation to expression of specific UGTIA subsets (UGTIAI, UGTIA3-.1A5, UGTIA6, and UGT1A7-lO). Specific Aim 3 will continue studies of the mechanisms controlling the hepatic expression of rat UGT1A6 and UGT1A7 by oltipraz and PAHs. To characterize possible species differences in regulation, a study will be performed to assess the responsiveness of human UGT1As in cultured human hepatocytes. Specific Aim 4 will develop novel in vivo approaches to assess the functional significance of UGT1A deficiency and replacement of UGTIA7 liver expression for B[a]P excretion and mutagenesis. To examine the influence of UGTIA deficiency and monitor B[a]P induced mutagenesis in a short term in vivo assay, a special strain of rat will be developed by crossing the Gunn rat onto the Big Blue lad transgenic F344 rat background. Replacement of UGT1A7 expression in liver will be achieved through the use of a recombinant adenovirus 5 engineered to express UGT1A7. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REACTIVE METABOLITES AND DRUG TOXICITY Principal Investigator & Institution: Hanzlik, Robert P.; Professor; Medicinal Chemistry; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2002; Project Start 01-AUG-1978; Project End 31-MAR-2004 Summary: Many simple organic molecules containing phenyl substituents or benzene rings become cytotoxic upon biotransformation to reactive electrophilic metabolites. Prime examples include halothane, acetaminophen and bromobenzene (BB). Their hepatotoxicity is correlated with covalent binding of reactive metabolites to cellular proteins. As a start toward elucidating the biochemical mechanism(s) of their cytotoxicity we identified the structures of ten adducts of BB metabolites to protein-SH groups; most arose via quinone metabolites, but we also found that BB-3,4-oxide (BBO),

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thought to be the primary "toxic" metabolite of BB, alkylates histidine and lysine as well as cysteine residues of rat liver proteins. Key questions concerning the mechanism of cell injury by reactive metabolites include the identity of the proteins they target and the functional consequences of their covalent modification. We recently identified several rat liver proteins targeted by BB metabolites. One was a nonspecific esterase also known to be a target for metabolites of halothane and molinate. Another, surprisingly, was epoxide hydrolase, which is supposed to detoxify BBO. To address the mechanism of BB-induced cytotoxicity it is essential to expand this list by identifying other liver proteins targeted by BB metabolites. In doing so we will emphasize mitochondrial proteins but will continue to explore cytosolic and microsomal proteins. To facilitate recognition of BBO adducts, we raised antibodies to p-bromophenylcysteine and demonstrated their utility for western blotting; we will now develop antibodies to p-bromophenyl-histidine and p-bromophenyl-lysine as well. These antibodies, coupled with [C14]-BB, will give us a broad and powerful means for finding and identifying those proteins of greatest toxicological interest. Very little is known about the chemistry and consequences of protein adduction by reactive metabolites. Thus we will elucidate in detail the specific site(s), metabolite(s) and linkage(s) involved in adduct formation for select BB target proteins. For those target proteins which are enzymes, we will evaluate the effect of adduction on catalytic activity to assess its potential contribution to cell injury. Comparing the proteins modified by bromobenzene to those modified by other small bioactivated toxins may reveal the existence, or the lack of, a "common pathway" for chemically-induced cytotoxic responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATING CEREBRAL MICROCIRCULATION BY ASTROCYTES Principal Investigator & Institution: Harder, David R.; Director; Physiology; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-APR-1985; Project End 31-MAR-2005 Summary: The brain relies almost exclusively on oxidative metabolism to support neural activity and is therefore critically dependent upon adequate blood flow. The hypotheses to be tested in this competing renewal are that astrocytes sense neural activity via spillover of excitatory transmitters and release dilatory metabolites to adjacent capillaries, thereby increasing distribution of blood flow to active neurons, and secondarily, that epoxygenases metabolites of astrocytes are mitogenic and endothelial cells. We have isolated, cloned and sequenced a cytochrome P450 gene of the 2C family of epoxygenases which catalyzes formation of vasodilatory epoxyeicosatrienoic acids (EETs) from arachidonic acid (AA). EETs increase K+ channel activity to hyperpolarize and relax arteriolar smooth muscle, and are released from astrocytes stimulated by glutamate. Inhibition of EETs formation by site directed molecular or pharmacological mechanisms prevents increase in nutritive blood flow measured by laser-Doppler flowmetry. The specific aims of this grant are three-fold. (1) We will determine the ability of astrocyte-released EETs to inhibit normal autoregulatory mechanisms caused by vasoconstrictors, shunting blood flow by opposing the depolarization of cerebral arterioles at physiological pressures. Nitric oxide (NO) also hyperpolarizes arterial muscle by mechanisms which include increasing outward K+ current, thus may amplify the hyperpolarizing and dilator action of EETs; therefore, the additional contribution of NO to countering autoregulatory mechanisms in cerebral vessels will be examined. (2) To begin to investigate the cellular and ionic mechanisms behind EETs induced modulation of autoregulation, we will examine the capacity of astrocyte- produced EETs to modulate K+ and Ca2+ channel activity and [Ca2+]i in cerebrovascular smooth

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muscle and endothelial cells. (3) Preliminary data show that EETs also initiate mitogenic activity of capillary endothelial cells and stimulate tube formation in co-culture with astrocytes, providing a mechanism to increase capillary endothelial cells and stimulate tube formation in co-culture with astrocytes, providing a mechanism to increase capillary density in areas of high neural activity. Therefore, the signal transduction cascade responsible for cellular growth by EETs increased from astrocytes will be examined by a combination of cellular, molecular, genetic and in vitro techniques to test the hypothesis set forth above. The physiological significance of these phenomenon cannot be over-stated. While many mechanisms are described involving formation of dilatory paracrine substances in the metabolic control of nutritive cerebral blood flow, we have gathered a wealth of data supporting a role for astrocytes and their ability to metabolize AA to vasoactive epoxides. Our investigations will provide vital new information defining mechanisms by which epoxygenase metabolites of astrocytes inhibit autoregulatory vasoconstriction of cerebral arteries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF PHOSPHOLIPASE A2 NUCLEAR TARGETING Principal Investigator & Institution: Leslie, Christina C.; Senior Faculty Member; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: Cytosolic phospholipase A2 (cPLA2) is a key regulatory enzyme that mediates agonist-induced arachidonic acid release. Arachidonic acid itself is an important intracellular regulator and can also be converted to a variety of potent lipid metabolites, the eicosanoids. This occurs through the lipoxygenase and cyclooxygenase pathways for the production of leukotrienes, and prostaglandins. These oxygenated metabolites of arachidonic acid play crucial roles in normal homeostasis and in mediating the inflammatory response. Intracellular levels of arachidonic acid are tightly controlled and cPLA2 is subject to complex mechanisms of activation that are poorly understood. cPLA2 is post-translationally regulated by phosphorylation and by levels of intracellular calcium. Agonist-induced serine phosphorylation of cPLA2 on Ser505 by mitogen activated protein kinase enhances cPLA2 activity. An increase in intracellular calcium triggers cPLA2 activation by inducing its translocation from cytosol to the nuclear envelope/endoplasmic reticulum (ER), where 5-lipoxygenase and cyclooxygenase are also localized. Calcium-induced binding of cPLA2 to membrane is mediated by the calcium-dependent phospholipid binding domain (CaLB or C2 domain) on the amino terminus of cPLA2. Although the role of the CaLB domain in membrane binding is established, the mechanisms involved in the specific targeting of cPLA2 to nuclear membrane/ER are not known, and their elucidation is the main objective of this proposal. The specific aims of the proposal include defining the role of the C2 domain and regions downstream of the C2 domain (including the plekstrin homology domain of cPLA2) in regulating nuclear targeting, and identifying proteins that bind cPLA2 and determining their role in regulating cPLA2 activity and translocation. Potential cPLA2 binding proteins have been identified using a biochemical approach and screening a phage display library. Domains of cPLA2 that are important in regulating nuclear targeting will be identified using site-directed mutagenesis. Effects of the mutations on agonist-induced arachidonic acid release and translocation of cPLA2 to the nucleus will be evaluated by expression in mammalian cells and in insect cells using baculovirus. Purified mutant constructs will also be evaluated for effects on enzymatic activity and lipid vesicle binding. Understanding the regulation of cPLA2 will provide greater insight into the signal transduction

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mechanisms involved in lipid mediator production, and lead to potential methods for pharmacological modulation of the inflammatory process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF PROTEIN KINASE C AND CELL CYCLE BY PAH O-QUINONES AND ROS Principal Investigator & Institution: Kazanietz, Marcelo G.; Associate Professor; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-AUG-2002; Project End 31-JUL-2007 Summary: Protein kinase C (PKC) isozymes are a family of related serinethreonine kinases that play an important role in the control of cell proliferation, death and differentiation. PKC isozymes are the target for the phorbol esters and are implicated in the molecular mechanisms of tumor promotion. A main objective of this proposal is to evaluate whether PAH oquinones and the ROS they generate affect PKC activity and signaling events resulting in phenotypic consequences on cell growth. Our preliminary data shows that PKC isozymes are direct targets for PAH o-quinones, suggesting that these compounds have epigenetic effects that could explain why PAH may act as complete carcinogens. Our studies will assess effects of these PAH metabolites on PKC in vitro as well as in bronchoalveolar cells. In Aim#1 we will evaluate the effect of DMBA-3,4-dione, BA-3,4-dione and BP-7,8-dione, which correspond to Class I, II, and III o-quinones, respectively on the activity of individual PKC isozymes expressed in baculovirus. We will assess whether the o-quinones or the ROS they generate affect PKC kinase activity and cofactor-dependent binding of phorbol esters. In Aim#2 we will evaluate whether PAH o-quinones or ROS affect translocation of PKC and activate or inhibit PKC isozymes in cells. We will take advantage of AKR1A1 overexpressors to determine whether o-quinones or ROS generated intracellularly affect the phosphorylation of endogenous PKC substrates (myristoylated alanine-rich C kinase substrates) and PKC-mediated AP-1 activation. In Aim # 3 we have shown that the phorbol ester, phorbol-12- myristate-13-acetate (PMA), inhibits the proliferation of bronchoalveolar cells by causing G1 arrest. Individual PKC isozymes will be infected into bronchoalveolar cells to identify the isoform responsible for this PMA effect. We have shown that PAH o-quinones inhibit PKC in vitro and stimulate S phase entry in bronchoalveolar cells. Therefore we will test the hypothesis that PAH o-quinones or ROS dysregulate components of the cell cycle controlled by PKC. We will correlate increased progression through G1 phase with changes in the expression of G1 phase cyclins and cdk inhibitors and the consequences for cdk activity and Rb phosphorylation. Importantly our studies will determine the effects of individual PKC isozymes on the proliferation of human lung epithelial cells and whether PAH oquinones dysregulate PKC mediated control of the cell cycle. The Project is reliant on the Bioanalytical Core-B for quality control of PAH-metabolites and determining PAH oquinone concentrations in cell culture. The Project is reliant on Core-A for biostatistical analysis of the in vitro and in vivo effects of PAH o-quinones and ROS on PKC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RESOURCE FOR DEVELOPMENT OF BIOMEDICAL MASS SPECTROMETRY Principal Investigator & Institution: Turteltaub, Kenneth W.; Biology & Biotechnology Res; University of Calif-Lawrnc Lvrmr Nat Lab Lawrence Livermore National Lab Livermore, Ca 945509234

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Timing: Fiscal Year 2004; Project Start 01-SEP-2000; Project End 31-AUG-2009 Summary: (provided by applicant): The National Resource for Accelerator Mass Spectrometry (AMS) was established in 1999 to enable biomedical researchers to accurately quantify very low levels of radioisotopes while exploring fundamental issues in biology. In this renewal, we will expand our present capabilities by developing methods to study biochemical pathways and cellular processes at the level of the single cell and small groups of cells, which will allow our collaborators to study the effect of aging in yeast. The Resource will also develop methods to quantify endogenous processes, such as protein and DNA oxidation in higher organisms. This will facilitate the study of inflammatory diseases ranging from atherosclerosis to neurodegenerative disorders to cancer. To further these goals, we will develop a sample presentation technology that will enable the analysis of much smaller samples than can be currently processed, as well as techniques for speciation of biomolecules in such samples. Throughout the tenure of the grant we will continue to provide a resource to the research community that will include service to investigators familiar with AMS, training of investigators in the technology and dissemination of the Resource. Towards these goals, our specific aims are to: 1.) Develop protocols for the online combustion of eluents from separatory instruments and couple the products to a gas accepting ion source to increase the sensitivity of AMS. 2.) Increase the value and information content of AMS measurements by quantitating isotope content in isolates of uniformly isotopelabeled systems or by quantitating derivatized biomarkers of modification or function on specific macromolecules. 3.) Provide quantitation of effector and effect in biological systems using multiple isotopic tracers within sampled materials. We will achieve this by developing a robust and higher throughput process for 3H sample preparation and by leveraging against other funded isotope measurements at the Center for Accelerator Mass Spectrometry (CAMS). 4.) Provide high throughput and precise quantitation for collaborative and service users. OVERALL CRITIQUE: This competitive renewal application for the Resource for Development of Biomedical Mass Spectrometry seeks to extend the applications of Accelerator Mass Spectrometry (AMS) for the study of biological systems. Three Core Technological R & D Projects focus on the development of improved sample processing and handling approaches and their application to problems in cell biology and biomarker analysis. These Core R & D Projects are coupled to a set of nine collaborative projects that provide biological motivations for extending the applications of AMS. Overall, this application proposes innovative approaches to significant biomedical problems to be performed by a highly accomplished team. It is clear that the Resource is very successfully developing AMS as an important new tool for the study of biological systems. Progress in the current research period has established a robust and viable national Resource and demonstrated important applications in toxicology and metabolism. The proposed technological R & D in this renewal application aims to broaden both the instrumentation capabilities and the sample preparation and analysis methods to extend AMS into new areas. This is a unique and significant technological Resource with significant outreach to the biomedical community. Presentations at the site visit clarified several technical issues raised in the application. The site visit gave the strong impression of a well integrated team of senior and more junior researchers who interact well with each other and with collaborators. The principal investigator (PI) and co-Investigator/Director are outstanding scientists and world leaders in the field of AMS, and their enthusiasm, as well as that of the team, was evident. Presentations by several collaborators were also very useful for emphasizing the biological impact of the technological R & D being proposed, as well as tight coupling between these collaborations and the Core Projects. Clear evidence of institutional support for AMS in general and this Resource, was

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evident. In the preceding inaugural research period, the AMS Resource sought to demonstrate methods for the use of AMS in biomedical research, to expand their measurement capabilities and capacities, and to increase collaborative access to the instrument. The major biological applications for these Aims centered on the characterization of the metabolism of vitamins and environmental toxins. A major focus was the binding and metabolism of heterocyclic amines, performed via collaborations with several internal and external collaborators. AMS was used to study the metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans and rodents, and to identify plasma and urine biomarkers of PhIP exposure. This work, conducted in collaboration with NIH-funded researcher, Dr. James Felton (LLNL), has led to several publications. This work was expanded to aid the development of strategies for reducing the amount of DNA damage following exposure to PhIP in collaboration with Dr. Andrew Clifford (UC Davis). The metabolism of several other environmental toxins, including acrylamide, orthophenylphenol, benzene, aflatoxin, atrazine, and diisopropylfluorophosphate, were the subject of additional collaborations and publications. The micronutrients, folic acid and beta-carotene, were also studied in collaborative projects that took advantage of the unique ability of AMS to detect very low levels of metabolites in biological samples. Significant methodological developments targeting the problems of trace laboratory contaminants, post-labeling methods, and streamlined methods to convert organics species for AMS were also achieved during the current research period, and have enhanced the usefulness of AMS for routine analysis of biological samples. An active collaborative and service portfolio is serving to define the needs for new capabilities for the biomedical applications of AMS and providing instrument access to the biological community. Overall, progress during the current research period was viewed as excellent. In this competitive renewal proposal, the AMS group proposes three Core R & D Projects. The first Core Project aims to address issues associated with the sample spectrometer interface. For coupling to separations instruments, an online sample and combustion interface to a gas sputter ion source will be developed. The gas-accepting ion source has limitations with regard to maximum ion current compared to ion sources for solid samples, but will allow the continuous analysis of very small samples eluting from microbore separations devices. For higher resolution analysis, improved methods will be developed for converting gases to solids, especially for tritium analysis, which is a significant extension of the carbon analysis that was the subject of the initial research period. While specific details of the coupling approaches outlined in the proposal were somewhat vague, and the amount of potential sample carryover undetermined, the review committee had a high degree of confidence that these challenges would be successfully addressed by this team. The review committee was enthusiastic about this Core Project. In the second Core R & D Project, AMS will be applied to the quantitative analysis of trace isotope in single cells or ultimately, cell parts. The proposed approach involves Aims for the extensive labeling of yeast cells with 14C, the isolation of single cells or organelles, analysis of samples using HPLC-AMS, and analysis of samples using SPE-AMS. These Aims will be demonstrated by measuring the ratio of NAD and NADH in yeast cells to evaluate the role of caloric restriction of these metabolites and by evaluation of the asymmetric segregation of oxidized proteins in budding yeast cells. This was viewed as a highly innovative project with a very significant goal, the extension of AMS to single cell analysis. The review committee's enthusiasm was tempered by the presence of several technical scientific issues, including the consequences of heavy labeling with radioactive isotopes, especially for studies of oxidized proteins and uncertainties with the quantification of cell mass. A clear statement of a validation process, in the absence of preliminary data regarding resolution of these challenges, would have strengthened this project. While the rationale for the choice of a yeast cell biology problem as a simple

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system was recognized by the committee, there was concern about the extensive effort required to answer fairly narrow biological questions. This project was seen as an innovative approach to a significant area but with these uncertainties, overall enthusiasm was moderate. The third Core R & D Project aims to develop methods to identify and monitor biomarkers of diseases based on modified DNA and proteins. The approach includes aims to develop methods for the pre-labeling and post-labeling of DNA and proteins and to demonstrate these via collaborative projects involving inflammatory diseases and ischemic reperfusion damage. This was viewed as a project with high significance, important goals, and very good collaborative interactions. The development of specific post-labeling strategies for analysis of DNA and protein oxidation products, with sensitivity that is orders of magnitude better than that currently available, was seen as particularly significant. The primary challenge will be to develop appropriate specificity, either through the labeling methods or the separation methods. There are clear issues with achieving specificity with post-labeling, although at the site visit, the team presented several encouraging approaches for achieving this specificity, especially for protein adducts. The detection of DNA adducts using enzymatic methods were seen as very dependent on the specificities of the enzymes used and, while promising data was presented at the site visit, there was some concern about the generality of the methods proposed. More information about alternative enzymes and their potential specificities would have alleviated these concerns. In view of the significant biological impact of this project, and the active involvement of biological collaborators, the review committee was enthusiastic about this project. Nine collaborative projects were presented to advance or test the technology being developed by the Resource. All represented important and interesting biological problems. Many clearly provided the required drivers for the Core Technological R & D, while for others this drive was not clear or absent, and these are more appropriately classified as service projects. Presentations at the site visit provided excellent examples of the intellectual contributions of the collaborators to the development and focus of the Core R & D Projects. Collaborative Project 1 (Purines and purine anti-metabolites in malaria; V Schramm) proposes to use 14C and 3H AMS to track the metabolism of purines in Plasmodium falciparum in order to understand metabolic pathways and to develop metabolic inhibitors. This is a very strong collaboration with an NIH investigator and a clear rationale for the use of AMS that will clearly drive the R & D of Core Project 1. Collaborative Project 2 (Neuronal turnover in the adult brain; J Friesen) aims to use 14C AMS and the bomb curve to estimate neuronal proliferation in adult brains. While a very interesting and important biological problem, it was not clear from the information provided in the application how this collaboration drives the core R & D and it was seen as a more appropriate service project. Collaborative Project 3 (Mechanisms of gene silencing using small interfering hybrids; L Dugan) proposes to use AMS to quantify the uptake of small inhibitory RNA-DNA hybrids by mammalian cells. Fluorescence and PCR-based methods to assess this have been unsuccessful. This logical application of cellular AMS, supported by LLNL internal funding, is tied to Core Project 2. Collaborative Project 4 (Quantification of osteoporosis therapeutics; H De Luca) will use tritium AMS to study the pharmacokinetics of vitamin D variants that may stimulate bone resorption. This collaboration supports Core Project 1, but will ultimately have a service-like nature. Collaborative Project 5 (Detection of ethylene oxide DNA adducts; K Brown) aims to use dual 14C and 3H labeling to simultaneously monitor endogenous and exogenous EtO DNA adduct formation. This was seen as a very strong collaboration that clearly drives Core Project 1 and addresses an important problem. Collaborative Project 6 (Phagocyte pathways for oxidative stress; J Heineke) aims to use AMS to measure protein oxidization products resulting from inflammation. The presentation given by Dr. Heineke highlighted the contribution of collaborators to the

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development of Resource goals. This was seen as a very strong collaboration driving the biomarker Core Project 3. Collaborative Project 7 (Quantification of oxidized 8-oxo-2' deoxyguanine lesions in DNA; C Burrows) aims to quantify DNA adduct oxidation products and is tied to biomarker Core Project 3. While this project was discussed to some extent in the description of Core Project 3, few details were provided about this collaboration. Collaborative Project 8 (Quantification of reperfusion injury; D MochlyRosen) proposes to use AMS to assess protein oxidation as a marker of reperfusion injury. It also proposes to evaluate the effect of inhibitory peptides derived from protein kinase C (PKC) on tissue reperfusion damage. This project has both collaborative and service components, and is tied to Core Project 3. Collaborative Project 9 (Quantification of cysteine sulfenic acids; J Eiserich) aims to use AMS for the analysis of protein sulfenic acid labeling. This collaboration, which appears to be at a preliminary stage, supports Core Project 3, and will depend on the availability of specific post-labeling methods. The Service, Training, and Dissemination plans were seen as very strong, with clear plans in place for allocating responsibilities and monitoring these activities. Active dissemination through the recruitment of new collaborators was seen as especially useful. Clear procedures for prioritization handling of service activities were presented. Excellent performance in the current research period gave the review committee great confidence that these plans will be carried out. Enthusiasm was very high for these components. The organizational structure and administration was seen as very strong. The PI and coInvestigator/Director are outstanding senior scientists with excellent records of accomplishment. The addition and integration of several newer scientists was seen as clear evidence that the Investigators are positioning the Resource to address new types of biological problems. The external advisory committee appears strong and engaged. Plans to rotate membership to incorporate expertise in new areas were seen as sound. The service and training plans were very well thought out. The Resource management does an excellent job of obtaining and leveraging institutional support for both personnel and facilities. TECHNOLOGICAL RESEARCH AND DEVELOPMENT: CORE PROJECTS: Core Project 1: Sample Spectrometer Interface Development Priority Score: 151 While AMS at LLNL has been extremely successful at quantifying biological samples, further instrumental advances are required to examine smaller sample sizes and to take advantage of analytical separations. In addition, the previous research cycle of this Resource was focused primarily on 14C quantitation with minor effort directed at 3H quantitation. In this renewal period, the PI proposes to develop appropriate sources and sample preparation approaches to use a gas-accepting source with the existing AMS system to allow for increased throughput in 3H quantitation, capabilities for dual 3H and 14C quantitation, and potential for coupling to external separation methods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF COX2 IN LUNG CANCER ANGIOGENESIS AND METASTASIS Principal Investigator & Institution: Johnson, David H.; Professor of Medical and Surgical Oncolo; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2002 Summary: (provided by applicant): Upregulation of cyclooxygenase-2 (COX-2) has been shown to be an early event in colon carcinogenesis. Multiple lines of evidence suggest that COX-2 upregulation is also an early event in the development of non-small cell lung cancer (NSCLC). In humans, COX-2 expression is upregulated in about one-third of atypical adenomatous hyperplasias and carcinoma in situ specimens obtained from lung, and in 70 percent-90 percent of invasive adenocarcinomas of the lung. The

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proportion of adenocarcinoma cells with increased COX-2 expression is much greater in lymph node metastases than in the corresponding primary tumors. Preclinical data indicate tumors with upregulation of COX-2 synthesize high levels of prostaglandin E2 (PGE2). High PGE2 levels are associated with increased production of proangiogenic factors and enhanced metastatic potential. These findings suggest that an increase in COX-2 expression may play a significant role in the development and growth of NSCLC and possibly with the acquisition of an invasive and metastatic phenotype. Specific inhibitors of COX-2 are now available and may prove useful in understanding the role of eicosanoids in lung cancer pathogenesis as well as in the management of established malignancies and possibly as chemopreventive agents. However, there are limited data on the function of tumor overexpression of COX-2 in lung cancer patients, and no data on whether selective inhibitors actually affect COX-2 activity within the targeted tumor in vivo. We propose to study the effects of specific inhibitors of COX-2 on COX-2 expression, serum VEGF levels and urinary metabolites of PGE2 in patients with lung cancer. Our results will serve as a prelude to clinical trials in which these agents are employed therapeutically. Our preliminary data suggest inhibitors of COX-2 rapidly reduce enzyme activity as determined by measurements of urinary metabolites of prostaglandin and assessment of enzyme activity within the tumor itself. These experiments will expand upon these preliminary results. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SAME AND FOLATE DEFICIENCY IN ALCOHOLIC MIRCROPIGS Principal Investigator & Institution: Halsted, Charles H.; Professor; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The overall hypothesis of the proposed research is that the pathogenesis of alcoholic liver disease (ALD) is regulated by changes in intrahepatic methionine metabolism that result from chronic ethanol consumption. Previously, we found that the combination of dietary ethanol and a folate deficient diet both maximized perturbations in methionine metabolism and accelerated the development of ALD in micropigs. The objective of the proposed research is to prove the hypothesis by demonstrating that the biochemical and histopathological features of ALD can be prevented or reversed by provision of supplemental S-adenosylmethionine (SAM) or folic acid to pigs maintained on chronic ethanol feeding with and without folate deficient diet. The first specific aim is to determine the efficacy and metabolic effects of intervention with SAM or folic acid in the prevention and treatment of ALD in micropigs. The second specific aim is to study the effects of abnormal methionine metabolism on known mediators and signal pathways of alcoholic liver injury. Micropigs will be fed diets with ethanol that are either folate sufficient or deficient and with or without supplemental SAM during development of liver injury, and with or without supplemental SAM or folic acid after development of alcoholic liver injury. Data collection will include methionine metabolites in plasma and liver, liver histopathology, markers of inflammation, necrosis, and apoptosis, products of lipid, protein, and DNA oxidation, antioxidant enzymes, and signal pathways of apoptosis. The data will be interpreted to confirm the role and establish potential mechanisms for abnormal methionine metabolism in the pathogenesis of ALD. While furthering understanding of interactions of methionine metabolites on pathways of liver injury, the project may establish novel approaches to the prevention and treatment of ALD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SCREENING HERBS FOR DRUG INTERACTIONS 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 2002; Project Start 05-JUN-2001; Project End 31-MAY-2004 Summary: The use of herbal agents by the lay public and medical professionals has accelerated in the last decade. Additionally, there has been increasing interest by the NIH National Center for Complementary & Alternative Medicine (NCCAM) and others in the safety and efficacy of herbal medicines in the treatment of a variety of medical and psychiatric conditions. It has also become evident that herbal medications are being used concomitantly with conventional prescription and over-the-counter medications. However, the systematic evaluation of the potential of these agents to interact with conventional medications has been generally neglected. Compounding this problem is the fact that even single entity herbal products can contain a multitude of naturally occurring chemicals which serve as candidates for potential herb-drug interactions by inhibiting or inducing specific hepatic isozymes. Numerous reports document the importance of pharmacokinetic interactions involving inhibition or induction of the cytochrome P450 (CYP) enzyme system. Importantly, recent publications have documented that clinically significant herb-drug interactions can occur. Prominent examples include herb-induced reductions in plasma concentrations of the anti-HIV medication indinavir and the immunosuppressant cyclosporine by St. John's wort (Hypericum perforatum). In vitro screening studies are of limited value due to difficulties in approximating physiologic concentrations, assessing the influence of nonhepatic metabolism, and accounting for the contribution of active metabolites. However, based upon findings of the effects of concurrently administered herbs on the metabolism of enzyme specific probe drug substrates alprazolam (CYP 3A4) and dextromethorphan (CYP 2D6), the potential specificity and magnitude of CYP enzyme inhibition and/or induction can be determined in normal volunteers. In a preliminary study in human subjects using this validated probe drug technique assessing inhibitory effects only, the investigators found no effects of St. John's wort on CYP 3A4 or CYP 2D6. In the present proposal, the 10 most commonly used herbal products in the US will be systematically evaluated for inhibition of CYP 3A4 and 2136, and induction of CYP 3A4. Collectively, these enzyme systems are involved in the metabolism of approximately 80% of all marketed medications. A combination of probe drugs will be given to normal volunteers both in the absence and presence of herbal medications. The plasma and urine concentration of these agents and their respective metabolites will be determined in order to evaluate individual herbal products degree and specificity of enzyme inhibitory or inductive effects. This data will fill a void regarding the relative safety of combining specific herbal agents with conventional medications and will serve as the basis for further investigations of other isozymes and herb interactions. Further, the proposed studies will complement existing and future NCCAM studies of agents such as St. John's wort and Gingko biloba. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SELENIUM AND PROSTATE CANCER APOPTOSIS PATHWAYS Principal Investigator & Institution: Lu, Junxuan; Associate Professor; Hormel Institute; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2004; Project Start 01-SEP-2004; Project End 31-AUG-2008

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Summary: (provided by applicant): Induction of prostate cancer (PCa) cell apoptosis can be an effective approach for the chemoprevention and treatment of this disease because clinically PCa is often characterized by low cell proliferation rate and does not respond to standard anti-mitogenic chemotherapy. The goal of this project is to elucidate the biochemical and molecular pathways through which cancer chemopreventive agent selenium (Se) induces P53-dependent, caspase-mediated PCa apoptosis. We hypothesize that wild type P53 tumor suppressor protein and its Ser15 phosphorylation (Ser15P) are crucial determinants for inducing caspase-mediated apoptosis by genotoxic Se metabolites such as selenite and are not critical for apoptosis induced by the nongenotoxic methyl Se. We further hypothesize that selenite exposure induces superoxide generation and DNA strand breaks which trigger P53 Ser15P mediated by ATM and/or ATR protein kinases and signaling to caspase activation. Three specific aims will be accomplished. 1. To establish a causal relationship of selenite induction and/or ATR as the protein kinases for P53 Ser15P. 2. To critically test that caspase-mediated apoptosis by selenite is dependent on wild type P53 and its Ser15P and that apoptosis induced by methyl Se is P53-independent. 3. To delineate the signaling cascade(s) of selenite induction of caspase activation, especially the roles of the mitochondria intrinsic pathway and the death receptor extrinsic pathway. A variety of approaches including enzyme inhibitors, RNA interference of ATM/ATR and P53 and other genetic manipulations will be used. Accomplishing these aims will be crucial for charting a roadmap for studying how Se metabolites selectively bring about the demise of PCa cells depending on their P53 status. The mechanistic insights will help to guide the design of novel Se agents with better efficacy and tolerance and to interpret the results of PCa prevention trials with Se. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STABLE ISOTOPE LABELED PROTEINS AND DRUG DISPOSITION Principal Investigator & Institution: Abramson, Fred P.; Professor; Pharmacology; George Washington University 2121 I St Nw Washington, Dc 20052 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: The 1990s has seen the arrival of many protein therapeutic drugs. In response to the increased availability and use of these macromolecular pharmacological agents, the FDA is moving its review of these products from the "biologicals" category into the "drugs" category. As such, increased emphasis on physiological disposition would be expected. Yet, suitable methods for studying protein drug disposition do not exist. Radioisotopes, bioassays, and immunoassays all present problems. In contrast, a new experimental approach developed in this laboratory promises more definitive results, especially in the area of metabolism. This approach uses uniformly stable-isotope labeled proteins as test species, separates biological fluids with HPLC, and quantifies stable- isotope enriched chromatographic peaks with Chemical Reaction Interface Mass Spectrometry (HPLC/CRIMS). Uniform labeling ensures that all metabolites of the protein can be detected. Such proteins can be generated by growing a suitable cell line in stable-isotope labeled medium. The three protein disposition studies proposed are: (1) the angiotensinogen cascade and the effect of a protease inhibitor on that cascade; (2) the intracellular proteolysis of fibroblast growth factor-1 (FGF-1); and (3) the kinetics and metabolism of insulin connecting peptide (C-peptide). The purpose of the first study is to demonstrate how the uniformly labeled protein + HPLC/CRIMS analysis provides a comprehensive survey of the consequences of an inhibitor of angiotensin converting enzyme (a dipeptidyl carboxypeptidase). In the FGF-1 experiments, the goals are to generate an unambiguous profile of the intracellular metabolites produced in NIH 3T3

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cells, evaluate which of these peptide metabolites contribute to the activity of FGF-1, and identify the active species using electrospray mass spectrometry. Recently, Cpeptide was shown to lessen the vascular and neurological consequences in experimentally-diabetic rats. Because C-peptide has long been believed to be inactive, little information exists about its kinetics, and nothing is known about its metabolic fate. Overall, this work will show he capabilities of a new strategy by which a more accurate understanding of the fundamental pharmacology of an increasingly important class of drugs can be gained. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSFER OF METABOLITES THROUGH LENS GAP JUNCTIONS Principal Investigator & Institution: Goldberg, Gary S.; Physiology and Biophysics; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): Lens cells require gap junction proteins to communicate with each other and develop properly. In particular, connexin43 (Cx43), Cx46, and Cx5O are needed for normal lens development and function. Knockout or mutations of genes encoding these connexins cause cataracts in mice and humans, respectively. Cx43, Cx46, and Cx5O form channels with different permeability characteristics. We hypothesize that transjunctional molecules needed for lens development pass through lens gap junctions, and that cataracts can result from an inability of cells to share these signals. We propose to identify and compare the transfer of endogenous metabolites that pass through these channels. This new research program will introduce a particularly innovative technological approach to investigate the role of gap junctions in the lens. In Specific Aim 1 we will determine the single channel size, total conductance, and number of functional gap junction channels expressed by mammalian cells transfected with connexins that are expressed in the lens. This will be done by standard dual voltage-clamp whole-cell recording methods. In Specific Aim 2 we will identify, quantitate, and compare the transfer of endogenous metabolites that pass through channels formed by connexins expressed in the lens. This will be accomplished with a novel strategy to identify and quantitate the transfer of endogenous molecules that pass through gap junctions between cells within a given time frame. Measurement will be taken at several time points to measure and compare the rates of transfer of specific metabolites through gap junction channels formed by Cx43, Cx46, and Cx5O. These results will be combined with data obtained from Aim 1 to calculate the permselectivity of these gap junctions to metabolites on a per channel basis. We hypothesize that lens connexins form channels that display selective permeabilities to specific metabolites, and that this connexin permselectivity can not be predicted solely on the basis of size and charge of the permeant. We will begin to identify the permeability characteristics and actual transjunctional molecules that are responsible for lens development, transparency, and disease. This work should lead to a greater understanding, and, ultimately, treatments, of eye diseases that result from aberrant gap junctional communication. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TSQ QUANTUM ESI-MS SURVEYOR BUNDLE Principal Investigator & Institution: Ford, David A.; Biochem and Molecular Biology; St. Louis University St. Louis, Mo 63103 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2005

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Summary: (provided by applicant): St. Louis University has a critical mass of NIH funded investigators whose research would be enhanced substantially by the purchase of a TSQ Quantum triple quadrupole ESI-MS/Surveyor HPLC instrument bundle. To support the ongoing studies integrating genomics, proteomics and metabolomics at Saint Louis University we request funds to purchase this instrument from Thermo Finnigan. The proposed users have appointments in five different departments at the Health Sciences Center, and are involved in basic and applied research in the fields of gene regulation, lysosomal storage diseases, heart disease, renal disease, diabetes, retinal disease, pulmonary disease, drug abuse and pathogenic mycology. The rapid progress in genomics and proteomics has created new opportunities for understanding metabolic processes controlled by macromolecular complexes. Understanding these metabolic processes by identifying the diverse metabolites Produced under different physiological and pathophysiological conditions represents an important new field of biomedical research described as metabolomics. Research in this field should provide both important diagnostic strategies as well as therapeutic targets for the treatment of many diseases. Triple quadrupole electrospray ionization-mass spectrometry (ESI-MS) instrumentation with an HPLC interface is required for many metabolomic studies. The triple quadrupole is required for identification of metabolites since it can be used for collisionally induced dissociation (CID) of molecular ions which provides structurallyinformative spectra. Additionally, HPLC resolved metabolites infused into the ESI source provides both important chromatographic characterization of metabolites and ESI-MS analysis of metabolites which together are often critical for the identification of metabolites. A major deficit of the instrument facility at Saint Louis University Health Sciences Center is the lack of a triple quadrupole ESI-MS instrument. This requested instrumentation will remedy this deficit in our otherwise well-equipped facility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VITAMIN A (RETINOL) AND 4 OXORETINOL IN BREAST CANCER Principal Investigator & Institution: Gudas, Lorraine J.; Professor and Chair; Pharmacology; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-JAN-2004 Summary: Retinoids, a group of compounds consisting of vitamin A (retinol) and its natural metabolites, have been shown in numerous experimental systems to act as cancer chemopreventive agents and cancer chemotherapeutic agents. While previous research has shown that retinoic acid (RA) is a very potent vitamin A metabolite which causes cell differentiation and inhibition of the growth of tumor cells, we have recently identified two new potent, bioactive vitamin A metabolites, 4-OHretinol and 4oxoretinol, in a number of cultured tumor cell lines. Although we first isolated these bioactive retinoids, 4- OHretinol and 4-oxoretinol, from a murine cell line (Achkar et al. (1996) PNAS 93:4879-4884), we have recently shown that estrogen receptor (ER) positive cultured human breast cancer cell lines such as MCF-7 can synthesize 4-OHretinol and 4-oxoretinol from retinol under certain culture conditions. In contrast, estrogen receptor negative breast cancer cells do not synthesize 4-OH-retinol and 4-oxoretinol from retinol. We have also recently shown that 4-oxoretinol is growth inhibitory for both ER positive and ER negative breast cancer lines, whereas RA is growth inhibitory in ER positive but not in ER negative breast tumor lines. In this proposal, we want to explore the activity of these new, bioactive retinol metabolites on normal human breast epithelial cells and on breast cancer cells: a) to determine more about the molecular mechanism by which 4-OHretinol and 4-oxoretinol can induce cell growth arrest, and b) to compare 4-oxoretinol with RA with respect to the regulation of gene expression. We

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will assess whether or not 4- oxoretinol synergizes with RXR specific ligands, N-(4hydroxyphenyl) retinamide, interferon, TGFbeta, and/or tamoxifen with respect to the growth arrest of breast cancer cells and the regulation of gene expression. We also plan to characterize biochemically the enzyme(s) which converts retinol to 4-OHretinol and 4-oxoretinol, to clone the gene(s) for the enzyme(s), and to delineate its regulation in human breast cancer cells. Tetracycline inducible antisense RNA techniques will be employed to block the expression of this gene. Our proposed studies may lead to the use of 4-oxoretinol or related compounds in the prevention and/or treatment of human breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VOLUMETRIC MR MOLECULAR IMAGING OF BRAIN Principal Investigator & Institution: Maudsley, Andrew A.; Professor; Radiology; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): This project will develop neuroimaging methods for acquisition and mapping of brain metabolites by short-TE proton MR Spectroscopic Imaging (MRSI). This measurement is typically complicated by spectral overlap, lineshape distortions, lipid contamination, and subject motion, and these effects limit the accuracy of the metabolite measurement as well as the number of metabolites that can potentially be detected. These limitations will be addressed by using high-speed acquisition methods to obtain multiple volumetric MRSI data sets that are each encoded with varying spectral information. Data analysis methods will be developed using multidimensional parametric modeling analysis approaches, to provide improved discrimination of overlapping spectral components. In addition, higher spatial resolution acquisition, field inhomogeneity correction, and motion compensation methods will be simultaneously included to obtain data with improved spatial response and spectral quality. Acquisition sequences will be implemented that exploit both spin relaxation and evolution parameters, and evaluated in normal subjects. Parameters will be optimized using numerical simulation techniques to maximize spectrat discrimination and signal to noise ratios, while also limiting the number of independent spectral measurements required. These same numerical methods will also be used to provide the prior information required for the spectral analysis procedures. The developed methods will be applied to mapping all metabolites observed using short-TE proton MR spectroscopy in normal human brain, and a 3D image database of metabolite levels will be generated. This will make use of spatial transformation and normalization procedures obtained through IRPG interactions with researchers at the MRS Unit, San Francisco (PIG. Matson). This development will establish the range and variance of normal metabolite profiles and provide valuable comparative data for numerous clinical investigations that use short-TE 1H MRS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: WHOLE CELL NMR STUDIES OF MYCOBACTERIA Principal Investigator & Institution: Lee, Richard Edward.; Assistant Professor; Pharmaceutical Sciences; University of Tennessee Health Sci Ctr Memphis, Tn 38163 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): This proposal aims to use live, whole-cell, high resolution magic angle spinning nuclear magnetic resonance spectroscopy (HRMASNMR) as a novel, nondestructive technique to study carbohydrate and carbonaceous

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metabolism in mycobacteria. There is currently intense research in genomic and proteomic studies of mycobacteria. However, complementary methodologies to study globally, the carbonaceous metabolic products from genes or proteins has been lacking and it is this deficit in knowledge that this proposal aims to address. Firstly, it is proposed to assign the complex, live, whole-cell HRMAS-NMR spectra of M. bovis BCG using purified standard metabolites and multi-dimensional NMR techniques. Secondly, it is proposed that mycobacteria can adapt their carbonaceous metabolism in response to different physiological conditions. Thus HRMAS-NMR, will be used to study changes in mycobacterial carbonaceous metabolites, including the cell wall, under different physiological conditions: (i) physical conditions of growth such as different media, temperature and pH; (ii) growth phase; (iii) exposure to anti-mycobacterial agents, including those which target the mycobacterial cell wall; (iv) the effects of conditions which may mimic growth in vivo; (v) differences in the HRMAS-NMR spectra between different mycobacterial species. The central hypothesis is that whole cell HRMAS-NMR will be an excellent way to study these changes. Thirdly, using whole cell NMR, a novel study will be performed of the mycobacterial cell wall tertiary structure. Initially, it is hoped to locate the position of metabolites identified in this study in the cell ultra structure. Finally, we plan to initiate 3D-NMR studies and studies of 3-bond torsional coupling constants that will provide 3-dimensional, conformational information on the macromolecules identified. The findings from these studies will lead to a better understanding of mycobacterial carbohydrate and lipid physiology and hence, their role in the virulence and pathogenesis of the tubercle bacilli. 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 “metabolites” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for metabolites in the PubMed Central database: •

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12(R)-hydroxyicosatetraenoic acid: a cytochrome-P450-dependent arachidonate metabolite that inhibits Na+,K+-ATPase in the cornea. by Schwartzman ML, Balazy M, Masferrer J, Abraham NG, McGiff JC, Murphy RC.; 1987 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=299491

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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14C-labeled metabolites in heterocysts and vegetative cells of Anabaena cylindrica filaments and their presumptive function as transport vehicles of organic carbon and nitrogen. by Juttner F.; 1983 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=217732

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A method for detection of aromatic metabolites at very low concentrations: application to detection of metabolites of anaerobic toluene degradation. by Edwards EA, Edwards AM, Grbic-Galic D.; 1994 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=201306

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A Nonaqueous Procedure for Isolating Starch Granules with Associated Metabolites from Maize (Zea mays L.) Endosperm. by Liu TT, Shannon JC.; 1981 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=425717

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A pathway for the metabolism of vitamin D3: Unique hydroxylated metabolites formed during catalysis with cytochrome P450scc (CYP11A1). by Guryev O, Carvalho RA, Usanov S, Gilep A, Estabrook RW.; 2003 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=299797

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Accumulation of soluble and wall-bound indolic metabolites in Arabidopsis thaliana leaves infected with virulent or avirulent Pseudomonas syringae pathovar tomato strains. by Hagemeier J, Schneider B, Oldham NJ, Hahlbrock K.; 2001 Jan 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=14660

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Active Metabolites of Isoxazolylpenicillins in Humans. by Thijssen HH, Mattie H.; 1976 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=429767

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Activities of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and its metabolites against herpes simplex virus types 1 and 2 in cell culture and in mice infected intracerebrally with herpes simplex virus type 2. by Schinazi RF, Fox JJ, Watanabe KA, Nahmias AJ.; 1986 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=180368

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Activity of metronidazole and its hydroxy and acid metabolites against clinical isolates of anaerobic bacteria. by O'Keefe JP, Troc KA, Thompson KD.; 1982 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=183761

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ADP and Other Metabolites Released from Acanthamoeba castellanii Lead to Human Monocytic Cell Death through Apoptosis and Stimulate the Secretion of Proinflammatory Cytokines. by Mattana A, Cappai V, Alberti L, Serra C, Fiori PL, Cappuccinelli P.; 2002 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128125

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Aflatoxin metabolism in humans: detection of metabolites and nucleic acid adducts in urine by affinity chromatography. by Groopman JD, Donahue PR, Zhu JQ, Chen JS, Wogan GN.; 1985 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=390743

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Aflavinines and other antiinsectan metabolites from the ascostromata of Eupenicillium crustaceum and related species. by Wang HJ, Gloer JB, Wicklow DT, Dowd PF.; 1995 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=167750

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Anthracycline metabolites of tetracenomycin C-nonproducing Streptomyces glaucescens mutants. by Yue S, Motamedi H, Wendt-Pienkowski E, Hutchinson CR.; 1986 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=212929

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Antibiotic Metabolites from a Marine Pseudomonad. by Wratten SJ, Wolfe MS, Andersen RJ, Faulkner DJ.; 1977 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351999

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Antifungal Metabolites (Monorden, Monocillin IV, and Cerebrosides) from Humicola fuscoatra Traaen NRRL 22980, a Mycoparasite of Aspergillus flavus Sclerotia. by Wicklow DT, Joshi BK, Gamble WR, Gloer JB, Dowd PF.; 1998 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106672

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Autoinduction of 2,4-Diacetylphloroglucinol Biosynthesis in the Biocontrol Agent Pseudomonas fluorescens CHA0 and Repression by the Bacterial Metabolites Salicylate and Pyoluteorin. by Schnider-Keel U, Seematter A, Maurhofer M, Blumer C, Duffy B, Gigot-Bonnefoy C, Reimmann C, Notz R, Defago G, Haas D, Keel C.; 2000 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=94405

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Bacterial Challenge Stimulates Formation of Arachidonic Acid Metabolites by Human Keratinocytes and Neutrophils In Vitro. by Eberhard J, Jepsen S, Pohl L, Albers HK, Acil Y.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119887

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Bacterial metabolism of alpha-pinene: pathway from alpha-pinene oxide to acyclic metabolites in Nocardia sp. strain P18.3. by Griffiths ET, Bociek SM, Harries PC, Jeffcoat R, Sissons DJ, Trudgill PW.; 1987 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=213895

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Biotransformation of aflatoxin B1 and its conjugated metabolites by rat gastrointestinal microfloras. by Wei C, Macy JM, Hsieh DP.; 1981 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=243730

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Bone marrow transplantation only partially restores purine metabolites to normal in adenosine deaminase-deficient patients. by Hirschhorn R, Roegner-Maniscalco V, Kuritsky L, Rosen FS.; 1981 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370939

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Ca-mediated stimulation of Cl secretion by reactive oxygen metabolites in human colonic T84 cells. by Tamai H, Gaginella TS, Kachur JF, Musch MW, Chang EB.; 1992 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=442848

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Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2Acetylaminofluorene and Other Aromatic Amine Carcinogens. by Ames BN, Gurney EG, Miller JA, Bartsch H.; 1972 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=389719

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Catabolism of premercapturic acid pathway metabolites of naphthalene to naphthols and methylthio-containing metabolites in rats. by Bakke J, Struble C, Gustafsson JA, Gustafsson B.; 1985 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=397106

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Changes in the Levels of Abscisic Acid and Its Metabolites in Excised Leaf Blades of Xanthium strumarium during and after Water Stress. by Zeevaart JA.; 1980 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=440701

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Characterization of gentamicin 2'-N-acetyltransferase from Providencia stuartii: its use of peptidoglycan metabolites for acetylation of both aminoglycosides and peptidoglycan. by Payie KG, Clarke AJ.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179228

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Characterization of Metabolites during Biodegradation of Hexahydro-1,3,5-Trinitro1,3,5-Triazine (RDX) with Municipal Anaerobic Sludge. by Hawari J, Halasz A, Sheremata T, Beaudet S, Groom C, Paquet L, Rhofir C, Ampleman G, Thiboutot S.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110595

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Characterization of Metabolites in the Biotransformation of 2,4,6-Trinitrotoluene with Anaerobic Sludge: Role of Triaminotoluene. by Hawari J, Halasz A, Paquet L, Zhou E, Spencer B, Ampleman G, Thiboutot S.; 1998 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106299

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Characterization of retinoyl beta-glucuronide as a minor metabolite of retinoic acid in bile. by Zile MH, Schnoes HK, DeLuca HF.; 1980 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=349588

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Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities. by Zhang KE, Wu E, Patick AK, Kerr B, Zorbas M, Lankford A, Kobayashi T, Maeda Y, Shetty B, Webber S.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90428

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Compartmentation of Sulfur Metabolites in Tobacco Cells : USE OF EFFLUX ANALYSIS. by Smith IK.; 1981 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=426016

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Complement membrane attack complex stimulates production of reactive oxygen metabolites by cultured rat mesangial cells. by Adler S, Baker PJ, Johnson RJ, Ochi RF, Pritzl P, Couser WG.; 1986 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=423461

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Conversion of 2-chloro-cis,cis-muconate and its metabolites 2-chloro- and 5chloromuconolactone by chloromuconate cycloisomerases of pJP4 and pAC27. by Vollmer MD, Schlomann M.; 1995 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=176974

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Corn metabolites affect growth and virulence of Agrobacterium tumefaciens. by Sahi SV, Chilton MD, Chilton WS.; 1990 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=54007

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Covalent modification of proteins by metabolites of NAD+. by Kun E, Chang AC, Sharma ML, Ferro AM, Nitecki D.; 1976 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=430955

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Cytochrome P450 metabolites of arachidonic acid are potent inhibitors of vasopressin action on rabbit cortical collecting duct. by Hirt DL, Capdevila J, Falck JR, Breyer MD, Jacobson HR.; 1989 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=304058

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Cytoplasmic Acidification and Secondary Metabolite Production in Different Plant Cell Suspensions (A Comparative Study). by Hagendoorn M, Wagner AM, Segers G, Van Der Plas L, Oostdam A, Van Walraven HS.; 1994 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=159580

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Cytotoxicity of T-2 toxin and its metabolites determined with the neutral red cell viability assay. by Babich H, Borenfreund E.; 1991 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=183530

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Deficiencies or Excesses of Metabolites Interfering with Differentiation. by Freese E, Ichikawa T, Oh YK, Freese EB, Prasad C.; 1974 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=434355

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Degradation of Ciprofloxacin by Basidiomycetes and Identification of Metabolites Generated by the Brown Rot Fungus Gloeophyllum striatum. by Wetzstein HG, Stadler M, Tichy HV, Dalhoff A, Karl W.; 1999 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91220

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Degradation of n-Hexadecane and Its Metabolites by Pseudomonas aeruginosa under Microaerobic and Anaerobic Denitrifying Conditions. by Chayabutra C, Ju LK.; 2000 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91854

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Degradation of Polychlorinated Biphenyl Metabolites by Naphthalene-Catabolizing Enzymes. by Barriault D, Durand J, Maaroufi H, Eltis LD, Sylvestre M.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90902

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Detection of metabolites by frequency-pulsed electron capture gas-liquid chromatography in serum and cerebrospinal fluid of a patient with Nocardia infection. by Brooks JB, Kasin JV, Fast DM, Daneshvar MI.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=265922

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Determination of apalcillin and its metabolites in human body fluids by highpressure liquid chromatography. by Borner K, Lode H, Elvers A.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185698

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Determination of Key Metabolites during Biodegradation of Hexahydro-1,3,5Trinitro-1,3,5-Triazine with Rhodococcus sp. Strain DN22. by Fournier D, Halasz A, Spain J, Fiurasek P, Hawari J.; 2002 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126592

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Determination of miloxacin and metabolites in human serum and urine by highpressure liquid chromatography. by Yoshitake A, Kawahara K, Shono F, Umeda I, Izawa A, Komatsu T.; 1980 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=283937

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Determination of the Carbon-Bound Electron Composition of Microbial Cells and Metabolites by Dichromate Oxidation. by Harris RF, Adams SS.; 1979 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=243194

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Development of a mechanism of action-based screen for anthelmintic microbial metabolites with avermectinlike activity and isolation of milbemycin-producing Streptomyces strains. by Haber CL, Heckaman CL, Li GP, Thompson DP, Whaley HA, Wiley VH.; 1991 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245273

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Developmental changes in the relation between phosphate metabolites and oxygen consumption in the sheep heart in vivo. by Portman MA, Heineman FW, Balaban RS.; 1989 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303701

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Different internal metabolites trigger the induction of glycolytic gene expression in Saccharomyces cerevisiae. by Muller S, Boles E, May M, Zimmermann FK.; 1995 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=177205

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Differential Compartmentation of Gibberellin A1 and Its Metabolites in Vacuoles of Cowpea and Barley Leaves. by Garcia-Martinez JL.; 1981 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=426001

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Discovery of sulfated metabolites in mycobacteria with a genetic and mass spectrometric approach. by Mougous JD, Leavell MD, Senaratne RH, Leigh CD, Williams SJ, Riley LW, Leary JA, Bertozzi CR.; 2002 Dec 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139265

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Distribution of Metabolites between Chloroplast and Cytoplasm during the Induction Phase of Photosynthesis in Leaf Protoplasts. by Robinson SP, Walker DA.; 1980 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=440447

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Effect of Carbon Source on Enzymes and Metabolites of Arginine Metabolism in Neurospora. by Drainas C, Weiss RL.; 1980 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=293564

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Effect of Different NADH Oxidase Levels on Glucose Metabolism by Lactococcus lactis: Kinetics of Intracellular Metabolite Pools Determined by In Vivo Nuclear Magnetic Resonance. by Neves AR, Ramos A, Costa H, van Swam II, Hugenholtz J, Kleerebezem M, de Vos W, Santos H.; 2002 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134407

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Effect of enzymatically generated reactive oxygen metabolites on the cyclic nucleotide content in isolated rat glomeruli. by Shah SV.; 1984 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370489

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Effect of light on several metabolites of carbohydrate metabolism in Phycomyces blakesleeanus. by Rua J, Rodriguez-Aparicio LB, Busto F, Soler J.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=211868

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Effect of Metabolites Produced by Trichoderma harzianum Biotypes and Agaricus bisporus on Their Respective Growth Radii in Culture. by Mumpuni A, Sharma HS, Brown AE.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90969

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Effect of Secondary Metabolites on the Organisms Producing Them: Effect of Nisin on Streptococcus lactis and Enterotoxin B on Staphylococcus aureus. by Hurst A, Kruse H.; 1972 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=444206

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Effect of Slow Growth on Metabolism of Escherichia coli, as Revealed by Global Metabolite Pool ("Metabolome") Analysis. by Tweeddale H, Notley-McRobb L, Ferenci T.; 1998 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107546

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Effects of Abscisic Acid Metabolites and Analogs on Freezing Tolerance and Gene Expression in Bromegrass (Bromus inermis Leyss) Cell Cultures. by Robertson AJ, Reaney M, Wilen RW, Lamb N, Abrams SR, Gusta LV.; 1994 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=160728

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Effects of Pentachloronitrobenzene and Some of Its Known and Possible Metabolites on Fungi. by Renner G, Ruckdeschel G.; 1983 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=239349

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Effects of pentachlorophenol and some of its known and possible metabolites on different species of bacteria. by Ruckdeschel G, Renner G, Schwarz K.; 1987 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=204177

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Effects of pentachlorophenol and some of its known and possible metabolites on fungi. by Ruckdeschel G, Renner G.; 1986 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=239076

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Effects of two metabolites of ochratoxin A, (4R)-4-hydroxyochratoxin A and ochratoxin alpha, on immune response in mice. by Creppy EE, Stormer FC, Roschenthaler R, Dirheimer G.; 1983 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=348057

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Electron Capture Gas-Liquid Chromatographic Study of Metabolites Produced by Some Arthritic Transudate-Associated Organisms In Vitro and In Vivo in Rabbit Models. by Brooks JB, Melton AR.; 1978 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=275260

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Engineering of Escherichia coli central metabolism for aromatic metabolite production with near theoretical yield. by Patnaik R, Liao JC.; 1994 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=201913

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Enzymatic Basis for Overproduction of Tryptophan and Its Metabolites in Hansenula polymorpha Mutants. by Denenu EO, Demain AL.; 1981 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=244043

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Enzymatic Defenses of the Mouse Heart Against Reactive Oxygen Metabolites ALTERATIONS PRODUCED BY DOXORUBICIN. by Doroshow JH, Locker GY, Myers CE.; 1980 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=371347

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Enzymic Determination of Metabolites in the Subcellular Compartments of Spinach Protoplasts. by Wirtz W, Stitt M, Heldt HW.; 1980 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=440555

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Erythropoietic Activity of Steroid Metabolites in Mice. by Gorshein D, Gardner FH.; 1970 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282944

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Estrogenic activity in vivo and in vitro of some diethylstilbestrol metabolites and analogs. by Korach KS, Metzler M, McLachlan JA.; 1978 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=411271

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Evaluation of active versus passive uptake of metabolites by Rhizobium japonicum bacteroids. by Reibach PH, Streeter JG.; 1984 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=215590

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Extraction of Vitamin D Metabolites by Bones of Normal Adult Dogs. by Olgaard K, Schwartz J, Finco D, Arbelaez M, Haddad J, Avioli L, Klahr S, Slatopolsky E.; 1982 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=371026

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Fialuridine and its Metabolites Inhibit DNA Polymerase [gamma] at Sites of Multiple Adjacent Analog Incorporation, Decrease mtDNA Abundance, and Cause Mitochondrial Structural Defects in Cultured Hepatoblasts. by Lewis W, Levine ES,

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Griniuviene B, Tankersley KO, Colacino JM, Sommadossi J, Watanabe KA, Perrino FW.; 1996 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39655 •

Flow Cytometry Analysis of Changes in the DNA Content of the Polychlorinated Biphenyl Degrader Comamonas testosteroni TK102: Effect of Metabolites on CellCell Separation. by Hiraoka Y, Yamada T, Tone K, Futaesaku Y, Kimbara K.; 2002 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126427

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Formation and Conversion of Oxygen Metabolites by Lactococcus lactis subsp. lactis ATCC 19435 under Different Growth Conditions. by van Niel EW, Hofvendahl K, Hahn-Hagerdal B.; 2002 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124107

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Formation of Methylated and Phosphorylated Metabolites During the Fermentation Process of Verdamicin. by Lee BK, Condon RG, Wagman GH, Weinstein MJ.; 1976 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=429748

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Formation of muconaldehyde, an open-ring metabolite of benzene, in mouse liver microsomes: an additional pathway for toxic metabolites. by Latriano L, Goldstein BD, Witz G.; 1986 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=386927

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Freon 11 Extraction of Volatile Metabolites Formed by Certain Lactic Acid Bacteria. by Tracey RP, Britz TJ.; 1989 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=202914

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Frequency-pulsed electron capture gas-liquid chromatographic analysis of metabolites produced by Clostridium difficile in broth enriched with amino acids. by Brooks JB, Nunez-Montiel OL, Wycoff BJ, Moss CW.; 1984 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=271368

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Gamma-interferon restores listericidal activity and concurrently enhances release of reactive oxygen metabolites in dexamethasone-treated human monocytes. by Schaffner A, Rellstab P.; 1988 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303602

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Genes Specific for the Biosynthesis of Clavam Metabolites Antipodal to Clavulanic Acid Are Clustered with the Gene for Clavaminate Synthase 1 in Streptomyces clavuligerus. by Mosher RH, Paradkar AS, Anders C, Barton B, Jensen SE.; 1999 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89136

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Genetic variation in rates of antipyrine metabolite formation: a study in uninduced twins. by Penno MB, Dvorchik BH, Vesell ES.; 1981 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=320370

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Glucose increases the synthesis of lipoxygenase-mediated metabolites of arachidonic acid in intact rat islets. by Metz SA.; 1985 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=396999

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Headspace analysis of volatile metabolites of Pseudomonas aeruginosa and related species by gas chromatography-mass spectrometry. by Labows JN, McGinley KJ, Webster GF, Leyden JJ.; 1980 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=273628

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Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells. by Chen JK, Capdevila J, Harris RC.; 2002 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122896

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Histopathology of Mycotoxicosis produced in Swiss albino mice by metabolites of some fungal isolates. by Gupta J, Pathak B, Sethi N, Vora VC.; 1981 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=243771

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Human immunodeficiency virus glycoprotein (gp120) induction of monocyte arachidonic acid metabolites and interleukin 1. by Wahl LM, Corcoran ML, Pyle SW, Arthur LO, Harel-Bellan A, Farrar WL.; 1989 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=286524

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Hydroxylated Metabolites of 2,4-Dichlorophenol Imply a Fenton-Type Reaction in Gloeophyllum striatum. by Schlosser D, Fahr K, Karl W, Wetzstein HG.; 2000 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=110563

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Identification of 7,12-dimethylbenz[a]anthracene metabolites that lead to mutagenesis in mammalian cells. by Huberman E, Chou MW, Yang SK.; 1979 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=383073

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Identification of a Novel Metabolite in the Degradation of Pyrene by Mycobacterium sp. Strain AP1: Actions of the Isolate on Two- and Three-Ring Polycyclic Aromatic Hydrocarbons. by Vila J, Lopez Z, Sabate J, Minguillon C, Solanas AM, Grifoll M.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93335

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Identification of four trans-3,4-dihydrodiol metabolites of 7,12dimethylbenz[a]anthracene and their in vitro DNA-binding activities upon further metabolism. by Chou MW, Yang SK.; 1978 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=392985

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Identification of Intermediate and Branch Metabolites Resulting from Biotransformation of 2-Benzoxazolinone by Fusarium verticillioides. by Glenn AE, Meredith FI, Morrison III WH, Bacon CW.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161504

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Identification of metabolites from the degradation of fluoranthene by Mycobacterium sp. strain PYR-1. by Kelley I, Freeman JP, Evans FE, Cerniglia CE.; 1993 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=202192

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Identification of mutagenic metabolites of benzo(a)pyrene in mammalian cells. by Huberman E, Sachs L, Yang SK, Gelboin V.; 1976 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=335960

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Identification of Neisseria by electron capture gas-liquid chromatography of metabolites in a chemically defined growth medium. by Morse CD, Brooks JB, Kellogg DS Jr.; 1977 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=274800

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Identification of various T-2 toxin metabolites in chicken excreta and tissues. by Visconti A, Mirocha CJ.; 1985 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=238536

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Imaging of metabolites by using a fusion protein between a periplasmic binding protein and GFP derivatives: From a chimera to a view of reality. by Stitt M.; 2002 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=124947

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Immunological and immunoassay studies of the binding protein for vitamin D and its metabolites in human serum. by Imawari M, Goodman DS.; 1977 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=333379

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In vitro activities of the lichen secondary metabolites vulpinic acid, (+)-usnic acid, and (-)-usnic acid against aerobic and anaerobic microorganisms. by Lauterwein M, Oethinger M, Belsner K, Peters T, Marre R.; 1995 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162980

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In vitro activity of the two principal oxidative metabolites of metronidazole against Bacteroides fragilis and related species. by Haller I.; 1982 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=183695

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In vitro effects of sulfadiazine and its metabolites alone and in combination with pyrimethamine on Toxoplasma gondii. by Schoondermark-van de Ven E, Vree T, Melchers W, Camps W, Galama J.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=162621

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In vitro evaluation of the antimicrobial activity of lichen metabolites as potential preservatives. by Ingolfsdottir K, Bloomfield SF, Hylands PJ.; 1985 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=180233

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In Vivo Incorporation of Radioactive Metabolites by Golgi Apparatus and Other Cell Fractions of Onion Stem. by Morre DJ.; 1970 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=396513

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Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis. by Thirman MJ, Albrecht JH, Krueger MA, Erickson RR, Cherwitz DL, Park SS, Gelboin HV, Holtzman JL.; 1994 Jun 7; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=44002

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Induction of Lipid and Oleosin Biosynthesis by (+)-Abscisic Acid and Its Metabolites in Microspore-Derived Embryos of Brassica napus L.cv Reston (Biological Responses

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in the Presence of 8[prime]-Hydroxyabscisic Acid). by Zou J, Abrams GD, Barton DL, Taylor DC, Pomeroy MK, Abrams SR.; 1995 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=157375 •

Influence of Actinobacillus pleuropneumoniae and its metabolites on porcine alveolar epithelial cells. by van de Kerkhof A, Haesebrouck F, Chiers K, Ducatelle R, Kamp EM, Smits MA.; 1996 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=174311

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Influence of tricarboxylic acid cycle intermediates and related metabolites on the biosynthesis of aflatoxin by resting cells of Aspergillus flavus. by Shantha T, Murthy VS.; 1981 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=244103

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Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3. by Crowle AJ, May MH.; 1990 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=172025

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Interaction of the Anticoagulant Drug Warfarin and Its Metabolites with Human Plasma Albumin. by O'Reilly RA.; 1969 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=322205

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Intestinal Calcium Absorption and Serum Vitamin D Metabolites in Normal Subjects and Osteoporotic Patients EFFECT OF AGE AND DIETARY CALCIUM. by Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB, Deluca HF.; 1979 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=372174

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Investigation of the Apparent Induction of Nitrate Uptake in Barley (Hordeum vulgare L.) Using NO3--Selective Microelectrodes (Modulation of Coarse Regulation of NO3- Uptake by Exogenous Application of Downstream Metabolites in the NO3Assimilatory Pathway). by Henriksen GH, Spanswick RM.; 1993 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=159060

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Isolation and identification of xanthomegnin, viomellein, rubrosulphin, and viopurpurin as metabolites of penicillium viridicatum. by Stack ME, Eppley RM, Dreifuss PA, Pohland AE.; 1977 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=170690

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Isoprenoid Biosynthesis. Metabolite Profiling of Peppermint Oil Gland Secretory Cells and Application to Herbicide Target Analysis. by Lange BM, Ketchum RE, Croteau RB.; 2001 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117986

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Isotactic polypropylene biodegradation by a microbial community: physicochemical characterization of metabolites produced. by Cacciari I, Quatrini P, Zirletta G, Mincione E, Vinciguerra V, Lupattelli P, Giovannozzi Sermanni G.; 1993 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=182519

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Kinetic profiles of diacetoxyscirpenol and two of its metabolites in blood serum of pigs. by Bauer J, Bollwahn W, Gareis M, Gedek B, Heinritzi K.; 1985 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=238455

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Kinetics of ofloxacin and its metabolites in cerebrospinal fluid after a single intravenous infusion of 400 milligrams of ofloxacin. by Nau R, Kinzig M, Dreyhaupt T, Kolenda H, Sorgel F, Prange HW.; 1994 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=284648

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Kinetics of Plasmodium falciparum thymidylate synthase: interactions with highaffinity metabolites of 5-fluoroorotate and D1694. by Hekmat-Nejad M, Rathod PK.; 1996 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=163385

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Lipid Metabolites of Carbon Tetrachloride. by Gordis E.; 1969 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=322206

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Lipoxygenase metabolites of arachidonic and linoleic acids modulate the adhesion of tumor cells to endothelium via regulation of protein kinase C. by Liu B, Timar J, Howlett J, Diglio CA, Honn KV.; 1991 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=361904

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Measurement of Metabolites Associated with Nonaqueously Isolated Starch Granules from Immature Zea mays L. Endosperm. by Liu TT, Shannon JC.; 1981 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=425718

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Metabolism of cerebroside sulfate and subcellular distribution of its metabolites in cultured skin fibroblasts from controls, metachromatic leukodystrophy, and globoid cell leukodystrophy. by Inui K, Furukawa M, Okada S, Yabuuchi H.; 1988 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=329572

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Metabolism of S-1108, a new oral cephem antibiotic, and metabolic profiles of its metabolites in humans. by Totsuka K, Shimizu K, Konishi M, Yamamoto S.; 1992 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=189391

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Microbial Anaerobic Demethylation and Dechlorination of Chlorinated Hydroquinone Metabolites Synthesized by Basidiomycete Fungi. by Milliken CE, Meier GP, Watts JE, Sowers KR, May HD.; 2004 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=321268

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Microbial Transformation of Terpenoids. I. Indentification of Metabolites Produced by a Pseudomonad from Citronellal and Citral. by Joglekar SS, Dhavlikar RS.; 1969 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=378197

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Mobilization of Metabolites from Leaves to Grains as the Cause of Monocarpic Senescence in Rice. by Ray S, Choudhuri MA.; 1981 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=426100

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Monitoring Key Reactions in Degradation of Chloroaromatics by In Situ 1H Nuclear Magnetic Resonance: Solution Structures of Metabolites Formed from cisDienelactone. by Pieper DH, Pollmann K, Nikodem P, Gonzalez B, Wray V.; 2002 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134862

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Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in CSF of healthy volunteers. by Jonsson EG, Bah J, Melke J, Abou Jamra R, Schumacher J, Westberg L, Ivo R, Cichon S, Propping P, Nothen MM, Eriksson E, Sedvall GC.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=387829

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Multiple N-Acyl-L-Homoserine Lactone Signal Molecules Regulate Production of Virulence Determinants and Secondary Metabolites in Pseudomonas aeruginosa. by Winson MK, Camara M, Latifi A, Fogliono M, Chhabra SR, Daykin M, Bally M, Chapon V, Salmond GP, Bycroft BW, Lazdunski A, Stewart GS, Williams P.; 1995 Sep 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=40998

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Mutagenicity of the Alternaria metabolites altertoxins I, II, and III. by Stack ME, Prival MJ.; 1986 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=239103

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New metabolites in the degradation of fluorene by Arthrobacter sp. strain F101. by Casellas M, Grifoll M, Bayona JM, Solanas AM.; 1997 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=168377

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Novel metabolites from Penicillium crustosum, including penitrem E, a tremorgenic mycotoxin. by Kyriakidis N, Waight ES, Day JB, Mantle PG.; 1981 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=243961

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Novel metabolites in phenanthrene and pyrene transformation by Aspergillus niger. by Sack U, Heinze TM, Deck J, Cerniglia CE, Cazau MC, Fritsche W.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=168586

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Novel Scheme for Biosynthesis of Aryl Metabolites from l-Phenylalanine in the Fungus Bjerkandera adusta. by Lapadatescu C, Ginies C, Le Quere JL, Bonnarme P.; 2000 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92016

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Oxidation of Two Hydroxylated Ochratoxin A Metabolites by Alcohol Dehydrogenase. by Syvertsen C, Stormer FC.; 1983 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=242520

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Oxidative Remodeling of Chromoplast Carotenoids Identification of the Carotenoid Dioxygenase CsCCD and CsZCD Genes Involved in Crocus Secondary Metabolite Biogenesis. by Bouvier F, Suire C, Mutterer J, Camara B.; 2003 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=143450

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Oxygen metabolites stimulate release of high-molecular-weight glycoconjugates by cell and organ cultures of rodent respiratory epithelium via an arachidonic aciddependent mechanism. by Adler KB, Holden-Stauffer WJ, Repine JE.; 1990 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296389

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Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs. by Tate RM, Morris HG, Schroeder WR, Repine JE.; 1984 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370513

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Peripheral Aromatic L-Amino Acids Decarboxylase Inhibitor in Parkinsonism. I. EFFECT ON O-METHYLATED METABOLITES OF L-DOPA-2-14C. by Messiha FS, Hsu TH, Bianchine JR.; 1972 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=302144

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Phagocytic cells synthesize 19-nor-10-keto-25-hydroxyvitamin D3, a metabolite that may induce differentiation of the human monoblastic cell line U937. by Gray TK, Millington DS, Maltby DA, Williams ME, Cohen MS, Dodd RC.; 1985 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=391474

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Pharmacokinetics of Pentoxifylline and Its Metabolites in Healthy Mice and in Mice Infected with Candida albicans. by Miller K, Louie A, Baltch AL, Smith RP, Davis PJ, Gordon MA.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105841

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Phosphate metabolites in lymphoid, Friend erythroleukemia, and HeLa cells observed by high-resolution 31P nuclear magnetic resonance. by Navon G, Navon R, Shulman RG, Yamane T.; 1978 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=411363

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Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR. by Kitareewan S, Burka LT, Tomer KB, Parker CE, Deterding LJ, Stevens RD, Forman BM, Mais DE, Heyman RA, McMorris T, Weinberger C.; 1996 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=275969

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Piperonylic Acid, a Selective, Mechanism-Based Inactivator of the trans-Cinnamate 4Hydroxylase: A New Tool to Control the Flux of Metabolites in the Phenylpropanoid Pathway. by Schalk M, Cabello-Hurtado F, Pierrel MA, Atanossova R, Saindrenan P, Werck-Reichhart D.; 1998 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34858

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Predominant generation of 15-lipoxygenase metabolites of arachidonic acid by epithelial cells from human trachea. by Hunter JA, Finkbeiner WE, Nadel JA, Goetzl EJ, Holtzman MJ.; 1985 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=390440

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Preparation of Metabolites of Spironolactone by Microbial Oxygenation. by Marsheck WJ, Karim A.; 1973 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=380879

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Production and Excretion of Nod Metabolites by Rhizobium leguminosarum bv. trifolii Are Disrupted by the Same Environmental Factors That Reduce Nodulation in the Field. by McKay IA, Djordjevic MA.; 1993 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=182463

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Products Formed from Analogues of 1,1,1-Trichloro-2,2-Bis(p-Chlorophenyl) Ethane (DDT) Metabolites by Pseudomonas putida. by Subba-Rao RV, Alexander M.; 1977 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=170590

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Putative metabolites derived from dietary combinations of calcium glucarate and N(4-hydroxyphenyl)retinamide act synergistically to inhibit the induction of rat mammary tumors by 7,12-dimethylbenz[a]anthracene. by Abou-Issa HM, Duruibe VA, Minton JP, Larroya S, Dwivedi C, Webb TE.; 1988 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=280390

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Quantitative Analysis of Indole-3-Acetic Acid Metabolites in Arabidopsis. by Kowalczyk M, Sandberg G.; 2001 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=133588

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Radioimmunoassay for metabolites of 9,3"-diacetylmidecamycin, a macrolide antibiotic. by Shimada N, Ueda T, Yokoshima T, Umemura K, Shomura T.; 1982 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185704

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Radioimmunoassay of the binding protein for vitamin D and its metabolites in human serum: concentrations in normal subjects and patients with disorders of mineral homeostasis. by Haddad JG Jr, Walgate J.; 1976 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=333290

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Rapid Method To Estimate the Presence of Secondary Metabolites in Microbial Extracts. by Higgs RE, Zahn JA, Gygi JD, Hilton MD.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92588

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Reactions of cysteamine and other amine metabolites with glyoxylate and oxygen catalyzed by mammalian D-amino acid oxidase. by Hamilton GA, Buckthal DJ, Mortensen RM, Zerby KW.; 1979 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=383660

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Reduced Levels of Nitric Oxide Metabolites in Cerebrospinal Fluid Are Associated with Equine Protozoal Myeloencephalitis. by Njoku CJ, Saville WJ, Reed SM, Oglesbee MJ, Rajala-Schultz PJ, Stich RW.; 2002 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=119978

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Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. by Silver J, Russell J, Sherwood LM.; 1985 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=397979

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Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. by Silver J, Naveh-Many T, Mayer H, Schmelzer HJ, Popovtzer MM.; 1986 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=423816

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Regulation of calcitonin gene transcription by vitamin D metabolites in vivo in the rat. by Naveh-Many T, Silver J.; 1988 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=442503

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Regulation of the Accumulation and Reduction of Nitrate by Nitrogen and Carbon Metabolites in Maize Seedlings. by Sivasankar S, Rothstein S, Oaks A.; 1997 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=158340

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Relationship between myocardial metabolites and contractile abnormalities during graded regional ischemia. Phosphorus-31 nuclear magnetic resonance studies of porcine myocardium in vivo. by Schaefer S, Schwartz GG, Gober JR, Wong AK, Camacho SA, Massie B, Weiner MW.; 1990 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=296486

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Role of Arachidonic Acid and Its Metabolites in the Priming of NADPH Oxidase in Human Polymorphonuclear Leukocytes by Peritoneal Dialysis Effluent. by Daniels I, Lindsay MA, Keany CI, Burden RP, Fletcher J, Haynes AP.; 1998 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95640

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Role of macrophages in malaria: O2 metabolite production and phagocytosis by splenic macrophages during lethal Plasmodium berghei and self-limiting Plasmodium yoelii infection in mice. by Brinkmann V, Kaufmann SH, Simon MM, Fischer H.; 1984 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=263687

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Role of Neutral Metabolites in Microbial Conversion of 3[beta]-Acetoxy-19Hydroxycholest-5-Ene into Estrone. by Madyastha KM, Shankar VN.; 1994 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=201510

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Role of two different guanine nucleotide-binding proteins in the antagonistic modulation of the S-type K+ channel by cAMP and arachidonic acid metabolites in Aplysia sensory neurons. by Volterra A, Siegelbaum SA.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282283

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Roles of tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, platelet-activating factor, and arachidonic acid metabolites in interleukin-1induced resistance to infection in neutropenic mice. by Vogels MT, Hermsen CC, Huys HL, Eling WM, van der Meer JW.; 1994 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=186467

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Secondary alcohol metabolites mediate iron delocalization in cytosolic fractions of myocardial biopsies exposed to anticancer anthracyclines. Novel linkage between anthracycline metabolism and iron-induced cardiotoxicity. by Minotti G, Cavaliere AF, Mordente A, Rossi M, Schiavello R, Zamparelli R, Possati G.; 1995 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=295656

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Secondary Metabolites of Flustra foliacea and Their Influence on Bacteria. by Peters L, Konig GM, Wright AD, Pukall R, Stackebrandt E, Eberl L, Riedel K.; 2003 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161538

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Secondary metabolites of the fluorescent pseudomonads. by Leisinger T, Margraff R.; 1979 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=281483

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Secondary metabolites resulting from degradation of PR toxin by Penicillium roqueforti. by Chang SC, Lu KL, Yeh SF.; 1993 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=202226

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Selenosugars are key and urinary metabolites for selenium excretion within the required to low-toxic range. by Kobayashi Y, Ogra Y, Ishiwata K, Takayama H, Aimi N, Suzuki KT.; 2002 Dec 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=138542

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Significant receptor affinities of metabolites and a degradation product of mometasone furoate. by Valotis A, Hogger P.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=499542

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Spatially localized 1H NMR spectra of metabolites in the human brain. by Hanstock CC, Rothman DL, Prichard JW, Jue T, Shulman RG.; 1988 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=279871

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Specific Inhibition of the Polymorphonuclear Leukocyte Chemotactic Response to Hydroxy-Fatty Acid Metabolites of Arachidonic Acid by Methyl Ester Derivatives. by Goetzl EJ, Valone FH, Reinhold VN, Gorman RR.; 1979 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=372066

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Stimulation of aryl metabolite production in the basidiomycete Bjerkandera sp. strain BOS55 with biosynthetic precursors and lignin degradation products. by Mester T, Swarts HJ, Romero i Sole S, de Bont JA, Field JA.; 1997 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=168489

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Structures of deepoxytrichothecene metabolites from 3'-hydroxy HT-2 toxin and T-2 tetraol in rats. by Yoshizawa T, Sakamoto T, Kuwamura K.; 1985 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=238687

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Studies of metabolites in diarrheal stool specimens containing Shigella species by frequency-pulsed electron capture gas-liquid chromatography. by Brooks JB, Basta MT, el Kholy AM.; 1985 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=271728

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Studies on the molecular mechanisms of human Fc receptor-mediated phagocytosis. Amplification of ingestion is dependent on the generation of reactive oxygen metabolites and is deficient in polymorphonuclear leukocytes from patients with chronic granulomatous disease. by Gresham HD, McGarr JA, Shackelford PG, Brown EJ.; 1988 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=442669

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Study of conditions of production of roquefortine and other metabolites of Penicillin roqueforti. by Scott PM, Kennedy BP, Harwig J, Blanchfield BJ.; 1977 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=170673

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Subcellular Localization of Secondary Lipid Metabolites Including Fragrance Volatiles in Carnation Petals. by Hudak KA, Thompson JE.; 1997 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=158355

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Sulfur K-edge x-ray absorption spectroscopy: A spectroscopic tool to examine the redox state of S-containing metabolites in vivo. by Rompel A, Cinco RM, Latimer MJ, McDermott AE, Guiles RD, Quintanilha A, Krauss RM, Sauer K, Yachandra VK, Klein MP.; 1998 May 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=27596

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Suppression of natural killing in vitro by monocytes and polymorphonuclear leukocytes: requirement for reactive metabolites of oxygen. by Seaman WE, Gindhart TD, Blackman MA, Dalal B, Talal N, Werb Z.; 1982 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=370142

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Synergistic Antimicrobial Activity of Metabolites Produced by a Nonobligate Bacterial Predator. by Cain CC, Lee D, Waldo III RH, Henry AT, Casida Jr. EJ, Wani MC, Wall ME, Oberlies NH, Falkinham III JO.; 2003 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=161883

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Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. by Challis GL, Hopwood DA.; 2003 Nov 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=304118

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Synthesis of thyroid hormone metabolites by photolysis of thyroxine and thyroxine analogs in the near UV. by van der Walt B, Cahnmann HJ.; 1982 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=346000

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T-2 metabolites in the excreta of broiler chickens administered 3H-labeled T-2 toxin. by Yoshizawa T, Swanson SP, Mirocha CJ.; 1980 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=291502

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Testosterone and its precursors and metabolites enhance guanylate cyclase activity. by Vesely DL.; 1979 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=383852

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The Impact of Interindividual Variation in NAT2 Activity on Benzidine Urinary Metabolites and Urothelial DNA Adducts in Exposed Workers. by Rothman N, Bhatnagar VK, Hayes RB, Zenser TV, Kashyap SK, Butler MA, Bell DA, Lakshmi V, Jaeger M, Kashyap R, Hirvonen A, Schulte PA, Dosemeci M, Hsu F, Parikh DJ, Davis BB, Talaska G.; 1996 May 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39410

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The Metabolites of the Herbicide L-Phosphinothricin (Glufosinate) (Identification, Stability, and Mobility in Transgenic, Herbicide-Resistant, and Untransformed Plants). by Droge-Laser W, Siemeling U, Puhler A, Broer I.; 1994 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=159341

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The Relative Amounts and Identification of Some 2,4-Dichlorophenoxyacetic Acid Metabolites Isolated from Soybean Cotyledon Callus Cultures. by Feung CS, Hamilton RH, Witham FH, Mumma RO.; 1972 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=367320

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The Role of Chloroplast Electron Transport and Metabolites in Modulating Rubisco Activity in Tobacco. Insights from Transgenic Plants with Reduced Amounts of Cytochrome b/f Complex or Glyceraldehyde 3-Phosphate Dehydrogenase. by Ruuska SA, Andrews TJ, Badger MR, Price GD, von Caemmerer S.; 2000 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58886

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The temporal reliability of serum estrogens, progesterone, gonadotropins, SHBG and urinary estrogen and progesterone metabolites in premenopausal women. by Williams AE, Maskarinec G, Franke AA, Stanczyk FZ.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140038

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The two-component PhoR-PhoP system controls both primary metabolism and secondary metabolite biosynthesis in Streptomyces lividans. by Sola-Landa A, Moura RS, Martin JF.; 2003 May 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=156338

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Toxicity of the Alternaria metabolites alternariol, alternariol methyl ether, altenuene, and tenuazonic acid in the chicken embryo assay. by Griffin GF, Chu FS.; 1983 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=239585

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Toxicity studies of metabolites of some fungal isolates in albino mice. by Pathak B, Sethi N, Gupta J, Vora VC.; 1983 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=239493

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Transgenic Tobacco and Arabidopsis Plants Expressing the Two Multifunctional Sorghum Cytochrome P450 Enzymes, CYP79A1 and CYP71E1, Are Cyanogenic and Accumulate Metabolites Derived from Intermediates in Dhurrin Biosynthesis. by Bak S, Olsen CE, Halkier BA, Moller BL.; 2000 Aug 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59100

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Transport and Retention of K+ and Other Metabolites in a Marine Pseudomonad and Their Relation to the Mechanism of Optical Effects. by Matula TI, Srivastava VS, Wong P, MacLeod RA.; 1970 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=247628

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Urinary Metabolites of 14C-Labeled Thyroxine in Man. by Pittman CS, Buck MW, Chambers JB Jr.; 1972 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=292323

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Use of Direct-Infusion Electrospray Mass Spectrometry To Guide Empirical Development of Improved Conditions for Expression of Secondary Metabolites from Actinomycetes. by Zahn JA, Higgs RE, Hilton MD.; 2001 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92589

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Use of Fluorinated Compounds To Detect Aromatic Metabolites from m-Cresol in a Methanogenic Consortium: Evidence for a Demethylation Reaction. by Londry KL, Fedorak PM.; 1993 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=182262

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Use of High-Pressure Liquid Chromatography to Determine Plasma Levels of Metronidazole and Metabolites After Intravenous Administration. by Wheeler LA, De Meo M, Halula M, George L, Heseltine P.; 1978 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=352215

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Vitamin D metabolites change the phenotype of monoblastic U937 cells. by Dodd RC, Cohen MS, Newman SL, Gray TK.; 1983 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=389987

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Volatile metabolites and other indicators of Penicillium aurantiogriseum growth on different substrates. by Borjesson T, Stollman U, Schnurer J.; 1990 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185055

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Volatile Metabolites Controlling Germination in Buried Weed Seeds. by Holm RE.; 1972 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=366127

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Volatile metabolites produced by six fungal species compared with other indicators of fungal growth on cereal grains. by Borjesson T, Stollman U, Schnurer J.; 1992 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=195827

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Whole-Nodule Carbon Metabolites Are Not Involved in the Regulation of the Oxygen Permeability and Nitrogenase Activity in White Clover Nodules. by Weisbach C, Hartwig UA, Heim I, Nosberger J.; 1996 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=157749

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Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. by Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, Bansal VS, Dufresne C, VanMiddlesworth FL, Hensens OD, et al.; 1993 Jan 1; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45603

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 metabolites, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “metabolites” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for metabolites (hyperlinks lead to article summaries): •

A comparison of red blood cell thiopurine metabolites in children with acute lymphoblastic leukemia who received oral mercaptopurine twice daily or once daily: a Pediatric Oncology Group study (now The Children's Oncology Group). Author(s): Bell BA, Brockway GN, Shuster JJ, Erdmann G, Sterikoff S, Bostrom B, Camitta BM; Pediatric Oncology Group study (now The Children's Oncology Group). Source: Pediatric Blood & Cancer. 2004 August; 43(2): 105-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15236274

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A software filter to remove interference ions from drug metabolites in accurate mass liquid chromatography/mass spectrometric analyses. Author(s): Zhang H, Zhang D, Ray K. Source: Journal of Mass Spectrometry : Jms. 2003 October; 38(10): 1110-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14595861

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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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Accumulation of vitamin E metabolites in the blood of renal failure patients. Author(s): Galli F, Floridi AG, Floridi A, Buoncristiani U. Source: Clinical Nutrition (Edinburgh, Lothian). 2004 April; 23(2): 205-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15030960

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Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors. Author(s): Thompson CM, Wojno H, Greiner E, May EL, Rice KC, Selley DE. Source: The Journal of Pharmacology and Experimental Therapeutics. 2004 February; 308(2): 547-54. Epub 2003 November 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14600248

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Acute and chronic effects of dinner with alcoholic beverages on nitric oxide metabolites in healthy men. Author(s): Sierksma A, van der Gaag MS, Grobbee DE, Hendriks HF. Source: Clinical and Experimental Pharmacology & Physiology. 2003 July; 30(7): 504-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12823267

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Adipose tissue metabolites and insulin resistance in nondiabetic Asian Indian men. Author(s): Abate N, Chandalia M, Snell PG, Grundy SM. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 June; 89(6): 2750-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15181053

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Aging may be associated with concentrations of tamoxifen and its metabolites in breast cancer patients. Author(s): Sheth HR, Lord G, Tkaczuk K, Danton M, Lewis LM, Langenberg P, Lim CK, Flaws JA. Source: Journal of Women's Health (2002). 2003 October; 12(8): 799-808. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14588130

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Air concentrations and urinary metabolites of polycyclic aromatic hydrocarbons among paving and remixing workers. Author(s): Vaananen V, Hameila M, Kontsas H, Peltonen K, Heikkila P. Source: Journal of Environmental Monitoring : Jem. 2003 October; 5(5): 739-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14587843

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Albumin adducts of naphthalene metabolites as biomarkers of exposure to polycyclic aromatic hydrocarbons. Author(s): Waidyanatha S, Zheng Y, Serdar B, Rappaport SM. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2004 January; 13(1): 117-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744742

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An investigation of nitric oxide metabolites during symptomatic myocardial ischaemia in relation to exercise tolerance test. Author(s): Elfatih A, Anderson NR, Mansoor S, Ahmed S, Horton R, Holland M, Gama R. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 December; 9(12): Cr511-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14646972

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Analysis of diclofenac and its metabolites by high-performance liquid chromatography: relevance of CYP2C9 genotypes in diclofenac urinary metabolic ratios. Author(s): Dorado P, Berecz R, Caceres MC, LLerena A. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 June 15; 789(2): 437-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742136

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Analysis of eighteen antidepressants, four atypical antipsychotics and active metabolites in serum by liquid chromatography: a simple tool for therapeutic drug monitoring. Author(s): Frahnert C, Rao ML, Grasmader K. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 August 25; 794(1): 35-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888196

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Analysis of the urinary excretion of ifosfamide and its N-dechloroethylated metabolites in children using 31P-NMR spectroscopy. Author(s): Misiura K, Zubowska M, Zielinska E. Source: Arzneimittel-Forschung. 2003; 53(5): 372-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12854365

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Analysis of topiramate and its metabolites in plasma and urine of healthy subjects and patients with epilepsy by use of a novel liquid chromatography-mass spectrometry assay. Author(s): Britzi M, Soback S, Isoherranen N, Levy RH, Perucca E, Doose DR, Maryanoff BE, Bialer M. Source: Therapeutic Drug Monitoring. 2003 June; 25(3): 314-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766560

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Angiotensin II AT1 receptor antagonists. Clinical implications of active metabolites. Author(s): Schmidt B, Schieffer B. Source: Journal of Medicinal Chemistry. 2003 June 5; 46(12): 2261-70. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12773029

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Antiestrogenic and DNA damaging effects induced by tamoxifen and toremifene metabolites. Author(s): Liu X, Pisha E, Tonetti DA, Yao D, Li Y, Yao J, Burdette JE, Bolton JL. Source: Chemical Research in Toxicology. 2003 July; 16(7): 832-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12870885

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Arsenite and its biomethylated metabolites interfere with the formation and repair of stable BPDE-induced DNA adducts in human cells and impair XPAzf and Fpg. Author(s): Schwerdtle T, Walter I, Hartwig A. Source: Dna Repair. 2003 December 9; 2(12): 1449-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642572

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Assessing human exposure to phthalates using monoesters and their oxidized metabolites as biomarkers. Author(s): Barr DB, Silva MJ, Kato K, Reidy JA, Malek NA, Hurtz D, Sadowski M, Needham LL, Calafat AM. Source: Environmental Health Perspectives. 2003 July; 111(9): 1148-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842765

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Bacterial challenge stimulates formation of arachidonic acid metabolites by human keratinocytes and neutrophils in vitro. Author(s): Eberhard J, Jepsen S, Pohl L, Albers HK, Acil Y. Source: Clinical and Diagnostic Laboratory Immunology. 2002 January; 9(1): 132-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11777842

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Baseline levels of glucose metabolites, glutamate and glycerol in malignant glioma assessed by stereotactic microdialysis. Author(s): Roslin M, Henriksson R, Bergstrom P, Ungerstedt U, Bergenheim AT. Source: Journal of Neuro-Oncology. 2003 January; 61(2): 151-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12622454

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Behavioral and biochemical investigations of bupropion metabolites. Author(s): Bondarev ML, Bondareva TS, Young R, Glennon RA. Source: European Journal of Pharmacology. 2003 August 1; 474(1): 85-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12909199

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Benzene metabolites antagonize etoposide-stabilized cleavable complexes of DNA topoisomerase IIalpha. Author(s): Baker RK, Kurz EU, Pyatt DW, Irons RD, Kroll DJ. Source: Blood. 2001 August 1; 98(3): 830-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11468185

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Beta-cell mitochondria and insulin secretion: messenger role of nucleotides and metabolites. Author(s): Wollheim CB, Maechler P. Source: Diabetes. 2002 February; 51 Suppl 1: S37-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11815456

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Bexarotene metabolism in rat, dog, and human, synthesis of oxidative metabolites, and in vitro activity at retinoid receptors. Author(s): Howell SR, Shirley MA, Grese TA, Neel DA, Wells KE, Ulm EH. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2001 July; 29(7): 990-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11408365

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Biliary excretion of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) and metabolites by Fischer 344 rats. Author(s): Musser SM, Egorin MJ, Zuhowski EG, Hamburger DR, Parise RA, Covey JM, White KD, Eiseman JL. Source: Cancer Chemotherapy and Pharmacology. 2003 August; 52(2): 139-46. Epub 2003 May 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12761648

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Binge drinking and nitric oxide metabolites in chronic liver disease. Author(s): Oekonomaki E, Notas G, Mouzas IA, Valatas V, Skordilis P, Xidakis C, Kouroumalis EA. Source: Alcohol and Alcoholism (Oxford, Oxfordshire). 2004 March-April; 39(2): 106-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14998825

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Bioactive metabolites from a marine-derived strain of the fungus Emericella variecolor. Author(s): Malmstrom J, Christophersen C, Barrero AF, Oltra JE, Justicia J, Rosales A. Source: Journal of Natural Products. 2002 March; 65(3): 364-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11908979

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Biocompatibility of hydroxylated metabolites of BISGMA and BFDGE. Author(s): Kostoryz EL, Eick JD, Glaros AG, Judy BM, Welshons WV, Burmaster S, Yourtee DM. Source: Journal of Dental Research. 2003 May; 82(5): 367-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709503

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Biologic effects of parathyroid hormone metabolites: implications for renal bone disease. Author(s): Akhtar I, Gonzalez EA. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2004 January; 52(1): 51-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14989370

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Biologically active secondary metabolites from Ginkgo biloba. Author(s): Bedir E, Tatli II, Khan RA, Zhao J, Takamatsu S, Walker LA, Goldman P, Khan IA. Source: Journal of Agricultural and Food Chemistry. 2002 May 22; 50(11): 3150-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12009978

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Biomonitoring of urinary tamoxifen and its metabolites from breast cancer patients using nonaqueous capillary electrophoresis with electrospray mass spectrometry. Author(s): Carter SJ, Li XF, Mackey JR, Modi S, Hanson J, Dovichi NJ. Source: Electrophoresis. 2001 August; 22(13): 2730-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11545399

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Biotransformation of fucoxanthinol into amarouciaxanthin A in mice and HepG2 cells: formation and cytotoxicity of fucoxanthin metabolites. Author(s): Asai A, Sugawara T, Ono H, Nagao A. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2004 February; 32(2): 205-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744942

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Biphasic hypercalcemia in severe rhabdomyolysis: serial analysis of PTH and vitamin D metabolites. A case report and literature review. Author(s): Shrestha SM, Berry JL, Davies M, Ballardie FW. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2004 March; 43(3): E31-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14981639

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Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs. Author(s): Xiao Y, Smith RD, Caruso FS, Kellar KJ. Source: The Journal of Pharmacology and Experimental Therapeutics. 2001 October; 299(1): 366-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11561100

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Blood glucose is correlated with cerebrospinal fluid neurotransmitter metabolites. Author(s): Umhau JC, Petrulis SG, Diaz R, Rawlings R, George DT. Source: Neuroendocrinology. 2003 December; 78(6): 339-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688447

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Bone mineral content and collagen metabolites in children receiving steroid treatment for nephrotic syndrome. Author(s): Esbjorner E, Arvidsson B, Jones IL, Palmer M. Source: Acta Paediatrica (Oslo, Norway : 1992). 2001 October; 90(10): 1127-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11697422

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Boron neutron capture therapy of brain tumors: investigation of urinary metabolites and oxidation products of sodium borocaptate by electrospray ionization mass spectrometry. Author(s): Gibson CR, Staubus AE, Barth RF, Yang W, Kleinholz NM, Jones RB, GreenChurch K, Tjarks W, Soloway AH. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2001 December; 29(12): 1588-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11717178

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C-3 epimerization of vitamin D3 metabolites and further metabolism of C-3 epimers: 25-hydroxyvitamin D3 is metabolized to 3-epi-25-hydroxyvitamin D3 and subsequently metabolized through C-1alpha or C-24 hydroxylation. Author(s): Kamao M, Tatematsu S, Hatakeyama S, Sakaki T, Sawada N, Inouye K, Ozono K, Kubodera N, Reddy GS, Okano T. Source: The Journal of Biological Chemistry. 2004 April 16; 279(16): 15897-907. Epub 2004 February 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14757768

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Cardiovascular pharmacology of estradiol metabolites. Author(s): Dubey RK, Tofovic SP, Jackson EK. Source: The Journal of Pharmacology and Experimental Therapeutics. 2004 February; 308(2): 403-9. Epub 2003 December 01. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14657266

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Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Author(s): Spencer JP, Abd-el-Mohsen MM, Rice-Evans C. Source: Archives of Biochemistry and Biophysics. 2004 March 1; 423(1): 148-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14989269

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95

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Changes in circulating levels of calcitonin gene-related peptide and nitric oxide metabolites in septic patients during direct hemoperfusion with polymyxin Bimmobilized fiber. Author(s): Shimizu T, Hanasawa K, Tani T, Endo Y, Kurumi Y, Ikeda T, Fujita N, Morita H, Imaizumi H, Sato T, Katayama H. Source: Blood Purification. 2003; 21(3): 237-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784050

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Changes in clinically relevant metabolites with psychological stress parameters. Author(s): Hapuarachchi JR, Chalmers AH, Winefield AH, Blake-Mortimer JS. Source: Behavioral Medicine (Washington, D.C.). 2003 Summer; 29(2): 52-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15147103

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Characterization of cysteinyl leukotriene receptors on human saphenous veins: antagonist activity of montelukast and its metabolites. Author(s): Mechiche H, Candenas L, Pinto FM, Nazeyrollas P, Clement C, Devillier P. Source: Journal of Cardiovascular Pharmacology. 2004 January; 43(1): 113-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668576

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Characterization of Ganstigmine metabolites in hepatocytes by low- and highresolution mass spectrometry coupled with liquid chromatography. Author(s): Pelizzi N, Puccini P, Riccardi B, Acerbi D, Catinella S. Source: Rapid Communications in Mass Spectrometry : Rcm. 2003; 17(15): 1691-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12872272

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Characterization of metabolites of hydroxycinnamates in the in vitro model of human small intestinal epithelium caco-2 cells. Author(s): Kern SM, Bennett RN, Needs PW, Mellon FA, Kroon PA, Garcia-Conesa MT. Source: Journal of Agricultural and Food Chemistry. 2003 December 31; 51(27): 7884-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14690369

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Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Author(s): Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT. Source: Endocrinology. 2003 August; 144(8): 3382-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865317

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Chromatographic determination of free lidocaine and its active metabolites in plasma from patients under epidural anesthesia. Author(s): Kakiuchi Y, Fukuda T, Miyabe M, Homma M, Toyooka H, Kohda Y. Source: Int J Clin Pharmacol Ther. 2002 November; 40(11): 493-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698986

96

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Collision-induced dissociation of valdecoxib metabolites: a novel rearrangement involving an isoxazole ring. Author(s): Zhang JY, Xu F, Breau AP. Source: Journal of Mass Spectrometry : Jms. 2004 March; 39(3): 295-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039937

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Combination of vitamin D metabolites with selective inhibitors of vitamin D metabolism. Author(s): Schuster I, Egger H, Reddy GS, Vorisek G. Source: Recent Results Cancer Res. 2003; 164: 169-88. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899522

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Comparison of the efficiency of various methods for the synthesis of models of metabolites: example of 4a-methylhexahydronaphtalenones. Author(s): Estour F, Menager S, Akagah B, Lafont O. Source: European Journal of Medicinal Chemistry. 2003 November-December; 38(11-12): 925-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642324

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Concentrations of dialkyl phosphate metabolites of organophosphorus pesticides in the U.S. population. Author(s): Barr DB, Bravo R, Weerasekera G, Caltabiano LM, Whitehead RD Jr, Olsson AO, Caudill SP, Schober SE, Pirkle JL, Sampson EJ, Jackson RJ, Needham LL. Source: Environmental Health Perspectives. 2004 February; 112(2): 186-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14754573

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Correspondence re: J. Lu et al., thalidomide metabolites in mice and patients with multiple myeloma. Clin. Cancer Res., 9: 1680-1688, 2003. Author(s): Zhou S. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 November 1; 9(14): 5429; Author Reply 5429. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14614031

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C-reactive protein, procalcitonin, interleukin-6, vascular endothelial growth factor and oxidative metabolites in diagnosis of infection and staging in patients with gastric cancer. Author(s): Ilhan N, Ilhan N, Ilhan Y, Akbulut H, Kucuksu M. Source: World Journal of Gastroenterology : Wjg. 2004 April 15; 10(8): 1115-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15069709

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97

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Current internal exposure to pesticides in children and adolescents in Germany: urinary levels of metabolites of pyrethroid and organophosphorus insecticides. Author(s): Heudorf U, Angerer J, Drexler H. Source: International Archives of Occupational and Environmental Health. 2004 January; 77(1): 67-72. Epub 2003 October 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14551781

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Cyclosporine and its metabolites before and 2 h post-dose: comparative measurements of a monoclonal and a polyclonal immunoassay. Author(s): Vyzantiadis T, Belechri AM, Memmos D, Axiotou M, Vyzantiadis A, Papadimitriou M. Source: Clinical Transplantation. 2003 June; 17(3): 231-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12780673

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Cytogenetic markers, DNA single-strand breaks, urinary metabolites, and DNA repair rates in styrene-exposed lamination workers. Author(s): Vodicka P, Tuimala J, Stetina R, Kumar R, Manini P, Naccarati A, Maestri L, Vodickova L, Kuricova M, Jarventaus H, Majvaldova Z, Hirvonen A, Imbriani M, Mutti A, Migliore L, Norppa H, Hemminki K. Source: Environmental Health Perspectives. 2004 June; 112(8): 867-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15175174

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DDT and its metabolites in breast milk from two regions in Saudi Arabia. Author(s): al-Saleh I, Shinwari N, Basile P, el-Doush I, al-Zahrani M, al-Shanshoury M, el-Din Mohammed G. Source: Journal of Occupational and Environmental Medicine / American College of Occupational and Environmental Medicine. 2003 April; 45(4): 410-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12708145

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Delayed neurological deficits detected by an ischemic pattern in the extracellular cerebral metabolites in patients with aneurysmal subarachnoid hemorrhage. Author(s): Skjoth-Rasmussen J, Schulz M, Kristensen SR, Bjerre P. Source: Journal of Neurosurgery. 2004 January; 100(1): 8-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14743906

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Detection and time course of cocaine N-oxide and other cocaine metabolites in human plasma by liquid chromatography/tandem mass spectrometry. Author(s): Lin SN, Walsh SL, Moody DE, Foltz RL. Source: Analytical Chemistry. 2003 August 15; 75(16): 4335-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14632155

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Determination of 3-keto-4-ene steroids and their hydroxylated metabolites catalyzed by recombinant human cytochrome P450 1B1 enzyme using gas chromatography-mass spectrometry with trimethylsilyl derivatization. Author(s): Song J, Wadhwa L, Bejjani BA, O'Brien WE. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 July 5; 791(1-2): 127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798173

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Determination of cyclooxygenase and arachidonic acid metabolites in invasive human prostate cancer cells. Author(s): Nithipatikom K, Borscheid CL, Kajdacsy-Balla A, Kaul S, Lindholm PF, Pytynia KB, Campbell WB. Source: Advances in Experimental Medicine and Biology. 2002; 507: 269-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12664596

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Determination of heroin metabolites in human urine using capillary zone electrophoresis with beta-cyclodextrin and UV detection. Author(s): Alnajjar A, McCord B. Source: Journal of Pharmaceutical and Biomedical Analysis. 2003 October 15; 33(3): 46373. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550865

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Determination of methamphetamine and its metabolites incorporated in hair by column-switching liquid chromatography-mass spectrometry. Author(s): Miki A, Katagi M, Tsuchihashi H. Source: Journal of Analytical Toxicology. 2003 March; 27(2): 95-102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12670003

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Determination of nicotine and its metabolites in urine by solid-phase extraction and sample stacking capillary electrophoresis-mass spectrometry. Author(s): Baidoo EE, Clench MR, Smith RF, Tetler LW. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 November 5; 796(2): 303-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581070

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Determination of testosterone metabolites in human hepatocytes. I. Development of an on-line sample preparation liquid chromatography technique and mass spectroscopic detection of 6beta-hydroxytestosterone. Author(s): Friedrich G, Rose T, Rissler K. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 January 25; 784(1): 49-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12504182

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Determination of three phthalate metabolites in human urine using on-line solidphase extraction-liquid chromatography-tandem mass spectrometry. Author(s): Kato K, Shoda S, Takahashi M, Doi N, Yoshimura Y, Nakazawa H. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 May 25; 788(2): 407-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12705982

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Determination of valdecoxib and its metabolites in human urine by automated solidphase extraction-liquid chromatography-tandem mass spectrometry. Author(s): Zhang JY, Fast DM, Breau AP. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 February 25; 785(1): 123-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12535845

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Determination of ximelagatran, an oral direct thrombin inhibitor, its active metabolite melagatran, and the intermediate metabolites, in biological samples by liquid chromatography-mass spectrometry. Author(s): Larsson M, Ahnoff M, Abrahamsson A, Logren U, Fakt C, Ohrman I, Persson BA. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 January 15; 783(2): 335-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12482476

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Detoxification of 4-hydroxynonenal (HNE) in keratinocytes: characterization of conjugated metabolites by liquid chromatography/electrospray ionization tandem mass spectrometry. Author(s): Aldini G, Granata P, Orioli M, Santaniello E, Carini M. Source: Journal of Mass Spectrometry : Jms. 2003 November; 38(11): 1160-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14648823

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Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Author(s): Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Source: British Journal of Anaesthesia. 2004 February; 92(2): 208-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14722170

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Direct measurement of alcohol and its metabolites. Author(s): Swift R. Source: Addiction (Abingdon, England). 2003 December; 98 Suppl 2: 73-80. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14984244

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Disease-related metabolites in culture medium of fibroblasts from patients with D-2hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, and combined D/L-2hydroxyglutaric aciduria. Author(s): Struys EA, Verhoeven NM, Roos B, Jakobs C. Source: Clinical Chemistry. 2003 July; 49(7): 1133-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12816910

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Distribution of methyl sulfone metabolites of polychlorinated biphenyls and p,p'DDE in human tissues. Author(s): Chu S, Covaci A, Jacobs W, Haraguchi K, Schepens P. Source: Environmental Health Perspectives. 2003 July; 111(9): 1222-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842777

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Drug and chemical metabolites in clinical toxicology investigations: the importance of ethylene glycol, methanol and cannabinoid metabolite analyses. Author(s): Fraser AD, Coffin L, Worth D. Source: Clinical Biochemistry. 2002 October; 35(7): 501-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12493577

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Drug metabolites in safety testing. Author(s): Hastings KL, El-Hage J, Jacobs A, Leighton J, Morse D, Osterberg RE. Source: Toxicology and Applied Pharmacology. 2003 July 1; 190(1): 91-2; Author Reply 93-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12831788

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Editorial comment--ADC and metabolites in stroke: even more confusion about diffusion? Author(s): Fiehler J. Source: Stroke; a Journal of Cerebral Circulation. 2003 July; 34(7): E87-8. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12817103

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Effect of tibolone and its metabolites on vascular endothelial growth factor isoforms 121 and 165 and thrombospondin-1 mRNA in Ishikawa cells. Author(s): Mirkin S, Mahony MC, Archer DF. Source: Menopause (New York, N.Y.). 2004 January-February; 11(1): 82-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14716187

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101

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Effects of clozapine and its metabolites on the 5-HT2 receptor system in cortical and hippocampal cells in vitro. Author(s): Heiser P, Schulte E, Hausmann C, Becker R, Remschmidt H, Krieg JC, Vedder H. Source: Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2004 March; 28(2): 297-302. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751426

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Effects of cysteinyl leukotrienes in small human bronchus and antagonist activity of montelukast and its metabolites. Author(s): Mechiche H, Naline E, Candenas L, Pinto FM, Birembault P, Advenier C, Devillier P. Source: Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 2003 July; 33(7): 887-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12859443

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Effects of heavy drinking, binge drinking, and family history of alcoholism on regional brain metabolites. Author(s): Meyerhoff DJ, Blumenfeld R, Truran D, Lindgren J, Flenniken D, Cardenas V, Chao LL, Rothlind J, Studholme C, Weiner MW. Source: Alcoholism, Clinical and Experimental Research. 2004 April; 28(4): 650-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15100618

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Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug. Author(s): Kato K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Kanno M, Otani K. Source: Therapeutic Drug Monitoring. 2003 August; 25(4): 473-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883232

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Effects of simvastatin and L-arginine on vasodilation, nitric oxide metabolites and endogenous NOS inhibitors in hypercholesterolemic subjects. Author(s): Pereira EC, Bertolami MC, Faludi AA, Salem M, Bersch D, Abdalla DS. Source: Free Radical Research. 2003 May; 37(5): 529-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12797474

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Effects of the mycotoxin ochratoxin A and some of its metabolites on human kidney cell lines. Author(s): Muller G, Burkert B, Rosner H, Kohler H. Source: Toxicology in Vitro : an International Journal Published in Association with Bibra. 2003 August; 17(4): 441-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12849727

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Elevated levels of some neuroactive progesterone metabolites, particularly isopregnanolone, in women with chronic fatigue syndrome. Author(s): Murphy BE, Abbott FV, Allison CM, Watts C, Ghadirian AM. Source: Psychoneuroendocrinology. 2004 February; 29(2): 245-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14604604

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Elevated urinary excretion of nitric oxide metabolites in young infants with Zellweger syndrome. Author(s): Surdacki A, Tsikas D, Mayatepek E, Frolich JC. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 August; 334(1-2): 111-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867281

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Enantioselective quantitation of the ecstasy compound (R)- and (S)-N-ethyl-3,4methylenedioxyamphetamine and its major metabolites in human plasma and urine. Author(s): Buechler J, Schwab M, Mikus G, Fischer B, Hermle L, Marx C, Gron G, Spitzer M, Kovar KA. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 August 15; 793(2): 207-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12906896

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Environmental fate of bisphenol A and its biological metabolites in river water and their xeno-estrogenic activity. Author(s): Suzuki T, Nakagawa Y, Takano I, Yaguchi K, Yasuda K. Source: Environmental Science & Technology. 2004 April 15; 38(8): 2389-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15116845

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Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. Author(s): Russo J, Hasan Lareef M, Balogh G, Guo S, Russo IH. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 October; 87(1): 1-25. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14630087

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Estrogen metabolites and the risk of breast cancer in older women. Author(s): Cauley JA, Zmuda JM, Danielson ME, Ljung BM, Bauer DC, Cummings SR, Kuller LH. Source: Epidemiology (Cambridge, Mass.). 2003 November; 14(6): 740-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14569192

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Estrogen metabolites: increasing evidence for their role in rheumatoid arthritis and systemic lupus erythematosus. Author(s): Cutolo M. Source: The Journal of Rheumatology. 2004 March; 31(3): 419-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14994382

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Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Author(s): Hirshman E, Merritt P, Wang CC, Wierman M, Budescu DV, Kohrt W, Templin JL, Bhasin S. Source: Hormones and Behavior. 2004 February; 45(2): 144-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15019802

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Exploitation of heparanase inhibitors from microbial metabolites using an efficient visual screening system. Author(s): Ishida K, Teruya T, Simizu S, Osada H. Source: J Antibiot (Tokyo). 2004 February; 57(2): 136-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15112962

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Exponential modeling, washout curve reconstruction, and estimation of half-life of toluene and its metabolites. Author(s): Pierce C, Chen Y, Hurtle W, Morgan M. Source: Journal of Toxicology and Environmental Health. Part A. 2004 July 23; 67(14): 1131-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15205028

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Extended application of an LC-MS/MS method for the analysis of vesnarinone and its metabolites in human urine and dialysate fluid. Author(s): Sekar KS, Bramer SL. Source: Journal of Pharmaceutical and Biomedical Analysis. 2003 November 24; 33(4): 711-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623597

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Extracellular matrix metabolites as potential biomarkers of disease activity in wound fluid: lessons learned from other inflammatory diseases? Author(s): Moseley R, Stewart JE, Stephens P, Waddington RJ, Thomas DW. Source: The British Journal of Dermatology. 2004 March; 150(3): 401-13. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15030321

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Family psychiatric history, cerebrospinal fluid monoamine metabolites, and temperament in infants. Author(s): Constantino JN, Murphy DL, Morris JA. Source: Biological Psychiatry. 1999 March 1; 45(5): 626-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10088050

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Fast quantification method for sirolimus and its major metabolites. Author(s): Kirchner GI, Jacobsen W, Deters M, Christians U, Nashan B, Winkler M, Vidal C, Kaever V, Sewing K, Manns MP. Source: Transplantation Proceedings. 2001 February-March; 33(1-2): 1091-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11267205

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Fatty acid ethyl esters. Ethanol metabolites that reflect ethanol intake. Author(s): Soderberg BL, Salem RO, Best CA, Cluette-Brown JE, Laposata M. Source: American Journal of Clinical Pathology. 2003 June; 119 Suppl: S94-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12951847

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Fatty acid ethyl esters: ethanol metabolites which mediate ethanol-induced organ damage and serve as markers of ethanol intake. Author(s): Laposata M. Source: Progress in Lipid Research. 1998 November; 37(5): 307-16. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10209651

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Fatty acid ethyl esters: nonoxidative ethanol metabolites with emerging biological and clinical significance. Author(s): Laposata M. Source: Lipids. 1999; 34 Suppl: S281-5. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10419178

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Fatty acid ethyl esters: toxic non-oxidative metabolites of ethanol and markers of ethanol intake. Author(s): Best CA, Laposata M. Source: Frontiers in Bioscience : a Journal and Virtual Library. 2003 January 1; 8: E20217. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12456329

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Flutamide-induced hepatic dysfunction in relation to steady-state plasma concentrations of flutamide and its metabolites. Author(s): Aizawa Y, Ikemoto I, Kishimoto K, Wada T, Yamazaki H, Ohishi Y, Kiyota H, Furuta N, Suzuki H, Ueda M. Source: Molecular and Cellular Biochemistry. 2003 October; 252(1-2): 149-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14577588

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105

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Fluvoxamine increases plasma and urinary levels of clozapine and its major metabolites in a time- and dose-dependent manner. Author(s): Fabrazzo M, La Pia S, Monteleone P, Mennella R, Esposito G, Pinto A, Maj M. Source: Journal of Clinical Psychopharmacology. 2000 December; 20(6): 708-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11106150

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Formation of nitrogen-containing metabolites from the main iridoids of Harpagophytum procumbens and H. zeyheri by human intestinal bacteria. Author(s): Baghdikian B, Guiraud-Dauriac H, Ollivier E, N'Guyen A, Dumenil G, Balansard G. Source: Planta Medica. 1999 March; 65(2): 164-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10193209

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Formation of novel bioactive metabolites from the reactions of pro-inflammatory oxidants with polyphenolics. Author(s): Boersma BJ, Patel RP, Botting N, White CR, Parks D, Barnes S, Darley-Usmar VM. Source: Biofactors (Oxford, England). 2001; 15(2-4): 79-81. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12016330

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Formation of propentdyopents and biliverdin, oxidized metabolites of bilirubin, in infants receiving oxygen therapy. Author(s): Kunikata T, Itoh S, Ozaki T, Kondo M, Isobe K, Onishi S. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2000 August; 42(4): 331-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10986860

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Fungal metabolites, asterric acid derivatives inhibit vascular endothelial growth factor (VEGF)-induced tube formation of HUVECs. Author(s): Lee HJ, Lee JH, Hwang BY, Kim HS, Lee JJ. Source: J Antibiot (Tokyo). 2002 June; 55(6): 552-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12195960

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Fungal metabolites, PF1092 compounds and their derivatives, are nonsteroidal and selective progesterone receptor modulators. Author(s): Tabata Y, Iizuka Y, Kashiwa J, Masuda NT, Shinei R, Kurihara K, Okonogi T, Hoshiko S, Kurata Y. Source: European Journal of Pharmacology. 2001 November 2; 430(2-3): 159-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11711027

106

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Further characterisation of the interaction of haloperidol metabolites with neurotransmitter transporters in rat neuronal cultures and in transfected COS-7 cells. Author(s): Siebert GA, Pond SM, Bryan-Lluka LJ. Source: Naunyn-Schmiedeberg's Archives of Pharmacology. 2000 March; 361(3): 255-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10731037

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gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor. Author(s): Basaki Y, Chikahisa L, Aoyagi K, Miyadera K, Yonekura K, Hashimoto A, Okabe S, Wierzba K, Yamada Y. Source: Angiogenesis. 2001; 4(3): 163-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11911014

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Gas chromatography mass spectrometry analysis of carboxyethyl-hydroxychroman metabolites of alpha- and gamma-tocopherol in human plasma. Author(s): Galli F, Lee R, Dunster C, Kelly FJ. Source: Free Radical Biology & Medicine. 2002 February 15; 32(4): 333-40. Erratum In: Free Radic Biol Med. 2002 April 15; 32(8): 785. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11841923

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GC-MS determination of heroin metabolites in meconium: evaluation of four solidphase extraction cartridges. Author(s): Salem MY, Ross SA, Murphy TP, ElSohly MA. Source: Journal of Analytical Toxicology. 2001 March; 25(2): 93-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11300513

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Gender differences in the levels of bisphenol A metabolites in urine. Author(s): Kim YH, Kim CS, Park S, Han SY, Pyo MY, Yang M. Source: Biochemical and Biophysical Research Communications. 2003 December 12; 312(2): 441-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14637157

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Gender differences in the urinary excretion rates of cortisol and androgen metabolites. Author(s): Shamim W, Yousufuddin M, Bakhai A, Coats AJ, Honour JW. Source: Annals of Clinical Biochemistry. 2000 November; 37 ( Pt 6): 770-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11085621

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Gender differences in urinary excretion rates of cortisol and androgen metabolites. Author(s): Lamb EJ, Noonan KA, Burrin JM. Source: Annals of Clinical Biochemistry. 2001 July; 38(Pt 4): 412. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11471888

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107

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Generation of reactive oxygen metabolites by the varicose vein wall. Author(s): Glowinski J, Glowinski S. Source: European Journal of Vascular and Endovascular Surgery : the Official Journal of the European Society for Vascular Surgery. 2002 June; 23(6): 550-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12093073

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Genotoxic activation of benzophenone and its two metabolites by human cytochrome P450s in SOS/umu assay. Author(s): Takemoto K, Yamazaki H, Nakajima M, Yokoi T. Source: Mutation Research. 2002 August 26; 519(1-2): 199-204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12160905

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Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. Author(s): Yue W, Santen RJ, Wang JP, Li Y, Verderame MF, Bocchinfuso WP, Korach KS, Devanesan P, Todorovic R, Rogan EG, Cavalieri EL. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 September; 86(3-5): 477-86. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623547

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Genotoxic potential of xenobiotic growth promoters and their metabolites. Author(s): Metzler M, Pfeiffer E. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 2001 February; 109(2): 89-95. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11398999

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Genotoxicity of benzene and its metabolites. Author(s): Whysner J, Reddy MV, Ross PM, Mohan M, Lax EA. Source: Mutation Research. 2004 March; 566(2): 99-130. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15164977

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Glucocorticoids inhibit interconversion of 7-hydroxy and 7-oxo metabolites of dehydroepiandrosterone: a role for 11beta-hydroxysteroid dehydrogenases? Author(s): Robinzon B, Michael KK, Ripp SL, Winters SJ, Prough RA. Source: Archives of Biochemistry and Biophysics. 2003 April 15; 412(2): 251-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12667489

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Glucuronidation of arachidonic and linoleic acid metabolites by human UDPglucuronosyltransferases. Author(s): Turgeon D, Chouinard S, Belanger P, Picard S, Labbe JF, Borgeat P, Belanger A. Source: Journal of Lipid Research. 2003 June; 44(6): 1182-91. Epub 2003 March 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12639971

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Glucuronidation patterns of common urinary and serum monoester phthalate metabolites. Author(s): Silva MJ, Barr DB, Reidy JA, Kato K, Malek NA, Hodge CC, Hurtz D 3rd, Calafat AM, Needham LL, Brock JW. Source: Archives of Toxicology. 2003 October; 77(10): 561-7. Epub 2003 June 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14574443

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Glutamine and glutamate as vital metabolites. Author(s): Newsholme P, Lima MM, Procopio J, Pithon-Curi TC, Doi SQ, Bazotte RB, Curi R. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 2003 February; 36(2): 153-63. Epub 2003 January 29. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12563517

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Glycoalkaloids and metabolites inhibit the growth of human colon (HT29) and liver (HepG2) cancer cells. Author(s): Lee KR, Kozukue N, Han JS, Park JH, Chang EY, Baek EJ, Chang JS, Friedman M. Source: Journal of Agricultural and Food Chemistry. 2004 May 19; 52(10): 2832-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15137822

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Granulocytic differentiation of human NB4 promyelocytic leukemia cells induced by all-trans retinoic acid metabolites. Author(s): Idres N, Benoit G, Flexor MA, Lanotte M, Chabot GG. Source: Cancer Research. 2001 January 15; 61(2): 700-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11212271

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Hair analysis for opiates, cocaine and metabolites. Evaluation of a method by interlaboratory comparison. Author(s): Montagna M, Polettini A, Stramesi C, Groppi A, Vignali C. Source: Forensic Science International. 2002 August 14; 128(1-2): 79-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12208026

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Haptenation of sulfonamide reactive metabolites to cellular proteins. Author(s): Manchanda T, Hess D, Dale L, Ferguson SG, Rieder MJ. Source: Molecular Pharmacology. 2002 November; 62(5): 1011-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12391263

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Heme oxygenase in liver transplantation: heme catabolism and metabolites in the search of function. Author(s): Bauer M. Source: Hepatology (Baltimore, Md.). 2003 August; 38(2): 286-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883470

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Hemoglobin metabolites mimic benzodiazepines and are possible mediators of hepatic encephalopathy. Author(s): Ruscito BJ, Harrison NL. Source: Blood. 2003 August 15; 102(4): 1525-8. Epub 2003 April 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12714506

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Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells. Author(s): Chen JK, Capdevila J, Harris RC. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 April 30; 99(9): 6029-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11983897

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Hepatic biotransformation of the new calcium-mimetic agent, RWJ-68025, in the rat and in man--API-MS/MS identification of metabolites. Author(s): Wu WN, McKown LA, Rybczynski PJ, Demarest K. Source: The Journal of Pharmacy and Pharmacology. 2003 May; 55(5): 631-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12831505

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High-performance liquid chromatographic assay for abacavir and its two major metabolites in human urine and cerebrospinal fluid. Author(s): Ravitch JR, Moseley CG. Source: J Chromatogr B Biomed Sci Appl. 2001 October 25; 762(2): 165-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11678376

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High-performance liquid chromatographic assay for alpha-lipoic acid and five of its metabolites in human plasma and urine. Author(s): Teichert J, Preiss R. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2002 April 5; 769(2): 269-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11996493

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High-performance liquid chromatographic assay of metabolites of thioguanine and mercaptopurine in capillary blood. Author(s): Erb N, Haverland U, Harms DO, Escherich G, Janka-Schaub G. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 October 25; 796(1): 87-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14552819

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High-performance liquid chromatographic method for determination of amodiaquine, chloroquine and their monodesethyl metabolites in biological samples. Author(s): Minzi OM, Rais M, Svensson JO, Gustafsson LL, Ericsson O. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 January 15; 783(2): 473-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12482490

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High-sensitivity analyses of metabolites in biological samples by capillary electrophoresis using dynamic pH junction-sweeping. Author(s): Britz-McKibbin P, Terabe S. Source: Chemical Record (New York, N.Y.). 2002; 2(6): 397-404. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12469351

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High-throughput quantification of drugs and their metabolites in biosamples by LCMS/MS and CE-MS/MS: possibilities and limitations. Author(s): Hopfgartner G, Husser C, Zell M. Source: Therapeutic Drug Monitoring. 2002 February; 24(1): 134-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11805734

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HPLC assay for albendazole and metabolites in human plasma for clinical pharmacokinetic studies. Author(s): Kitzman D, Cheng KJ, Fleckenstein L. Source: Journal of Pharmaceutical and Biomedical Analysis. 2002 October 15; 30(3): 80113. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12367706

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Human biomonitoring of pyrethrum and pyrethroid insecticides used indoors: determination of the metabolites E-cis/trans-chrysanthemumdicarboxylic acid in human urine by gas chromatography-mass spectrometry with negative chemical ionization. Author(s): Elflein L, Berger-Preiss E, Preiss A, Elend M, Levsen K, Wunsch G. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 October 5; 795(2): 195-207. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14522024

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Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin. Author(s): Day AJ, Mellon F, Barron D, Sarrazin G, Morgan MR, Williamson G. Source: Free Radical Research. 2001 December; 35(6): 941-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11811545

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Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. Author(s): Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G. Source: The Journal of Experimental Medicine. 2003 January 20; 197(2): 163-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538656

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Human uridine diphosphate-glucuronosyltransferase UGT2B7 conjugates mineralocorticoid and glucocorticoid metabolites. Author(s): Girard C, Barbier O, Veilleux G, El-Alfy M, Belanger A. Source: Endocrinology. 2003 June; 144(6): 2659-68. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746330

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Hydroxylated PCB metabolites and PCBs in serum from pregnant Faroese women. Author(s): Fangstrom B, Athanasiadou M, Grandjean P, Weihe P, Bergman A. Source: Environmental Health Perspectives. 2002 September; 110(9): 895-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12204824

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Identification of novel metabolites of pioglitazone in rat and dog. Author(s): Shen Z, Reed JR, Creighton M, Liu DQ, Tang YS, Hora DF, Feeney W, Szewczyk J, Bakhtiar R, Franklin RB, Vincent SH. Source: Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 2003 May; 33(5): 499-509. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12746106

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Improved quantitative detection of 11 urinary phthalate metabolites in humans using liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry. Author(s): Silva MJ, Malek NA, Hodge CC, Reidy JA, Kato K, Barr DB, Needham LL, Brock JW. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 June 15; 789(2): 393-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742130

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In vitro antimalarial activities of the microbial metabolites. Author(s): Otoguro K, Ui H, Ishiyama A, Arai N, Kobayashi M, Takahashi Y, Masuma R, Shiomi K, Yamada H, Omura S. Source: J Antibiot (Tokyo). 2003 March; 56(3): 322-4. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12760691

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In vitro metabolism of ethoxidine by human CYP1A1 and rat microsomes: identification of metabolites by high-performance liquid chromatography combined with electrospray tandem mass spectrometry and accurate mass measurements by time-of-flight mass spectrometry. Author(s): Deroussent A, Re M, Hoellinger H, Vanquelef E, Duval O, Sonnier M, Cresteil T. Source: Rapid Communications in Mass Spectrometry : Rcm. 2004; 18(4): 474-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14966856

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In vivo 1H NMR spectroscopy of individual human brain metabolites at moderate field strengths. Author(s): Trabesinger AH, Meier D, Boesiger P. Source: Magnetic Resonance Imaging. 2003 December; 21(10): 1295-302. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14725936

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Induction of apoptosis by vitamin D metabolites and analogs in a glioma cell line. Author(s): Elias J, Marian B, Edling C, Lachmann B, Noe CR, Rolf SH, Schuster I. Source: Recent Results Cancer Res. 2003; 164: 319-32. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899531

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Induction of apoptosis in cultured human proximal tubule cells by fumonisins and fumonisin metabolites. Author(s): Seefelder W, Humpf HU, Schwerdt G, Freudinger R, Gekle M. Source: Toxicology and Applied Pharmacology. 2003 October 15; 192(2): 146-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550748

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Induction of oxidative DNA damage by arsenite and its trivalent and pentavalent methylated metabolites in cultured human cells and isolated DNA. Author(s): Schwerdtle T, Walter I, Mackiw I, Hartwig A. Source: Carcinogenesis. 2003 May; 24(5): 967-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12771042

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Infiltration and adsorption of dissolved atrazine and atrazine metabolites in buffalograss filter strips. Author(s): Krutz LJ, Senseman SA, Dozier MC, Hoffman DW, Tierney DP. Source: J Environ Qual. 2003 November-December; 32(6): 2319-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14674556

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Infiltration of acetochlor and two of its metabolites in two contrasting soils. Author(s): Baran N, Mouvet C, Dagnac T, Jeannot R. Source: J Environ Qual. 2004 January-February; 33(1): 241-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14964378

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Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Author(s): Kirchheiner J, Stormer E, Meisel C, Steinbach N, Roots I, Brockmoller J. Source: Pharmacogenetics. 2003 August; 13(8): 473-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893985

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Inhibition of Na+, K+-ATPase activity in rat striatum by the metabolites accumulated in Lesch-Nyhan disease. Author(s): Bavaresco CS, Zugno AI, Tagliari B, Wannmacher CM, Wajner M, Wyse AT. Source: International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience. 2004 February; 22(1): 11-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15013074

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Interindividual variation in the ratio between plasma morphine and its metabolites in cancer patients. Author(s): Tateishi M, Ohashi K, Kobayashi K, Hashimoto T, Yamaguchi J, Fujioka H, Izawa K, Masada M. Source: Int J Clin Pharmacol Res. 2003; 23(2-3): 75-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15018021

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Investigations on the pharmacokinetics of trofosfamide and its metabolites-first report of 4-hydroxy-trofosfamide kinetics in humans. Author(s): Preiss R, Baumann F, Stefanovic D, Niemeyer U, Ponisch W, Niederwieser D. Source: Cancer Chemotherapy and Pharmacology. 2004 June; 53(6): 496-502. Epub 2004 January 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138712

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Is survival possible without arachidonate metabolites in the brain during systemic infection? Author(s): Zhang J, Rivest S. Source: News in Physiological Sciences : an International Journal of Physiology Produced Jointly by the International Union of Physiological Sciences and the American Physiological Society. 2003 August; 18: 137-42. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12869612

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Isotope dilution high-performance liquid chromatography-tandem mass spectrometry method for quantifying urinary metabolites of synthetic pyrethroid insecticides. Author(s): Baker SE, Olsson AO, Barr DB. Source: Archives of Environmental Contamination and Toxicology. 2004 April; 46(3): 281-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15195798

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Kinetic phenotypic diagnosis of N-acetylation polymorphism in patients based on ratio of urinary metabolites of salicylazosulfapyridine. Author(s): Yokogawa K, Nakaharu T, Ishizaki J, Ozaki E, Takeda Y, Mabuchi H, Matsushita R, Kimura K, Nakashima E, Ichimura F, Miyamoto K. Source: International Journal of Pharmaceutics. 2001 October 23; 229(1-2): 183-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11604271

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Kinetics of kavain and its metabolites after oral application. Author(s): Tarbah F, Mahler H, Kardel B, Weinmann W, Hafner D, Daldrup T. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 June 5; 789(1): 115-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12726850

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Lactic acid bacteria secrete metabolites retaining anti-inflammatory properties after intestinal transport. Author(s): Menard S, Candalh C, Bambou JC, Terpend K, Cerf-Bensussan N, Heyman M. Source: Gut. 2004 June; 53(6): 821-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138208

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Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity. Author(s): Coller JK, Krebsfaenger N, Klein K, Wolbold R, Nussler A, Neuhaus P, Zanger UM, Eichelbaum M, Murdter TE. Source: British Journal of Clinical Pharmacology. 2004 January; 57(1): 105-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678348

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Last performance with VIAGRA: post-mortem identification of sildenafil and its metabolites in biological specimens including hair sample. Author(s): Dumestre-Toulet V, Cirimele V, Gromb S, Belooussoff T, Lavault D, Ludes B, Kintz P. Source: Forensic Science International. 2002 March 28; 126(1): 71-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11955836

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LC determination of moclobemide and three metabolites in plasma. Author(s): Misztal G, Skibinski R, Olajossy M, Paw B. Source: Journal of Pharmaceutical and Biomedical Analysis. 2002 November 7; 30(4): 1277-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12408918

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LC/MS/MS determination of omapatrilat, a sulfhydryl-containing vasopeptidase inhibitor, and its sulfhydryl- and thioether-containing metabolites in human plasma. Author(s): Jemal M, Khan S, Teitz DS, McCafferty JA, Hawthorne DJ. Source: Analytical Chemistry. 2001 November 15; 73(22): 5450-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11816572

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LC-atmospheric pressure chemical ionization-MS/ MS analysis of multiple illicit drugs, methadone, and their metabolites in oral fluid following protein precipitation. Author(s): Dams R, Murphy CM, Choo RE, Lambert WE, De Leenheer AP, Huestis MA. Source: Analytical Chemistry. 2003 February 15; 75(4): 798-804. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12622369

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LC-MS/MS identification of in vitro metabolites of a new H+/K+ ATPase inhibitor, KR-60436 produced by rat and human liver microsomes. Author(s): Choi SJ, Ji HY, Baek SK, Lee HY, Choi JK, Cheon HG, Lee DH, Lim H, Lee HS. Source: Journal of Pharmaceutical and Biomedical Analysis. 2002 June 1; 28(5): 897-902. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12039631

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Leakage of metabolites from tissue biopsies can result in large errors in quantitation by MRS. Author(s): Bourne R, Dzendrowskyj T, Mountford C. Source: Nmr in Biomedicine. 2003 April; 16(2): 96-101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730950

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Linoleic acid induces interleukin-8 production by Crohn's human intestinal smooth muscle cells via arachidonic acid metabolites. Author(s): Alzoghaibi MA, Walsh SW, Willey A, Yager DR, Fowler AA 3rd, Graham MF. Source: American Journal of Physiology. Gastrointestinal and Liver Physiology. 2004 April; 286(4): G528-37. Epub 2003 December 04. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14656710

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Liquid chromatographic determination of oxcarbazepine and its metabolites in plasma of epileptic patients after solid-phase extraction. Author(s): Mandrioli R, Ghedini N, Albani F, Kenndler E, Raggi MA. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 January 5; 783(1): 253-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12450546

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Liquid chromatographic method for simultaneous determination of mycophenolic acid and its phenol- and acylglucuronide metabolites in plasma. Author(s): Khoschsorur G, Erwa W. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2004 January 25; 799(2): 355-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14670756

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Liquid chromatographic-mass spectrometric determination of cyclooxygenase metabolites of arachidonic acid in cultured cells. Author(s): Nithipatikom K, Laabs ND, Isbell MA, Campbell WB. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 February 25; 785(1): 135-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12535846

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Liquid chromatographic-mass spectrometric determination of haloperidol and its metabolites in human plasma and urine. Author(s): Arinobu T, Hattori H, Iwai M, Ishii A, Kumazawa T, Suzuki O, Seno H. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2002 August 25; 776(1): 107-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12127331

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Liquid chromatography with amperometric detection using functionalized multi-wall carbon nanotube modified electrode for the determination of monoamine neurotransmitters and their metabolites. Author(s): Zhang W, Xie Y, Ai S, Wan F, Wang J, Jin L, Jin J. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 July 5; 791(1-2): 217-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798181

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Liquid chromatography-electrospray ionization ion trap mass spectrometry for analysis of mesocarb and its metabolites in human urine. Author(s): Appolonova SA, Shpak AV, Semenov VA. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2004 February 5; 800(1-2): 281-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698267

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Liquid chromatography-mass spectrometry method for the analysis of the anti-cancer agent capecitabine and its nucleoside metabolites in human plasma. Author(s): Xu Y, Grem JL. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 January 5; 783(1): 273-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12450548

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Liquid chromatography-tandem mass spectrometry identification of metabolites of three phenylcarboxyl derivatives of the 5-HT(1A) antagonist, N-(2-(4-(2methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) trans-4fluorocyclohexanecarboxamide (FCWAY), produced by human and rat hepatocytes. Author(s): Ma Y, Lang L, Kiesewetter DO, Eckelman WC. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2002 November 15; 780(1): 99-110. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12383485

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Long saphenous vein stripping reduces local level of reactive oxygen metabolites in patients with varicose disease of the lower limbs. Author(s): Flore R, Santoliquido A, Antonio DL, Pola E, Flex A, Pola R, Muzi MG, Farinon A, Rulli F, Gaetani E, Tondi P, Gerardino L, Gasbarrini A. Source: World Journal of Surgery. 2003 April; 27(4): 473-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12658495

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Longitudinal study of MRS metabolites in Rasmussen encephalitis. Author(s): Wellard RM, Briellmann RS, Wilson JC, Kalnins RM, Anderson DP, Federico P, Fabinyi GC, Scheffer IE, Harvey AS, Jackson GD. Source: Brain; a Journal of Neurology. 2004 June; 127(Pt 6): 1302-12. Epub 2004 April 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15069020

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Long-term pharmacokinetics of the metabolites of everolimus and cyclosporine in renal transplant recipients. Author(s): Kirchner G, Mueller L, Winkler M, Loss M, Roechte F, Deters M, Christians U, Kaever V, Klempnauer J, Sewing K, Manns M. Source: Transplantation Proceedings. 2002 September; 34(6): 2233-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12270379

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Metabolism of a new antiepileptic drug, N-methyltetramethylcyclopropanecarboxamide, and anticonvulsant activity of its metabolites. Author(s): Isoherranen N, Levy RH, Yagen B, Woodhead JH, White HS, Bialer M. Source: Epilepsy Research. 2004 January; 58(1): 1-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15066669

118

Metabolites

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Metabolites of a tobacco-specific lung carcinogen in nonsmoking casino patrons. Author(s): Anderson KE, Kliris J, Murphy L, Carmella SG, Han S, Link C, Bliss RL, Puumala S, Murphy SE, Hecht SS. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 December; 12(12): 1544-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14693752

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Metabolites of orally administered Magnolia officinalis extract in rats and man and its antidepressant-like effects in mice. Author(s): Nakazawa T, Yasuda T, Ohsawa K. Source: The Journal of Pharmacy and Pharmacology. 2003 November; 55(11): 1583-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14713371

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Metabolites: a helping hand for pathway evolution? Author(s): Schmidt S, Sunyaev S, Bork P, Dandekar T. Source: Trends in Biochemical Sciences. 2003 June; 28(6): 336-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826406

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Methods for detection of reactive metabolites of oxygen and nitrogen: in vitro and in vivo considerations. Author(s): Tarpey MM, Wink DA, Grisham MB. Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2004 March; 286(3): R431-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14761864

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Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Author(s): Nygaard U, Toft N, Schmiegelow K. Source: Clinical Pharmacology and Therapeutics. 2004 April; 75(4): 274-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15060506

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Methylated metabolites of arsenic trioxide are more potent than arsenic trioxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells. Author(s): Chen GQ, Zhou L, Styblo M, Walton F, Jing Y, Weinberg R, Chen Z, Waxman S. Source: Cancer Research. 2003 April 15; 63(8): 1853-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702573

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Microdialysate metabolites before, during and after vascular surgery for chronic leg ischaemia. Author(s): Metzsch C, Lundberg CJ, Danielsson P, Norgren L. Source: European Journal of Vascular and Endovascular Surgery : the Official Journal of the European Society for Vascular Surgery. 2003 May; 25(5): 438-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12713783

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Modifications of plasma and platelet levels of L-DOPA and its direct metabolites during treatment with tolcapone or entacapone in patients with Parkinson's disease. Author(s): Blandini F, Nappi G, Fancellu R, Mangiagalli A, Samuele A, Riboldazzi G, Calandrella D, Pacchetti C, Bono G, Martignoni E. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2003 August; 110(8): 911-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12898346

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Multiple dose pharmacokinetics of quetiapine and some of its metabolites in Chinese suffering from schizophrenia. Author(s): Li KY, Li X, Cheng ZN, Peng WX, Zhang BK, Li HD. Source: Acta Pharmacologica Sinica. 2004 March; 25(3): 390-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15000896

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N-acetylated metabolites in urine: proton nuclear magnetic resonance spectroscopic study on patients with inborn errors of metabolism. Author(s): Engelke UF, Liebrand-van Sambeek ML, de Jong JG, Leroy JG, Morava E, Smeitink JA, Wevers RA. Source: Clinical Chemistry. 2004 January; 50(1): 58-66. Epub 2003 November 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633929

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Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases. Author(s): Burke WJ, Li SW, Chung HD, Ruggiero DA, Kristal BS, Johnson EM, Lampe P, Kumar VB, Franko M, Williams EA, Zahm DS. Source: Neurotoxicology. 2004 January; 25(1-2): 101-15. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14697885

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New cytotoxic indolic metabolites from a marine Streptomyces. Author(s): Sanchez Lopez JM, Martinez Insua M, Perez Baz J, Fernandez Puentes JL, Canedo Hernandez LM. Source: Journal of Natural Products. 2003 June; 66(6): 863-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12828477

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New cytotoxic metabolites from a marine sponge Homaxinella sp. Author(s): Mansoor TA, Hong J, Lee CO, Sim CJ, Im KS, Lee DS, Jung JH. Source: Journal of Natural Products. 2004 April; 67(4): 721-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15104515

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New secondary metabolites from the marine endophytic fungus Apiospora montagnei. Author(s): Klemke C, Kehraus S, Wright AD, Konig GM. Source: Journal of Natural Products. 2004 June; 67(6): 1058-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15217297

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Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6. Author(s): Denton TT, Zhang X, Cashman JR. Source: Biochemical Pharmacology. 2004 February 15; 67(4): 751-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14757175

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Nitric oxide metabolites in cisternal CSF correlate with cerebral vasospasm in patients with a subarachnoid haemorrhage. Author(s): Woszczyk A, Deinsberger W, Boker DK. Source: Acta Neurochirurgica. 2003 April; 145(4): 257-63; Discussion 263-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748885

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Nitric oxide metabolites in preterm and induced labor. Author(s): Diejomaoh MF, Omu AE, Taher S, Al-Busiri N, Fatinikun T, Fernandes S, AlOthman S. Source: Gynecologic and Obstetric Investigation. 2003; 56(4): 197-202. Epub 2003 October 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14576471

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Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients. Author(s): Stiasny-Kolster K, Moller JC, Zschocke J, Bandmann O, Cassel W, Oertel WH, Hoffmann GF. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2004 February; 19(2): 192-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14978675

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Observation and identification of metabolites emerging during postmortem decomposition of brain tissue by means of in situ 1H-magnetic resonance spectroscopy. Author(s): Ith M, Bigler P, Scheurer E, Kreis R, Hofmann L, Dirnhofer R, Boesch C. Source: Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2002 November; 48(5): 915-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12418008

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Occupational exposure to styrene: modulation of cytogenetic damage and levels of urinary metabolites of styrene by polymorphisms in genes CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1. Author(s): Teixeira JP, Gaspar J, Silva S, Torres J, Silva SN, Azevedo MC, Neves P, Laffon B, Mendez J, Goncalves C, Mayan O, Farmer PB, Rueff J. Source: Toxicology. 2004 February 15; 195(2-3): 231-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14751678

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On-line clean-up by multidimensional liquid chromatography-electrospray ionization tandem mass spectrometry for high throughput quantification of primary and secondary phthalate metabolites in human urine. Author(s): Koch HM, Gonzalez-Reche LM, Angerer J. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 January 25; 784(1): 169-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12504195

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On-line, simultaneous quantification of ethanol, some metabolites and water vapour in breath following the ingestion of alcohol. Author(s): Smith D, Wang T, Spanel P. Source: Physiological Measurement. 2002 August; 23(3): 477-89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12214757

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Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor gamma. Author(s): Hsi LC, Wilson LC, Eling TE. Source: The Journal of Biological Chemistry. 2002 October 25; 277(43): 40549-56. Epub 2002 August 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12189136

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Optimized separation and determination of methyl sulfone metabolites of polychlorinated biphenyls (PCBs) and p,p'-DDE in biota samples. Author(s): Chu S, Covaci A, Haraguchi K, Schepens P. Source: The Analyst. 2002 December; 127(12): 1621-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12537370

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Oral choline increases choline metabolites in human brain. Author(s): Babb SM, Ke Y, Lange N, Kaufman MJ, Renshaw PF, Cohen BM. Source: Psychiatry Research. 2004 January 15; 130(1): 1-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14972364

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Oxidized LDL metabolites with high family risk for premature cardiovascular disease. Author(s): Kelishadi R, Nadery GA, Asgary S. Source: Indian J Pediatr. 2002 September; 69(9): 755-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12420906

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Oxygen administration improves the serum level of nitric oxide metabolites in patients with obstructive sleep apnea syndrome. Author(s): Teramoto S, Kume H, Matsuse T, Ishii T, Miyashita A, Akishita M, Toba K, Ouchi Y. Source: Sleep Medicine. 2003 September; 4(5): 403-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14592281

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Ozone-mediated cytotoxicity after short-term exposure and its relation to the production of cellular metabolites (NO, H2O2). Author(s): Klestadt D, Laval-Gilly P, Falla J. Source: Cell Biology and Toxicology. 2002; 18(4): 259-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12206138

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Performance of a microtiter plate ELISA for screening of postmortem blood for cocaine and metabolites. Author(s): Spiehler V, Isenschmid DS, Matthews P, Kemp P, Kupiec T. Source: Journal of Analytical Toxicology. 2003 November-December; 27(8): 587-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14670138

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Pharmacokinetics and dose-proportionality of oxymorphone extended release and its metabolites: results of a randomized crossover study. Author(s): Adams MP, Ahdieh H. Source: Pharmacotherapy. 2004 April; 24(4): 468-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15098800

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Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term daily oral administration to healthy young men. Author(s): Acacio BD, Stanczyk FZ, Mullin P, Saadat P, Jafarian N, Sokol RZ. Source: Fertility and Sterility. 2004 March; 81(3): 595-604. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15037408

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Pharmacokinetics of levosimendan and its circulating metabolites in patients with heart failure after an extended continuous infusion of levosimendan. Author(s): Antila S, Kivikko M, Lehtonen L, Eha J, Heikkila A, Pohjanjousi P, Pentikainen PJ. Source: British Journal of Clinical Pharmacology. 2004 April; 57(4): 412-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15025738

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Phenolic acid metabolites as biomarkers for tea- and coffee-derived polyphenol exposure in human subjects. Author(s): Hodgson JM, Chan SY, Puddey IB, Devine A, Wattanapenpaiboon N, Wahlqvist ML, Lukito W, Burke V, Ward NC, Prince RL, Croft KD. Source: The British Journal of Nutrition. 2004 February; 91(2): 301-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14756917

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Postmortem distribution of heroin metabolites in femoral blood, liver, cerebrospinal fluid, and vitreous humor. Author(s): Wyman J, Bultman S. Source: Journal of Analytical Toxicology. 2004 May-June; 28(4): 260-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15189677

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Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Author(s): Wang YH, Jones DR, Hall SD. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2004 February; 32(2): 259-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744949

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Production of toxic metabolites in Aspergillus niger, Aspergillus oryzae, and Trichoderma reesei: justification of mycotoxin testing in food grade enzyme preparations derived from the three fungi. Author(s): Blumenthal CZ. Source: Regulatory Toxicology and Pharmacology : Rtp. 2004 April; 39(2): 214-28. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15041150

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Profile of urinary arsenic metabolites during pregnancy. Author(s): Hopenhayn C, Huang B, Christian J, Peralta C, Ferreccio C, Atallah R, Kalman D. Source: Environmental Health Perspectives. 2003 December; 111(16): 1888-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644662

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Proton T1 relaxation times of cerebral metabolites differ within and between regions of normal human brain. Author(s): Brief EE, Whittall KP, Li DK, MacKay A. Source: Nmr in Biomedicine. 2003 December; 16(8): 503-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14696008

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Quantification of proteins and metabolites by mass spectrometry without isotopic labeling or spiked standards. Author(s): Wang W, Zhou H, Lin H, Roy S, Shaler TA, Hill LR, Norton S, Kumar P, Anderle M, Becker CH. Source: Analytical Chemistry. 2003 September 15; 75(18): 4818-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14674459

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Quantification of tamoxifen and three metabolites in plasma by high-performance liquid chromatography with fluorescence detection: application to a clinical trial. Author(s): Lee KH, Ward BA, Desta Z, Flockhart DA, Jones DR. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 July 5; 791(1-2): 245-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12798184

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Quantification of the O- and N-demethylated metabolites of hydrocodone and oxycodone in human liver microsomes using liquid chromatography with ultraviolet absorbance detection. Author(s): Menelaou A, Hutchinson MR, Quinn I, Christensen A, Somogyi AA. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 February 25; 785(1): 81-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12535841

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Quantitation of oxcarbazepine and its metabolites in human plasma by micellar electrokinetic chromatography. Author(s): Pucci V, Kenndler E, Raggi MA. Source: Biomedical Chromatography : Bmc. 2003 June; 17(4): 231-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12833388

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Quantitative 1H NMR spectroscopy of blood plasma metabolites. Author(s): de Graaf RA, Behar KL. Source: Analytical Chemistry. 2003 May 1; 75(9): 2100-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12720347

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Quantitative analysis of selegiline and three metabolites (N-desmethylselegiline, methamphetamine, and amphetamine) in human plasma by high-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry. Author(s): Slawson MH, Taccogno JL, Foltz RL, Moody DE. Source: Journal of Analytical Toxicology. 2002 October; 26(7): 430-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12422997

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Quantitative analysis of the novel anticancer drug ABT-518, a matrix metalloproteinase inhibitor, plus the screening of six metabolites in human plasma using high-performance liquid chromatography coupled with electrospray tandem mass spectrometry. Author(s): Stokvis E, Rosing H, Crul M, Rieser MJ, Heck AJ, Schellens JH, Beijnen JH. Source: Journal of Mass Spectrometry : Jms. 2004 March; 39(3): 277-88. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15039935

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Quantitative determination of omapatrilat and its metabolites in human plasma by HPLC coupled with tandem mass spectrometry. Author(s): Wang HY, Hu YF, Jiang J, Hu P. Source: Acta Pharmacologica Sinica. 2003 January; 24(1): 74-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12511233

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Quantitative determination of trimebutine maleate and its three metabolites in human plasma by liquid chromatography-tandem mass spectrometry. Author(s): Wang H, Zhou H, Horimoto S, Jiang J, Mayumi T, Hu P. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2002 November 5; 779(2): 173-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12361732

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Rapid induction of apoptosis in prostate cancer cells by selenium: reversal by metabolites of arachidonate 5-lipoxygenase. Author(s): Ghosh J. Source: Biochemical and Biophysical Research Communications. 2004 March 12; 315(3): 624-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14975747

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Reactive metabolites and adverse drug reactions: clinical considerations. Author(s): Knowles SR, Shapiro LE, Shear NH. Source: Clinical Reviews in Allergy & Immunology. 2003 June; 24(3): 229-38. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12721394

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Reactive oxygen metabolites (ROMs) as an index of oxidative stress in obstructive sleep apnea patients. Author(s): Christou K, Markoulis N, Moulas AN, Pastaka C, Gourgoulianis KI. Source: Sleep & Breathing = Schlaf & Atmung. 2003 September; 7(3): 105-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14569521

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Real-time breath monitoring of propofol and its volatile metabolites during surgery using a novel mass spectrometric technique: a feasibility study. Author(s): Harrison GR, Critchley AD, Mayhew CA, Thompson JM. Source: British Journal of Anaesthesia. 2003 December; 91(6): 797-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633747

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Recent advances in the determination of enantiomeric drugs and their metabolites in biological fluids by capillary electrophoresis-mediated microanalysis. Author(s): Bonato PS. Source: Electrophoresis. 2003 December; 24(22-23): 4078-94. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14661235

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Receptor assay based on surface plasmon resonance for the assessment of the complex formation activity of cyclosporin A and its metabolites. Author(s): Vollenbroeker B, Fobker M, Specht B, Bartetzko N, Erren M, Spener F, Hohage H. Source: Int J Clin Pharmacol Ther. 2003 June; 41(6): 248-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12816177

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Regulation of cellular differentiation and apoptosis by fatty acids and their metabolites. Author(s): Rudolph IL, Kelley DS, Klasing KC, Erickson KL. Source: Nutrition Research (New York, N.Y.). 2001 January-February; 21(1-2): 381-93. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12749359

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Relationship between urinary endogenous steroid metabolites and lower urinary tract function in postmenopausal women. Author(s): Bai SW, Jung BH, Chung BC, Kim SK, Park KH. Source: Yonsei Medical Journal. 2003 April 30; 44(2): 279-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12728469

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Relaxation times of 31P-metabolites in human calf muscle at 3 T. Author(s): Meyerspeer M, Krssak M, Moser E. Source: Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2003 April; 49(4): 620-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12652531

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Role of cytochrome P450-dependent arachidonic acid metabolites in liver physiology and pathophysiology. Author(s): Sacerdoti D, Gatta A, McGiff JC. Source: Prostaglandins & Other Lipid Mediators. 2003 October; 72(1-2): 51-71. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14626496

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Simultaneous analytical method for the determination of TCH346 and its four metabolites in human plasma by liquid chromatography/tandem mass spectrometry. Author(s): Hara H, Uchimura T, Akashi N, Naganuma T, Aizawa T, Nagae Y, Masuda N. Source: Rapid Communications in Mass Spectrometry : Rcm. 2004; 18(4): 377-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14966843

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Simultaneous determination of the urinary metabolites of benzene, toluene, xylene and styrene using high-performance liquid chromatography/hybrid quadrupole timeof-flight mass spectrometry. Author(s): Marchese S, Curini R, Gentili A, Perret D, Rocca LM. Source: Rapid Communications in Mass Spectrometry : Rcm. 2004; 18(3): 265-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14755610

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Structure and enzymology of ADP-ribosyl cyclases: conserved enzymes that produce multiple calcium mobilizing metabolites. Author(s): Schuber F, Lund FE. Source: Current Molecular Medicine. 2004 May; 4(3): 249-61. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15101683

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Studies on the influence of vitamin D3 metabolites on apoptosis induction in human neoplastic cells. Author(s): Gruber BM, Anuszewska EL. Source: Acta Pol Pharm. 2003 September-October; 60(5): 363-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15005419

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Sulfation of tibolone and tibolone metabolites by expressed human cytosolic sulfotransferases. Author(s): Falany JL, Macrina N, Falany CN. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2004 April; 88(4-5): 383-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15145448

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Syntheses and characterization of the acyl glucuronide and hydroxy metabolites of diclofenac. Author(s): Kenny JR, Maggs JL, Meng X, Sinnott D, Clarke SE, Park BK, Stachulski AV. Source: Journal of Medicinal Chemistry. 2004 May 20; 47(11): 2816-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15139759

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Thalidomide metabolites in mice and patients with multiple myeloma. Author(s): Lu J, Palmer BD, Kestell P, Browett P, Baguley BC, Muller G, Ching LM. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2003 May; 9(5): 1680-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12738721

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The effect of alpha- and gamma-tocopherol and their carboxyethyl hydroxychroman metabolites on prostate cancer cell proliferation. Author(s): Galli F, Stabile AM, Betti M, Conte C, Pistilli A, Rende M, Floridi A, Azzi A. Source: Archives of Biochemistry and Biophysics. 2004 March 1; 423(1): 97-102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14871472

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The oral-to-intravenous equianalgesic ratio of morphine based on plasma concentrations of morphine and metabolites in advanced cancer patients receiving chronic morphine treatment. Author(s): Takahashi M, Ohara T, Yamanaka H, Shimada A, Nakaho T, Makoto Y. Source: Palliative Medicine. 2003 December; 17(8): 673-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14694918

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The role of lipids and lipid metabolites in urinary bladder dysfunction induced by partial outlet obstruction. Author(s): Hass MA, Levin RM. Source: Advances in Experimental Medicine and Biology. 2003; 539(Pt A): 217-37. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15088907

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The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes. Author(s): Misiti F, Giardina B, Mordente A, Clementi ME. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 2003 December; 36(12): 1643-51. Epub 2003 November 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14666248

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The toxicity of opiates and their metabolites in HepG2 cells. Author(s): Jairaj M, Watson DG, Grant MH, Skellern GG. Source: Chemico-Biological Interactions. 2003 October 25; 146(2): 121-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14597126

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Tibolone and its metabolites induce antimitogenesis in human coronary artery smooth muscle cells: role of estrogen, progesterone, and androgen receptors. Author(s): Dubey RK, Gillespie DG, Grogli M, Kloosterboer HJ, Imthurn B. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 February; 89(2): 852-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14764805

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Transepithelial transport of chlorogenic acid, caffeic acid, and their colonic metabolites in intestinal caco-2 cell monolayers. Author(s): Konishi Y, Kobayashi S. Source: Journal of Agricultural and Food Chemistry. 2004 May 5; 52(9): 2518-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15113150

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Tumour metabolites regulate tissue kallikrein in human umbilical vein endothelial cells. Author(s): Naidoo S, Raidoo D, Mahabeer R, McLean M. Source: Biochimica Et Biophysica Acta. 2004 May 3; 1691(2-3): 117-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15110992

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Urinary catecholamines and metabolites in the immediate postoperative period following major surgery. Author(s): Syed AA, Wheatley HA, Badminton MN, McDowell IF. Source: Journal of Clinical Pathology. 2004 May; 57(5): 548-50. Erratum In: J Clin Pathol. 2004 July; 57(7): 784. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15113868

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Urinary hydroxy-metabolites of naphthalene, phenanthrene and pyrene as markers of exposure to diesel exhaust. Author(s): Kuusimaki L, Peltonen Y, Mutanen P, Peltonen K, Savela K. Source: International Archives of Occupational and Environmental Health. 2004 January; 77(1): 23-30. Epub 2003 October 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14564527

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Urinary levels of creatine and other metabolites in the assessment of polymyositis and dermatomyositis. Author(s): Chung YL, Wassif WS, Bell JD, Hurley M, Scott DL. Source: Rheumatology (Oxford, England). 2003 February; 42(2): 298-303. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12595626

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Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Author(s): Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP, Brock JW, Needham LL, Calafat AM. Source: Environmental Health Perspectives. 2004 March; 112(3): 331-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14998749

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Urinary metabolites of leukotriene B4 in the human subject. Author(s): Berry KA, Borgeat P, Gosselin J, Flamand L, Murphy RC. Source: The Journal of Biological Chemistry. 2003 July 4; 278(27): 24449-60. Epub 2003 April 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709426

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Urinary nitric oxide metabolites and lipid peroxidation by-products in migraine. Author(s): Ciancarelli I, Tozzi-Ciancarelli MG, Di Massimo C, Marini C, Carolei A. Source: Cephalalgia : an International Journal of Headache. 2003 February; 23(1): 39-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12534579

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Urinary PAH metabolites influenced by genetic polymorphisms of GSTM1 in male hospital incinerator workers. Author(s): Lee KH, Cho SH, Hong YC, Lee KH, Kwan HJ, Choi I, Kang D. Source: Journal of Occupational Health. 2003 May; 45(3): 168-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14646292

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Urinary profile of androgen metabolites in a population of sportswomen during the menstrual cycle. Author(s): Bricout VA, Wright F, Lagoguey M. Source: International Journal of Sports Medicine. 2003 April; 24(3): 197-202. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740739

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Urine drug testing for opioids, cocaine, and metabolites by direct injection liquid chromatography/tandem mass spectrometry. Author(s): Dams R, Murphy CM, Lambert WE, Huestis MA. Source: Rapid Communications in Mass Spectrometry : Rcm. 2003; 17(14): 1665-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12845594

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Use of high-performance liquid chromatographic and microbiological analyses for evaluating the presence or absence of active metabolites of the antifungal posaconazole in human plasma. Author(s): Kim H, Kumari P, Laughlin M, Hilbert MJ, Indelicato SR, Lim J, Lin CC, Nomeir AA. Source: J Chromatogr A. 2003 February 14; 987(1-2): 243-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12613818

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Validated determination of total arsenic species of toxicological interest (arsenite, arsenate and their metabolites) by atomic absorption spectrometry after separation from dietary arsenic by liquid extraction: toxicological applications. Author(s): Benramdane L, Accominotti M, Vallon JJ. Source: The Analyst. 1998 August; 123(8): 1711-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10071385

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Validated high-performance liquid chromatographic assay for simultaneous determination of dacarbazine and the plasma metabolites 5-(3-hydroxymethyl-3methyl-1-triazeno)imidazole-4-carboxamide and 5-(3-methyl-1-triazeno)imidazole-4carboxamide. Author(s): Safgren SL, Reid JM, Rios R, Ames MM. Source: J Chromatogr B Biomed Sci Appl. 2001 April 15; 754(1): 91-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11318431

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Validation of an ion-trap gas chromatographic-mass spectrometric method for the determination of cocaine and metabolites and cocaethylene in post mortem whole blood. Author(s): Chasin AA, Midio AF. Source: Forensic Science International. 2000 March 13; 109(1): 1-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10759067

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Validation of biomarkers in humans exposed to benzene: urine metabolites. Author(s): Qu Q, Melikian AA, Li G, Shore R, Chen L, Cohen B, Yin S, Kagan MR, Li H, Meng M, Jin X, Winnik W, Li Y, Mu R, Li K. Source: American Journal of Industrial Medicine. 2000 May; 37(5): 522-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10723046

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Valproic acid has temporal variability in urinary clearance of metabolites. Author(s): Reith DM, Andrews J, McLaughlin D. Source: Chronobiology International. 2001 January; 18(1): 123-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11247111

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Variable correlation between 6-mercaptopurine metabolites in erythrocytes and hematologic toxicity: implications for drug monitoring in children with acute lymphoblastic leukemia. Author(s): Innocenti F, Danesi R, Favre C, Nardi M, Menconi MC, Di Paolo A, Bocci G, Fogli S, Barbara C, Barachini S, Casazza G, Macchia P, Del Tacca M. Source: Therapeutic Drug Monitoring. 2000 August; 22(4): 375-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10942174

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Various forms of plasma cysteine and its metabolites in patients undergoing hemodialysis. Author(s): Wlodek PJ, Iciek MB, Milkowski A, Smolenski OB. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2001 February; 304(1-2): 9-18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11165194

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Verapamil: identification of novel metabolites in cultures of primary human hepatocytes and human urine by LC-MS(n) and LC-NMR. Author(s): Borlak J, Walles M, Elend M, Thum T, Preiss A, Levsen K. Source: Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 2003 June; 33(6): 655-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12851041

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Volatile metabolites from mold growth on building materials and synthetic media. Author(s): Wilkins K, Larsen K, Simkus M. Source: Chemosphere. 2000 August; 41(3): 437-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11057606

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Why and how to measure urinary sex steroid metabolites in epidemiological studies in women. Author(s): Muti P, Deutsch A, Freudenheim J, Bolelli G, Hill L, Trevisan M. Source: Nutr Metab Cardiovasc Dis. 2000 April; 10(2): 85-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10919173

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

Finding Nutrition Studies on Metabolites 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 “metabolites” (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 is a typical result when searching for recently indexed consumer information on metabolites: •

Effects of dose of ingested glucose on plasma metabolite and hormone responses in type II diabetic subjects. Author(s): Metabolic Research Laboratory, Veterans Administration Medical Center, Minneapolis, MN 55417. Source: Gannon, M C Nuttall, F Q Westphal, S A Neil, B J Seaquist, E R Diabetes-Care. 1989 September; 12(8): 544-52 0149-5992

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Fructose-2,6-bisphosphate in control of hepatic gluconeogenesis. From metabolites to molecular genetics. Author(s): Department of Physiology and Biophysics, School of Medicine, SUNY, Stony Brook 11794-8661. Source: Pilkis, S J el Maghrabi, M R Claus, T H Diabetes-Care. 1990 June; 13(6): 582-99 0149-5992

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

An analytical method for irinotecan (CPT-11) and its metabolites using a highperformance liquid chromatography: parallel detection with fluorescence and mass spectrometry. Author(s): Project Team for Pharmacogenetics, National Institute of Health Sciences, 118-1 Kamiyohga, Setagaya-ku, Tokyo 158-8501, Japan. [email protected] Source: Sai, Kimie Kaniwa, Naoko Ozawa, Shogo Sawada, June ichi BiomedChromatogr. 2002 May; 16(3): 209-18 0269-3879

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Analysis of immediate changes of water-soluble metabolites in alkali-burned rabbit cornea, aqueous humor and lens by high-resolution 1H-NMR spectroscopy. Author(s): Faculty of Physics, Informatics and Mathematics, Norwegian University of Science and Technology (NTNU), Trondheim. [email protected] Source: Risa, O Saether, O Midelfart, A Krane, J Cejkova, J Graefes-Arch-Clin-ExpOphthalmol. 2002 January; 240(1): 49-55 0721-832X

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Anti-/pro-oxidant effects of phenolic compounds in cells: are colchicine metabolites chain-breaking antioxidants? Author(s): Department of Environmental and Occupational Health, University of Pittsburgh, FORBL Room 234, 3343 Forbes Avenue, Pittsburgh, PA 15260, USA. [email protected] Source: Modriansky, Martin Tyurina, Yulia Y Tyurin, Vladimir A Matsura, Tatsuya Shvedova, Anna A Yalowich, Jack C Kagan, Valerian E Toxicology. 2002 August 1; 177(1): 105-17 0300-483X

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Cytochrome p-450 epoxygenase metabolites of docosahexaenoate potently dilate coronary arterioles by activating large-conductance calcium-activated potassium channels. Author(s): Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA. Source: Ye, D Zhang, D Oltman, C Dellsperger, K Lee, H C VanRollins, M J-PharmacolExp-Ther. 2002 November; 303(2): 768-76 0022-3565

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Cytochrome P450 metabolites of arachidonic acid in the control of renal function. Author(s): Department of Physiology, Medical College of Wisconsin, Milwaukee 53226, USA.

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Source: Maier, K G Roman, R J Curr-Opin-Nephrol-Hypertens. 2001 January; 10(1): 81-7 1062-4821 •

Determination of the plasma levels of metyrapone and its enantiomeric metyrapol metabolites by direct plasma injection and multidimensional achiral-chiral chromatography. Author(s): Departamento de Quimica, Universidade Federal de Sao Carlos, SP, Brazil. Source: Cassiano, N M Cass, Q B Degani, A L Wainer, I W Chirality. 2002 October; 14(9): 731-5 0899-0042

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Differential effects of linoleic Acid metabolites on cardiac sodium current. Author(s): Tulane University, New Orleans, Louisiana, USA. Source: Harrell, M D Stimers, J R J-Pharmacol-Exp-Ther. 2002 October; 303(1): 347-55 0022-3565

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Effects of betahistine and of its metabolites on vestibular sensory organs. Author(s): Departments of Physiological and Pharmacological Sciences, University of Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy. Source: Botta, L Mira, E Valli, S Zucca, G Benvenuti, C Fossati, A Soto, E Guth, P Valli, P Acta-Otorhinolaryngol-Ital. 2001 June; 21(3 Suppl 66): 24-30 0392-100X

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Effects of caffeine and its reactive metabolites theophylline and theobromine on the differentiating testis. Author(s): Department of Biological Sciences, Macquarie University, Sydney, NSW, Australia. [email protected] Source: Pollard, I Locquet, O Solvar, A Magre, S Reprod-Fertil-Devolume 2001; 13(5-6): 435-41 1031-3613

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Effects of dietary chromium picolinate and ascorbic acid supplementation on egg production, egg quality and some serum metabolites of laying hens reared under a low ambient temperature (6 degrees C). Author(s): Department of Animal Nutrition, Faculty of Veterinary, University of Firat, Elazig, Turkey. [email protected] Source: Sahin, K Onderci, M Sahin, N Aydin, S Arch-Tierernahr. 2002 February; 56(1): 41-9 0003-942X

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Effects of exercise on muscle metabolites and sarcoplasmic reticulum function in ovariectomized rats. Author(s): Institute of Biology and Experimental Medicine-CONICET, Buenos Aires, Argentina. Source: Gigli, I Bussmann, L E Physiol-Res. 2002; 51(3): 247-54 0862-8408

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Green coffee bean extract and its metabolites have a hypotensive effect in spontaneously hypertensive rats. Author(s): Biological Science Laboratories, Kao Corp., Tochigi, Japan. Source: Suzuki, A Kagawa, D Ochiai, R Tokimitsu, I Saito, I Hypertens-Res. 2002 January; 25(1): 99-107 0916-9636

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Identification of o-quinone/quinone methide metabolites of quercetin in a cellular in vitro system. Author(s): Laboratory of Biochemistry, Wageningen University, Dreijenlaan 3, 6703 HA Wageningen, The Netherlands. Source: Awad, Hanem M Boersma, Marelle G Boeren, Sjef van der Woude, Hester van Zanden, Jelmer van Bladeren, Peter J Vervoort, Jacques Rietjens, Ivonne M C M FEBSLett. 2002 June 5; 520(1-3): 30-4 0014-5793

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In vitro effects of aceclofenac and its metabolites on the production by chondrocytes of inflammatory mediators. Author(s): Bone and Cartilage Metabolism Research Unit, Institute of Pathology, CHU Sart-Tilman, Liege, Belgium. [email protected] Source: Henrotin, Y de Leval, X Mathy Hartet, M Mouithys Mickalad, A Deby Dupont, G Dogne, J M Delarge, J Reginster, J Y Inflamm-Res. 2001 August; 50(8): 391-9 1023-3830

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Involvement of caspase 3 mediated apoptosis in hematopoietic cytotoxicity of metabolites of ethylene glycol monomethyl ether. Author(s): Department of Medical Technology, Nagoya University School of Health Sciences, Daiko Minami 1-1-20, Higashi-ku, Nagoya 461-8673, Japan. Source: Takagi, A Yamada, T Hayashi, K Nakade, Y Kojima, T Takamatsu, J Shibata, E Ichihara, G Takeuchi, Y Murate, T Ind-Health. 2002 October; 40(4): 371-4 0019-8366

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Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis. Author(s): Department of Preclinical and Clinical Pharmacology, Viale Pieraccini 6, 50139, Florence, Italy. Source: Chiarugi, A Cozzi, A Ballerini, C Massacesi, L Moroni, F Neuroscience. 2001; 102(3): 687-95 0306-4522

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Mass spectrometric analysis of leukotriene A4 and other chemically reactive metabolites of arachidonic acid. Author(s): Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA. Source: Dickinson, J S Murphy, R C J-Am-Soc-Mass-Spectrom. 2002 October; 13(10): 1227-34 1044-0305

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Methyl psilalate: a new antimicrobial metabolite from Psila boliviensis. Source: Erazo, S. Negrete, R. Zaldivar, M. Backhouse, N. Delporte, C. Silva, I. Belmonte, E. Lopez Perez, J.L. San Feliciano, A. Planta-med. Stuttgart : Georg Thieme Verlag,. January 2002. volume 68 (1) page 66-67. 0032-0943

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Nitric oxide metabolites in gnotobiotic piglets orally infected with Salmonella enterica serovar typhimurium. Author(s): Department of Immunology and Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, 549 22 Novy Hradek, Czechia. [email protected] Source: Trebichavsky, I Zidek, Z Frankova, D Zahradnickova, M Splichal, I FoliaMicrobiol-(Praha). 2001; 46(4): 353-8 0015-5632

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Norepinephrine-induced stimulation of p38 mitogen-activated protein kinase is mediated by arachidonic acid metabolites generated by activation of cytosolic phospholipase A(2) in vascular smooth muscle cells. Author(s): Department of Pharmacology and Centers for Vascular Biology and Connective Tissue Diseases, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. Source: Kalyankrishna, S Malik, K U J-Pharmacol-Exp-Ther. 2003 February; 304(2): 76172 0022-3565

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Oxidative metabolites and genotoxic potential of mammalian and plant lignans in vitro. Author(s): Institute of Food Chemistry and Toxicology, University of Karlsruhe, PO Box 6980, D-76128, Karlsruhe, Germany. Source: Niemeyer, H B Metzler, M J-Chromatogr-B-Analyt-Technol-Biomed-Life-Sci. 2002 September 25; 777(1-2): 321-7 1570-0232

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Regulation by interferon beta-1a of reactive oxygen metabolites production by lymphocytes and monocytes and serum sulfhydryls in relapsing multiple sclerosis patients. Author(s): Molecular Biology Service of the Virgen Macarena University Hospital, Avda. Dr. Fedriani 3, 41071 Seville, Spain. [email protected] Source: Lucas, M Rodriguez, M C Gata, J M Zayas, M D Solano, F Izquierdo, G Neurochem-Int. 2003 January; 42(1): 67-71 0197-0186

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Simultaneous determination of oleuropein and its metabolites in plasma by highperformance liquid chromatography. Author(s): GAIA Research Center, Bioanalytical Department, The Goulandris Natural History Museum, 13 Levidou street, GR-145 62, Kifissia, Greece Source: Tsarbopoulos, A Gikas, E Papadopoulos, N Aligiannis, N Kafatos, A JChromatogr-B-Analyt-Technol-Biomed-Life-Sci. 2003 February 25; 785(1): 157-64 15700232

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Sulfoxides as urinary metabolites of S-allyl-L-cysteine in rats: evidence for the involvement of flavin-containing monooxygenases. Author(s): Department of Comparative Biosciences and the Center for Molecular and Environmental Toxicology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. Source: Krause, R J Glocke, S C Elfarra, A A Drug-Metab-Dispos. 2002 October; 30(10): 1137-42 0090-9556

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Synthesis and microbiological activity of some N-(2-hydroxy-4substitutedphenyl)benzamides, phenylacetamides and furamides as the possible metabolites of antimicrobial active benzoxazoles. Author(s): Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandogan, Turkey. [email protected] Source: Aki Sener, E Bingol, K K Temiz Arpaci, O Yalcin, I Altanlar, N Farmaco. 2002 June; 57(6): 451-6 0014-827X

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Umbelliferone, a stress metabolite of Chamomilla recutita (L.) Rauschert. Source: Repcak, M. Imrich, J. Franekova, M. J-plant-physiol. Stuttgart; New York : G. Fischer,. August 2001. volume 158 (8) page 1085-1087. 0176-1617

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Vitamin D3 and D3 metabolites in poultry feeding programs. Source: Applegate, T.J. Angel, R. Proc-Md-Nutr-Conf-Feed-Manuf. [College Park, Md.] : The Conference, 1961-. 2002. (49th) page 181-191. 0542-8386

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Minerals Biotin Source: Integrative Medicine Communications; www.drkoop.com Calcium Source: Integrative Medicine Communications; www.drkoop.com Copper Source: Integrative Medicine Communications; www.drkoop.com Lecithin/Phosphatidylcholine/Choline Source: Healthnotes, Inc.; www.healthnotes.com

Nutrition

Quercetin Source: Integrative Medicine Communications; www.drkoop.com Stinging Nettle Alternative names: Urtica dioica, Urtica urens, Nettle Source: Integrative Medicine Communications; www.drkoop.com Vitamin H (Biotin) Source: Integrative Medicine Communications; www.drkoop.com •

Food and Diet Athletic Performance Source: Healthnotes, Inc.; www.healthnotes.com HMB Source: Healthnotes, Inc.; www.healthnotes.com Tyramine-Free Diet Source: Healthnotes, Inc.; www.healthnotes.com

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

20(S)-Protopanaxatriol, one of ginsenoside metabolites, inhibits inducible nitric oxide synthase and cyclooxygenase-2 expressions through inactivation of nuclear factorkappaB in RAW 264.7 macrophages stimulated with lipopolysaccharide. Author(s): Oh GS, Pae HO, Choi BM, Seo EA, Kim DH, Shin MK, Kim JD, Kim JB, Chung HT. Source: Cancer Letters. 2004 March 8; 205(1): 23-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15036657

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5 alpha-reductase-catalyzed conversion of testosterone to dihydrotestosterone is increased in prostatic adenocarcinoma cells: suppression by 15-lipoxygenase metabolites of gamma-linolenic and eicosapentaenoic acids. Author(s): Pham H, Ziboh VA.

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Source: The Journal of Steroid Biochemistry and Molecular Biology. 2002 November; 82(4-5): 393-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12589947 •

A comparative study of growth-inhibitory effects of isoflavones and their metabolites on human breast and prostate cancer cell lines. Author(s): Xiang H, Schevzov G, Gunning P, Williams HM, Silink M. Source: Nutrition and Cancer. 2002; 42(2): 224-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12416264

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A toxicokinetic model of malathion and its metabolites as a tool to assess human exposure and risk through measurements of urinary biomarkers. Author(s): Bouchard M, Gosselin NH, Brunet RC, Samuel O, Dumoulin MJ, Carrier G. Source: Toxicological Sciences : an Official Journal of the Society of Toxicology. 2003 May; 73(1): 182-94. Epub 2003 March 25. Erratum In: Toxicol Sci. 2003 August; 74(2): Following Table of Contents. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12657741

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Alternate energy dissipation? Phenolic metabolites and the xanthophyll cycle. Author(s): Close DC, Beadle CL. Source: Journal of Plant Physiology. 2003 April; 160(4): 431-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12756924

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Analysis of the nutritional supplement 1AD, its metabolites, and related endogenous hormones in biological matrices using liquid chromatography-tandem mass spectrometry. Author(s): Reilly CA, Crouch DJ. Source: Journal of Analytical Toxicology. 2004 January-February; 28(1): 1-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14987417

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Anthocyanin metabolites in human urine and serum. Author(s): Kay CD, Mazza G, Holub BJ, Wang J. Source: The British Journal of Nutrition. 2004 June; 91(6): 933-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15228048

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Anti-Helicobacter pylori metabolites from Rhizoctonia sp. Cy064, an endophytic fungus in Cynodon dactylon. Author(s): Ma YM, Li Y, Liu JY, Song YC, Tan RX. Source: Fitoterapia. 2004 July; 75(5): 451-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15261382

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Antimalarial activity of plant metabolites. Author(s): Schwikkard S, van Heerden FR.

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Source: Natural Product Reports. 2002 December; 19(6): 675-92. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521264 •

Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol). Author(s): Grimm T, Schafer A, Hogger P. Source: Free Radical Biology & Medicine. 2004 March 15; 36(6): 811-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14990359

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Antioxidant and free radical scavenging activity of isoflavone metabolites. Author(s): Rimbach G, De Pascual-Teresa S, Ewins BA, Matsugo S, Uchida Y, Minihane AM, Turner R, VafeiAdou K, Weinberg PD. Source: Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 2003 September; 33(9): 913-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14514441

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Assessing the separation of neutral plant secondary metabolites by micellar electrokinetic chromatography. Author(s): Micke GA, Moraes EP, Farah JP, Tavares MF. Source: J Chromatogr A. 2003 July 4; 1004(1-2): 131-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12929969

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Beneficial effects of a diet rich in a mixture of n - 6/n - 3 essential fatty acids and of their metabolites on cyclosporine - nephrotoxicity. Author(s): Tsipas G, Morphake P. Source: The Journal of Nutritional Biochemistry. 2003 November; 14(11): 626-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14629893

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Beneficial effects of a diet rich in a mixture of n - 6/n - 3 essential fatty acids and of their metabolites on cyclosporine - nephrotoxicity. Author(s): Tsipas G, Morphake P. Source: The Journal of Nutritional Biochemistry. 2003 August; 14(8): 480-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12948879

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Biliary excretion of irinotecan and its metabolites. Author(s): Itoh T, Takemoto I, Itagaki S, Sasaki K, Hirano T, Iseki K. Source: Journal of Pharmacy & Pharmaceutical Sciences [electronic Resource] : a Publication of the Canadian Society for Pharmaceutical Sciences, Societe Canadienne Des Sciences Pharmaceutiques. 2004 January 23; 7(1): 13-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15144730

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Binding of polychlorinated biphenyls/metabolites to hemoglobin. Author(s): Tampal N, Myers S, Robertson LW.

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Source: Toxicology Letters. 2003 April 30; 142(1-2): 53-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12765239 •

Chrysanthones, a new source of fungal metabolites with potential antitumor and antiangiogenesis properties. Author(s): Giannini G, Penco S, Pisano C, Riccioni T, Nasini G, Candiani G. Source: Fitoterapia. 2003 June; 74(4): 323-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12781801

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Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Author(s): Garcea G, Jones DJ, Singh R, Dennison AR, Farmer PB, Sharma RA, Steward WP, Gescher AJ, Berry DP. Source: British Journal of Cancer. 2004 March 8; 90(5): 1011-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14997198

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Determination of flavonol metabolites in plasma and tissues of rats by HPLCradiocounting and tandem mass spectrometry following oral ingestion of [2(14)C]quercetin-4'-glucoside. Author(s): Mullen W, Graf BA, Caldwell ST, Hartley RC, Duthie GG, Edwards CA, Lean ME, Crozier A. Source: Journal of Agricultural and Food Chemistry. 2002 November 6; 50(23): 6902-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12405795

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Differential effect of ginsenoside metabolites on the 5-HT3A receptor-mediated ion current in Xenopus oocytes. Author(s): Lee BH, Jeong SM, Lee JH, Kim DH, Kim JH, Kim JI, Shin HC, Lee SM, Nah SY. Source: Molecules and Cells. 2004 February 29; 17(1): 51-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15055527

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Effect of catechin O-methylated metabolites and analogues on human LDL oxidation. Author(s): Cren-Olive C, Teissier E, Duriez P, Rolando C. Source: Free Radical Biology & Medicine. 2003 April 1; 34(7): 850-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654473

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Effects of biotin supplementation on peripartum performance and metabolites of holstein cows. Author(s): Rosendo O, Staples CR, McDowell LR, McMahon R, Badinga L, Martin FG, Shearer JF, Seymour WM, Wilkinson NS. Source: Journal of Dairy Science. 2004 August; 87(8): 2535-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15328277

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Effects of dietary chromium picolinate and ascorbic acid supplementation on egg production, egg quality and some serum metabolites of laying hens reared under a low ambient temperature (6 degrees C). Author(s): Sahin K, Onderci M, Sahin N, Aydin S. Source: Archiv Fur Tierernahrung. 2002 February; 56(1): 41-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12389221

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Flavonoid metabolites and susceptibility of rat lipoproteins to oxidation. Author(s): Benito S, Buxaderas S, Mitjavila MT. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2004 August 12 [epub Ahead of Print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15308478

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Four new andrographolide metabolites in human urine. Author(s): Cui L, Qiu F, Wang N, Yao X. Source: Chemical & Pharmaceutical Bulletin. 2004 June; 52(6): 772-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15187407

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Free diet selection by broilers as influenced by dietary macronutrient ratio and corticosterone supplementation. 1. Diet selection, organ weights, and plasma metabolites. Author(s): Malheiros RD, Moraes VM, Collin A, Decuypere E, Buyse J. Source: Poultry Science. 2003 January; 82(1): 123-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12580254

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Garlic metabolites fail to inhibit the activation of the transcription factor NF-kappaB and subsequent expression of the adhesion molecule E-selectin in human endothelial cells. Author(s): Dirsch VM, Keiss HP, Vollmar AM. Source: European Journal of Nutrition. 2004 February; 43(1): 55-9. Epub 2004 January 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14991270

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Genistein and daidzein induce cell proliferation and their metabolites cause oxidative DNA damage in relation to isoflavone-induced cancer of estrogen-sensitive organs. Author(s): Murata M, Midorikawa K, Koh M, Umezawa K, Kawanishi S. Source: Biochemistry. 2004 March 9; 43(9): 2569-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14992594

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Genotoxic activity of four metabolites of the soy isoflavone daidzein. Author(s): Schmitt E, Metzler M, Jonas R, Dekant W, Stopper H.

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Source: Mutation Research. 2003 December 9; 542(1-2): 43-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14644352 •

Ginkgo biloba Extract (EGb761) and FK506 Preserve Energy Metabolites in the Striatum during Focal Cerebral Ischemia and Reperfusion in Gerbils Monitored by Microdialysis. Author(s): Lin JY, Cheng FC, Chung SY, Lin MC. Source: Journal of Biomedical Science. 2004 September-October; 11(5): 611-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15316136

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Glucuronides are the main isoflavone metabolites in women. Author(s): Zhang Y, Hendrich S, Murphy PA. Source: The Journal of Nutrition. 2003 February; 133(2): 399-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12566474

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High-performance liquid chromatographic assay with fluorescence detection for the simultaneous measurement of carboxylate and lactone forms of irinotecan and three metabolites in human plasma. Author(s): Owens TS, Dodds H, Fricke K, Hanna SK, Crews KR. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 May 5; 788(1): 65-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12668072

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HPLC-DAD-MS identification of bioactive secondary metabolites from Ferula communis roots. Author(s): Arnoldi L, Ballero M, Fuzzati N, Maxia A, Mercalli E, Pagni L. Source: Fitoterapia. 2004 June; 75(3-4): 342-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15158993

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Human intestinal Caco-2 cells display active transport of benzo[a]pyrene metabolites. Author(s): Buesen R, Mock M, Nau H, Seidel A, Jacob J, Lampen A. Source: Chemico-Biological Interactions. 2003 January 6; 142(3): 201-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453661

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Identification and biological activity of microbial metabolites of xanthohumol. Author(s): Herath W, Ferreira D, Khan SI, Khan IA. Source: Chemical & Pharmaceutical Bulletin. 2003 November; 51(11): 1237-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14600365

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Identification of major metabolites in Aloe littoralis by high-performance liquid chromatography-nuclear magnetic resonance spectroscopy. Author(s): Karagianis G, Viljoen A, Waterman PG.

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Source: Phytochemical Analysis : Pca. 2003 September-October; 14(5): 275-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14515998 •

Identification of metabolites in plasma and urine of Uruguayan propolis-treated rats. Author(s): Kumazawa S, Shimoi K, Hayashi K, Ishii T, Hamasaka T, Nakayama T. Source: Journal of Agricultural and Food Chemistry. 2004 May 19; 52(10): 3083-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15137857

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Identification of metabolites of (-)-epicatechin gallate and their metabolic fate in the rat. Author(s): Kohri T, Suzuki M, Nanjo F. Source: Journal of Agricultural and Food Chemistry. 2003 August 27; 51(18): 5561-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12926915

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Identification of nitric oxide metabolites in various honeys: effects of intravenous honey on plasma and urinary nitric oxide metabolites concentrations. Author(s): Al-Waili NS. Source: Journal of Medicinal Food. 2003 Winter; 6(4): 359-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14977445

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Identification of novel electrophilic metabolites of piper methysticum Forst (Kava). Author(s): Johnson BM, Qiu SX, Zhang S, Zhang F, Burdette JE, Yu L, Bolton JL, van Breemen RB. Source: Chemical Research in Toxicology. 2003 June; 16(6): 733-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12807356

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Identification of puerarin and its metabolites in rats by liquid chromatographytandem mass spectrometry. Author(s): Prasain JK, Jones K, Brissie N, Moore R, Wyss JM, Barnes S. Source: Journal of Agricultural and Food Chemistry. 2004 June 16; 52(12): 3708-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15186086

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Identification of the metabolites of 9-nitro-20(S)-camptothecin in rats. Author(s): Li K, Chen X, Zhong D, Li Y. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2003 June; 31(6): 792-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12756214

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In vitro formation of quinoid metabolites of the dietary supplement Cimicifuga racemosa (black cohosh). Author(s): Johnson BM, van Breemen RB.

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Source: Chemical Research in Toxicology. 2003 July; 16(7): 838-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12870886 •

In vitro inhibition of adrenal catecholamine secretion by steroidal metabolites of ginseng saponins. Author(s): Tachikawa E, Kudo K, Hasegawa H, Kashimoto T, Sasaki K, Miyazaki M, Taira H, Lindstrom JM. Source: Biochemical Pharmacology. 2003 December 1; 66(11): 2213-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609746

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In vivo measurement of brain metabolites using two-dimensional double-quantum MR spectroscopy--exploration of GABA levels in a ketogenic diet. Author(s): Wang ZJ, Bergqvist C, Hunter JV, Jin D, Wang DJ, Wehrli S, Zimmerman RA. Source: Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2003 April; 49(4): 615-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12652530

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In vivo metabolism of diallyl disulphide in the rat: identification of two new metabolites. Author(s): Germain E, Auger J, Ginies C, Siess MH, Teyssier C. Source: Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 2002 December; 32(12): 1127-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12593760

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Inhibiting Activities of the Secondary Metabolites of Phlomis brunneogaleata against Parasitic Protozoa and Plasmodial Enoyl-ACP Reductase, a Crucial Enzyme in Fatty Acid Biosynthesis. Author(s): Kirmizibekmez H, Calis I, Perozzo R, Brun R, Donmez AA, Linden A, Ruedi P, Tasdemir D. Source: Planta Medica. 2004 August; 70(8): 711-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15326547

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Inhibition by eicosapentaenoic acid of IL-1beta-induced PGHS-2 expression in human microvascular endothelial cells: involvement of lipoxygenase-derived metabolites and p38 MAPK pathway. Author(s): Ait-Said F, Elalamy I, Werts C, Gomard MT, Jacquemin C, Couetil JP, Hatmi M. Source: Biochimica Et Biophysica Acta. 2003 February 20; 1631(1): 77-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12573452

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Inhibitory effects of urinary metabolites on platelet aggregation after orally administering Shimotsu-To, a traditional Chinese medicine, to rats. Author(s): Yasuda T, Takasawa A, Nakazawa T, Ueda J, Ohsawa K.

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Source: The Journal of Pharmacy and Pharmacology. 2003 February; 55(2): 239-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12631416 •

Interactions of phytoestrogens with estrogen receptors alpha and beta (III). Estrogenic activities of soy isoflavone aglycones and their metabolites isolated from human urine. Author(s): Kinjo J, Tsuchihashi R, Morito K, Hirose T, Aomori T, Nagao T, Okabe H, Nohara T, Masamune Y. Source: Biological & Pharmaceutical Bulletin. 2004 February; 27(2): 185-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758030

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Interstrand cross-linking of DNA by FK317 and its deacetylated metabolites FR70496 and FR157471. Author(s): Williams RM, Ducept P. Source: Biochemistry. 2003 December 16; 42(49): 14696-701. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14661983

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Involvement of multidrug resistance-associated proteins in regulating cellular levels of (-)-epigallocatechin-3-gallate and its methyl metabolites. Author(s): Hong J, Lambert JD, Lee SH, Sinko PJ, Yang CS. Source: Biochemical and Biophysical Research Communications. 2003 October 10; 310(1): 222-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14511674

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Mass spectrometric methods for the analysis of chlorinated and nitrated isoflavonoids: a novel class of biological metabolites. Author(s): Prasain JK, Patel R, Kirk M, Wilson L, Botting N, Darley-Usmar VM, Barnes S. Source: Journal of Mass Spectrometry : Jms. 2003 July; 38(7): 764-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12898656

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Measurement of paclitaxel in biological matrices: high-throughput liquid chromatographic-tandem mass spectrometric quantification of paclitaxel and metabolites in human and dog plasma. Author(s): Alexander MS, Kiser MM, Culley T, Kern JR, Dolan JW, McChesney JD, Zygmunt J, Bannister SJ. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 March 5; 785(2): 253-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12554138

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Measurement of vitamin E metabolites by high-performance liquid chromatography during high-dose administration of alpha-tocopherol. Author(s): Morinobu T, Yoshikawa S, Hamamura K, Tamai H.

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Source: European Journal of Clinical Nutrition. 2003 March; 57(3): 410-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12627176 •

Metabolism of (R)-(+)-menthofuran in Fischer-344 rats: identification of sulfonic acid metabolites. Author(s): Chen LJ, Lebetkin EH, Burka LT. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2003 October; 31(10): 1208-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12975329

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Metabolism of capsaicin by cytochrome P450 produces novel dehydrogenated metabolites and decreases cytotoxicity to lung and liver cells. Author(s): Reilly CA, Ehlhardt WJ, Jackson DA, Kulanthaivel P, Mutlib AE, Espina RJ, Moody DE, Crouch DJ, Yost GS. Source: Chemical Research in Toxicology. 2003 March; 16(3): 336-49. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12641434

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Metabolism of the soy isoflavones daidzein, genistein and glycitein in human subjects. Identification of new metabolites having an intact isoflavonoid skeleton. Author(s): Heinonen SM, Hoikkala A, Wahala K, Adlercreutz H. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2003 December; 87(4-5): 285-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698210

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Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. Author(s): Lyoo IK, Kong SW, Sung SM, Hirashima F, Parow A, Hennen J, Cohen BM, Renshaw PF. Source: Psychiatry Research. 2003 June 30; 123(2): 87-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12850248

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Natural antimycobacterial metabolites: current status. Author(s): Okunade AL, Elvin-Lewis MP, Lewis WH. Source: Phytochemistry. 2004 April; 65(8): 1017-32. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15110681

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Novel liquid chromatography-electrospray ionization mass spectrometry method for the quantification in human urine of microbial aromatic acid metabolites derived from dietary polyphenols. Author(s): Gonthier MP, Rios LY, Verny M, Remesy C, Scalbert A.

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Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 June 15; 789(2): 247-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742116 •

Optimal dietary concentration of chromium for alleviating the effect of heat stress on growth, carcass qualities, and some serum metabolites of broiler chickens. Author(s): Sahin K, Sahin N, Onderci M, Gursu F, Cikim G. Source: Biological Trace Element Research. 2002 October; 89(1): 53-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12413051

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Pharmacokinetics of irinotecan and its metabolites. Author(s): Siderov J. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2002 December 1; 20(23): 4609; Author Reply 4609-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12454126

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Pharmacologically active plant metabolites as survival strategy products. Author(s): Attardo C, Sartori F. Source: Boll Chim Farm. 2003 March-April; 142(2): 54-65. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12705091

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Phenolic Metabolites from Honeybush Tea (Cyclopia subternata). Author(s): Kamara BI, Brand DJ, Brandt EV, Joubert E. Source: Journal of Agricultural and Food Chemistry. 2004 August 25; 52(17): 5391-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15315375

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Phenolic metabolites of Dalea versicolor that enhance antibiotic activity against model pathogenic bacteria. Author(s): Belofsky G, Percivill D, Lewis K, Tegos GP, Ekart J. Source: Journal of Natural Products. 2004 March; 67(3): 481-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15043439

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Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor alpha (ERalpha) and ERbeta in human cells. Author(s): Mueller SO, Simon S, Chae K, Metzler M, Korach KS. Source: Toxicological Sciences : an Official Journal of the Society of Toxicology. 2004 July; 80(1): 14-25. Epub 2004 April 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15084758

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Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide. Author(s): Klein CE, Gupta E, Reid JM, Atherton PJ, Sloan JA, Pitot HC, Ratain MJ, Kastrissios H.

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Source: Clinical Pharmacology and Therapeutics. 2002 December; 72(6): 638-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12496745 •

Potential therapeutic applications of some antinutritional plant secondary metabolites. Author(s): Singh B, Bhat TK, Singh B. Source: Journal of Agricultural and Food Chemistry. 2003 September 10; 51(19): 5579-97. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952405

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Protective effects of quercetin and its metabolites on H2O2-induced chromosomal damage to WIL2-NS cells. Author(s): Saito A, Sugisawa A, Umegaki K, Sunagawa H. Source: Bioscience, Biotechnology, and Biochemistry. 2004 February; 68(2): 271-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14981287

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Quercetin metabolites downregulate cyclooxygenase-2 transcription in human lymphocytes ex vivo but not in vivo. Author(s): de Pascual-Teresa S, Johnston KL, DuPont MS, O'Leary KA, Needs PW, Morgan LM, Clifford MN, Bao Y, Williamson G. Source: The Journal of Nutrition. 2004 March; 134(3): 552-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14988445

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Recent progress in the chemistry of indole alkaloids and mould metabolites. Author(s): Saxton JE. Source: Natural Product Reports. 1994 October; 11(5): 493-531. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15200025

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Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats. Author(s): Horikawa M, Kato Y, Sugiyama Y. Source: Pharmaceutical Research. 2002 September; 19(9): 1345-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12403072

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Screening of nonpolyenic antifungal metabolites produced by clinical isolates of actinomycetes. Author(s): Lemriss S, Laurent F, Couble A, Casoli E, Lancelin JM, Saintpierre-Bonaccio D, Rifai S, Fassouane A, Boiron P. Source: Canadian Journal of Microbiology. 2003 November; 49(11): 669-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14735216

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Secondary metabolites from marine cyanobacteria and algae inhibit LFA-1/ICAM-1 mediated cell adhesion. Author(s): Takamatsu S, Nagle DG, Gerwick WH. Source: Planta Medica. 2004 February; 70(2): 127-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14994189

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Sensitive HPLC-fluorescence method for irinotecan and four major metabolites in human plasma and saliva: application to pharmacokinetic studies. Author(s): Poujol S, Pinguet F, Malosse F, Astre C, Ychou M, Culine S, Bressolle F. Source: Clinical Chemistry. 2003 November; 49(11): 1900-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14578322

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Serum cholesterol, precursors and metabolites and cognitive performance in an aging population. Author(s): Teunissen CE, De Vente J, von Bergmann K, Bosma H, van Boxtel MP, De Bruijn C, Jolles J, Steinbusch HW, Lutjohann D. Source: Neurobiology of Aging. 2003 January-February; 24(1): 147-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12493560

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Serum steroid hormones, sex hormone-binding globulin concentrations, and urinary hydroxylated estrogen metabolites in post-menopausal women in relation to daidzein-metabolizing phenotypes. Author(s): Frankenfeld CL, McTiernan A, Tworoger SS, Atkinson C, Thomas WK, Stanczyk FZ, Marcovina SM, Weigle DS, Weiss NS, Holt VL, Schwartz SM, Lampe JW. Source: The Journal of Steroid Biochemistry and Molecular Biology. 2004 April; 88(4-5): 399-408. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15145450

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Simultaneous determination of glycyrrhizin metabolites formed by the incubation of glycyrrhizin with rat feces by semi-micro high-performance liquid chromatography. Author(s): Okamura N, Miyauchi H, Choshi T, Ishizu T, Yagi A. Source: Biological & Pharmaceutical Bulletin. 2003 May; 26(5): 658-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12736507

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Studies of the in vitro intestinal metabolism of isoflavones aid in the identification of their urinary metabolites. Author(s): Heinonen SM, Wahala K, Liukkonen KH, Aura AM, Poutanen K, Adlercreutz H. Source: Journal of Agricultural and Food Chemistry. 2004 May 5; 52(9): 2640-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15113171

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Submerged cultivation of medicinal mushrooms for production of valuable bioactive metabolites. Author(s): Zhong JJ, Tang YJ.

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Source: Adv Biochem Eng Biotechnol. 2004; 87: 25-59. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15217103 •

The effects of an isoflavone intervention on the urinary excretion of hormone metabolites in premenopausal women. Author(s): Maskarinec G, Franke AA, Williams AE, Stanczyk FC. Source: Iarc Sci Publ. 2002; 156: 375-7. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12484210

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Transcription factors: tools to engineer the production of pharmacologically active plant metabolites. Author(s): Gantet P, Memelink J. Source: Trends in Pharmacological Sciences. 2002 December; 23(12): 563-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12457774

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Two new metabolites from the mangrove endophytic fungus no. 2524. Author(s): Li HJ, Lin YC, Yao JH, Vrijmoed LL, Jones GE. Source: Journal of Asian Natural Products Research. 2004 September; 6(3): 185-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15224415

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Urinary metabolites of nobiletin orally administered to rats. Author(s): Yasuda T, Yoshimura Y, Yabuki H, Nakazawa T, Ohsawa K, Mimaki Y, Sashida Y. Source: Chemical & Pharmaceutical Bulletin. 2003 December; 51(12): 1426-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14646323

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Validated method for the determination of six metabolites derived from artichoke leaf extract in human plasma by high-performance liquid chromatographycoulometric-array detection. Author(s): Wittemer SM, Veit M. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 August 15; 793(2): 367-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12906912

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Verapamil metabolites: potential P-glycoprotein-mediated multidrug resistance reversal agents. Author(s): Woodland C, Koren G, Wainer IW, Batist G, Ito S. Source: Canadian Journal of Physiology and Pharmacology. 2003 August; 81(8): 800-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12897809

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Vitamin E supplementation increases circulating vitamin E metabolites tenfold in end-stage renal disease patients. Author(s): Smith KS, Lee CL, Ridlington JW, Leonard SW, Devaraj S, Traber MG.

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Source: Lipids. 2003 August; 38(8): 813-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14577659

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The following is a specific Web list relating to metabolites; 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 Bone Marrow Disorders Source: Integrative Medicine Communications; www.drkoop.com Breast Cancer Source: Healthnotes, Inc.; www.healthnotes.com Chronic Myelogenous Leukemia Source: Integrative Medicine Communications; www.drkoop.com Eating Disorders Source: Healthnotes, Inc.; www.healthnotes.com

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Food Poisoning Source: Integrative Medicine Communications; www.drkoop.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Miscarriage Source: Integrative Medicine Communications; www.drkoop.com Myelofibrosis Source: Integrative Medicine Communications; www.drkoop.com Myeloproliferative Disorders Source: Integrative Medicine Communications; www.drkoop.com Osteoarthritis Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Healthnotes, Inc.; www.healthnotes.com Osteoporosis Source: Prima Communications, Inc.www.personalhealthzone.com Polycythemia Vera Source: Integrative Medicine Communications; www.drkoop.com Preeclampsia Source: Healthnotes, Inc.; www.healthnotes.com Pregnancy and Postpartum Support Source: Healthnotes, Inc.; www.healthnotes.com Scleroderma Source: Integrative Medicine Communications; www.drkoop.com Spontaneous Abortion Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Healthnotes, Inc.; www.healthnotes.com Thrombocytosis Source: Integrative Medicine Communications; www.drkoop.com •

Herbs and Supplements 7-Keto Source: Healthnotes, Inc.; www.healthnotes.com Acebutolol Source: Healthnotes, Inc.; www.healthnotes.com

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Acorus Alternative names: Sweet Flag; Acorus calamus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org ALA Source: Integrative Medicine Communications; www.drkoop.com Aloe Alternative names: Aloe vera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Alpha-Linolenic Acid (ALA) Source: Integrative Medicine Communications; www.drkoop.com Arctium Alternative names: Burdock, Gobo; Arctium lappa L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Astragalus Sp Alternative names: Vetch, Rattlepod, Locoweed; Astragalus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Brimonidine Source: Healthnotes, Inc.; www.healthnotes.com Cat’s Claw Alternative names: Uncaria tomentosa Source: Healthnotes, Inc.; www.healthnotes.com Cat's Claw Alternative names: Uncaria tomentosa Source: Integrative Medicine Communications; www.drkoop.com Chemotherapy Source: Healthnotes, Inc.; www.healthnotes.com Chitosan Source: Healthnotes, Inc.; www.healthnotes.com Clozapine Source: Healthnotes, Inc.; www.healthnotes.com Curcuma Alternative names: Turmeric; Curcuma longa L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Cyclosporine Source: Healthnotes, Inc.; www.healthnotes.com Dehydroepiandrosterone (DHEA) Source: Healthnotes, Inc.; www.healthnotes.com

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Metabolites

DHA Source: Integrative Medicine Communications; www.drkoop.com Diltiazem Source: Healthnotes, Inc.; www.healthnotes.com DMSO Source: Healthnotes, Inc.; www.healthnotes.com Docosahexaenoic Acid (DHA) Source: Integrative Medicine Communications; www.drkoop.com Eicosapentaenoic Acid (EPA) Source: Integrative Medicine Communications; www.drkoop.com EPA Source: Integrative Medicine Communications; www.drkoop.com Estrogens (Combined) Source: Healthnotes, Inc.; www.healthnotes.com Flaxseed Alternative names: Linum usitatissimum, Linseed Source: Integrative Medicine Communications; www.drkoop.com GABA (Gamma-Amino Butyric Acid) Source: Healthnotes, Inc.; www.healthnotes.com Ginkgo Alternative names: Ginkgo biloba Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Glycyrrhiza glabra Source: Integrative Medicine Communications; www.drkoop.com Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org HMB (Hydroxymethyl Butyrate) Source: Prima Communications, Inc.www.personalhealthzone.com Hydrastis Alternative names: Goldenseal; Hydrastis canadensis L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Illicium Alternative names: Star Anise; Illicium verum (Hook, F.) Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Insulin Source: Healthnotes, Inc.; www.healthnotes.com

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Ipriflavone Source: Healthnotes, Inc.; www.healthnotes.com Ipriflavone Source: Prima Communications, Inc.www.personalhealthzone.com Lavandula Alternative names: Lavender; Lavandula sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Licorice Alternative names: Glycyrrhiza glabra, Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com Linseed Source: Integrative Medicine Communications; www.drkoop.com Linum Usitatissimum Source: Integrative Medicine Communications; www.drkoop.com Mentha Alternative names: Pennyroyal; Mentha/Hedeoma pulegium Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Methotrexate Source: Healthnotes, Inc.; www.healthnotes.com Mixed Amphetamines Source: Healthnotes, Inc.; www.healthnotes.com Musa Banana Alternative names: Plantain, Banana; Musa sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Nettle Source: Integrative Medicine Communications; www.drkoop.com Oral Corticosteroids Source: Healthnotes, Inc.; www.healthnotes.com Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Pennyroyal Alternative names: Hedeoma pulegoides, Mentha pulegium Source: Healthnotes, Inc.; www.healthnotes.com Piper Alternative names: Kava; Piper methysticum Forst.f Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

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Piper Nigrum Alternative names: Black Pepper Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Pueraria Alternative names: Kudzu; Pueraria lobata Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Pygeum Alternative names: African Prune; Pygeum africanum Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Quinapril Source: Healthnotes, Inc.; www.healthnotes.com Rosmarinus Alternative names: Rosemary; Rosmarinus officinalis L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Ruta Alternative names: Rue; Ruta graveolens L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Sassafras Alternative names: Sassafras albidum (Nuttall) Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com St. John's Wort Source: Prima Communications, Inc.www.personalhealthzone.com Stevia Alternative names: Sweetleaf; Stevia rebaudiana Bertoni Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Strontium Source: Healthnotes, Inc.; www.healthnotes.com Symphytum Alternative names: Comfrey; Symphytum officinale L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Tacrine Source: Healthnotes, Inc.; www.healthnotes.com Theophylline Alternative names: Accurbron, Aerolate, Aquaphyllin, Asmalix, Elixomin, Elixophyllin, Lanophyllin, Quibron-T, Quibron-T-SR, Slo-bid, Slo-Phyllin, T-Phyl, Theo-24, Theo-Dur, Theo-Sav, Theo-X, Theobid, Theochron, Theoclear L.A.,

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Theoclear-80, Theolair, Theolair-SR, Theospan-SR, Theostat 80, Theovent, Uni-Dur, Uniphyl Source: Prima Communications, Inc.www.personalhealthzone.com Trigonella Alternative names: Fenugreek; Trigonella foenum graecum L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Uncaria Tomentosa Source: Integrative Medicine Communications; www.drkoop.com Urtica Dioica Source: Integrative Medicine Communications; www.drkoop.com Urtica Urens Source: Integrative Medicine Communications; www.drkoop.com Valeriana Alternative names: Valerian; Valeriana officinalis Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Withania Ashwagandha Alternative names: Ashwagandha; Withania somnifera L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Yellow Dock Alternative names: Rumex crispus Source: Healthnotes, Inc.; www.healthnotes.com Zingiber Alternative names: Ginger; Zingiber officinale Roscoe Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org

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

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

Dissertations on Metabolites 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 metabolites. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

A mass-spectrometric assay for electrophilic metabolites of natural-product mixtures by Johnson, Benjamin Maxwell, PhD from UNIVERSITY OF ILLINOIS AT CHICAGO, HEALTH SCIENCES CENTER, 2003, 156 pages http://wwwlib.umi.com/dissertations/fullcit/3111430

•

A pharmacokinetic study of p,p'-DDT and its metabolites during flight of the whitecrowned sparrow, Zonotrichia leucophrys by Scollon, Edward Joseph, PhD from TEXAS TECH UNIVERSITY, 2003, 158 pages http://wwwlib.umi.com/dissertations/fullcit/3108727

•

Bioactive metabolites of Alternaria brassicae and Monocillium nordinii by Rodriguez, Luis Manuel Peña, PhD from UNIVERSITY OF ALBERTA (CANADA), 1985 http://wwwlib.umi.com/dissertations/fullcit/NL22906

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•

Biochemical and ecotoxicological effects of 2,4,6-trinitrotoluene (TNT) and its metabolites on the soil invertebrate, Enchytraeus albidus by Dodard, Sabine Geralda, MSc from CONCORDIA UNIVERSITY (CANADA), 2003, 82 pages http://wwwlib.umi.com/dissertations/fullcit/MQ77664

•

Biosynthesis, production and structural studies of secondary metabolites in cultured marine cyanobacteria by Vulpanovici, Florina Alexandra, PhD from OREGON STATE UNIVERSITY, 2004, 149 pages http://wwwlib.umi.com/dissertations/fullcit/3116165

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Chemical and biological studies of secondary metabolites from Lissoclinum patella by Richardson, Adam David, PhD from THE UNIVERSITY OF UTAH, 2003, 206 pages http://wwwlib.umi.com/dissertations/fullcit/3094279

•

Chemical studies of the metabolites of Lachnellula fuscosanguinea by Villar, Jose Daniel Figueroa, PhD from UNIVERSITY OF ALBERTA (CANADA), 1984 http://wwwlib.umi.com/dissertations/fullcit/NK67475

•

Chemistry of the metabolites of Stereum purpureum by Saeedi Ghomi, M. H, PhD from UNIVERSITY OF ALBERTA (CANADA), 1981 http://wwwlib.umi.com/dissertations/fullcit/NK51580

•

Chemopreventive and chemotherapeutic mechanisms of sphingolipid metabolites in human colon cancer cells and breast stem, normal, and tumorigenic cells by Ahn, Eun Hyun, PhD from MICHIGAN STATE UNIVERSITY, 2003, 212 pages http://wwwlib.umi.com/dissertations/fullcit/3092109

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Contribution a l'etude des metabolites secondaires chez les lichens fructiculeux Cladina stellaris et Cladina rangiferina (French text) by Dahl, Wivecke, MSc from UNIVERSITE DU QUEBEC A CHICOUTIMI (CANADA), 2003, 193 pages http://wwwlib.umi.com/dissertations/fullcit/MQ77136

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DDT and its metabolites signal nuclear transcriptional regulators through a non-ERmediated mechanism: A model of environmental stress signaling by Frigo, Daniel E., PhD from TULANE UNIVERSITY, 2003, 192 pages http://wwwlib.umi.com/dissertations/fullcit/3116888

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Determination of platinum, organoplatinum and their metabolites in clinical samples by spectroscopy and liquid chromatography by Yang, Zheng, PhD from WAKE FOREST UNIVERSITY, 2004, 161 pages http://wwwlib.umi.com/dissertations/fullcit/3121779

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Dietary clay (HSCAS) reduces urinary aflatoxin metabolites in dogs by Bingham, Allen Kunz, PhD from TEXAS A&M UNIVERSITY, 2003, 206 pages http://wwwlib.umi.com/dissertations/fullcit/3088118

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Effects of ultrasound on cell growth and secondary metabolite production in plant cell cultures by Lin, Lidong, PhD from HONG KONG POLYTECHNIC UNIVERSITY (PEOPLE'S REPUBLIC OF CHINA), 2003, 224 pages http://wwwlib.umi.com/dissertations/fullcit/3074201

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Energetic consequences, trade-offs and elimination of plant secondary metabolites in a specialist (Neotoma stephensi) and generalist (Neotoma albigula) mammalian herbivore by Sorensen, Jennifer Sue, PhD from THE UNIVERSITY OF UTAH, 2003, 155 pages http://wwwlib.umi.com/dissertations/fullcit/3105813

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Enhancing the yield of target tissue and secondary metabolites in Calendula officinalis L., a medicinal plant by Stewart, Christie Lynn, MSc from UNIVERSITY OF WINDSOR (CANADA), 2003, 178 pages http://wwwlib.umi.com/dissertations/fullcit/MQ80512

•

Fermentation, biosynthesis, and identification of secondary metabolites from Penicillium species by Sumarah, Mark William, MSc from CARLETON UNIVERSITY (CANADA), 2003, 106 pages http://wwwlib.umi.com/dissertations/fullcit/MQ79819

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Genotoxic effects induced by equine estrogen metabolites in breast cancer cells by Liu, Xuemei, PhD from UNIVERSITY OF ILLINOIS AT CHICAGO, HEALTH SCIENCES CENTER, 2003, 125 pages http://wwwlib.umi.com/dissertations/fullcit/3083949

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Immunoetalonnage de steroides avec anticorps monoclonaux et traceurs isotopiques et non isotopiques l'etude des 5alpha-steroides-C19-glucuronides, metabolites des steroides-C19 testiculaires et surrenaliens by Brochu, Michèle, PhD from UNIVERSITE LAVAL (CANADA), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL34678

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Les interactions des principaux metabolites de l'acide arachidonique et du Paf-acether sur la fonction renale by Hébert, Richard L, PhD from UNIVERSITE DE SHERBROOKE (CANADA), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL49542

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Les metabolites microbiens dans le traitement de l'eau potable (French text) by Dandres, Thomas, MScA from ECOLE POLYTECHNIQUE, MONTREAL (CANADA), 2003, 268 pages http://wwwlib.umi.com/dissertations/fullcit/MQ81539

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Les metabolites secondaires des plantes dans la nutrition du campagnol des champs une relation avec les fluctuations cycliques? by Jean, Yves , PhD from UNIVERSITE DE SHERBROOKE (CANADA), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL33508

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Mechanisms of growth factor receptor-like signaling by benzo(a)pyrene metabolites in human mammary epithelial cells by Burdick, Andrew D., PhD from THE UNIVERSITY OF NEW MEXICO, 2003, 148 pages http://wwwlib.umi.com/dissertations/fullcit/3112362

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Metabolites of Armillaria mellea and synthetic studies on a potential iron-binding fungal metabolite and analogues by Macaulay, John Beverley, PhD from UNIVERSITY OF ALBERTA (CANADA), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL32481

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On some metabolites of medicinal plants by Kasitu, Gertrude Chisoswa, PhD from UNIVERSITY OF ALBERTA (CANADA), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL52853

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Postpartum changes in hormones and metabolites during early lactation in summer and winter calving Holstein cows by Nordbladh, Louise I., MS from NORTH CAROLINA STATE UNIVERSITY, 2003, 75 pages http://wwwlib.umi.com/dissertations/fullcit/EP10191

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•

Pyoluteorin as a signaling molecule regulating secondary metabolite production and transport genes in Pseudomonas fluorescens Pf-5 by Brodhagen, Marion L., PhD from OREGON STATE UNIVERSITY, 2004, 212 pages http://wwwlib.umi.com/dissertations/fullcit/3107721

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Some metabolites of Cyathus helenae by Taube, Hubert, PhD from UNIVERSITY OF ALBERTA (CANADA), 1972 http://wwwlib.umi.com/dissertations/fullcit/NK13592

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Speciation and identification of low molecular weight organoselenium metabolites in human urine by Hoang, Tiffany Truc, PhD from GEORGIA INSTITUTE OF TECHNOLOGY, 2003, 217 pages http://wwwlib.umi.com/dissertations/fullcit/3084958

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Structural and synthetic studies on some fungal metabolites [microform] by McCaskill, Robert Hugh, PhD from UNIVERSITY OF ALBERTA (CANADA), 1980 http://wwwlib.umi.com/dissertations/fullcit/NK51538

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Structural, synthetic and 13Cmr studies on fungal metabolites and related compounds by Fung, Steven, PhD from UNIVERSITY OF ALBERTA (CANADA), 1978 http://wwwlib.umi.com/dissertations/fullcit/NK40154

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The relationship between exercise-induced delayed muscle soreness and the excretion of urine metabolites and creatinine, 3-methylhistidine and hydroxyproline by HORSWILL, CRAIG ALAN, PHD from UNIVERSITY OF ILLINOIS AT URBANACHAMPAIGN, 1986, 208 pages http://wwwlib.umi.com/dissertations/fullcit/8623324

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The role of selected plant and microbial metabolites in the nutrient solution of closed growing systems in greenhouses by Jung, M. C. Victoria, Fildr from SVERIGES LANTBRUKSUNIVERSITET (SWEDEN), 2003, 45 pages http://wwwlib.umi.com/dissertations/fullcit/f219297

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

Patents on Metabolites By performing a patent search focusing on metabolites, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 8Adapted

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

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

Antibodies to specific regions of cyclosporine related compounds Inventor(s): Malcolm; Andrew J. (Alberta, CA), Naicker; S. Selvaraj (Alberta, CA), Yatscoff; Randall W. (Alberta, CA) Assignee(s): Isotechnika, Inc. (Edmonton, CA) Patent Number: 6,686,454 Date filed: September 3, 1999 Abstract: This invention relates to the production of polyclonal and monoclonal antibodies to specific regions of cyclosporine (CSA) and/or CSA metabolites/derivatives. The reactivity of these polyclonal and monoclonal antibodies make them particularly useful for immunoassays for therapeutic drug monitoring (TDM). These immunoassays or TDM kits may include polyclonal or monoclonal antibodies to specific sites of CSA and/or CSA metabolites. These kits may also include various combinations of polyclonal antibodies, polyclonal and monoclonal antibodies or a panel of monoclonal antibodies. Cyclosporine or CSA metabolite conjugate immunogens are prepared for the immunization of a host animal to produce antibodies directed against specific regions of the CSA or CSA metabolite molecule. By determining the specific binding region of a particular antibody, immunoassays which are capable of distinguishing between the parent molecule, active metabolites, inactive metabolites and other structurally similar immunosuppressant compounds are developed. The use of divinyl sulfone (DVS) as the linker arm molecule for forming cyclosporine and cyclosporine metabolite protein conjugate immunogens is described. Excerpt(s): This invention relates to the production of polyclonal and monoclonal antibodies to specific sites of cyclosporine and/or cyclosporine metabolites, derivatives and analogues. The reactivity of these polyclonal and monoclonal antibodies makes them particularly useful for immunoassays for therapeutic drug monitoring (TDM). These immunoassays or TDM kits may include polyclonal or monoclonal antibodies to specific sites of cyclosporine (CSA) and/or metabolites, derivatives and analogues of cyclosporine. These kits may also include various combinations of polyclonal antibodies, polyclonal and monoclonal antibodies or a panel of monoclonal antibodies. Currently, the two immunosuppressive drugs administered most often to prevent organ rejection in transplant patients are cyclosporine (CSA) and tacrolimus (FK-506 or FK). Rapamycin (Rapa) is another known immunnosuppressant. Cyclosporine's primary target appears to be the helper T lymphocytes. Cyclosporine acts early in the process of T cell activation, it has secondary effects on other cell types that are normally activated by factors produced by the T cells. Cyclosporine inhibits the production of interleukin 2 (IL2) by helper T cells, thereby blocking T cell activation and proliferation (amplification of immune response). It is effective both in the prevention and in the treatment of ongoing acute rejection. The current model for the mechanism of action of CSA suggests that, in the T cell cytoplasm, CSA binds to a specific binding protein called immunophilin. The CSA-immunophilin complex in turn binds to and blocks a phosphatase called calcineurin. The latter is required for the translocation of an activation factor (NF-ATc) from the cytosol to the nucleus, where it would normally bind to and activate enhancers/promoters of certain genes. In the presence of CSA, the cytosolic activation factor is unable to reach the nucleus, and the transcription of IL-2 (and other early activation factors) is strongly inhibited. As a result of this inhibition, T cells do not

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proliferate, secretion of gamma-interferon is inhibited, no MHC class II antigens are induced, and no further activation of the macrophages occurs. Various side effects are associated with cyclosporine therapy, including nephrotoxicity, hypertension, hyperkalemia, hypomagnesemia and hyperuricemia. Neuro- or nephrotoxicity has been correlated with certain cyclosporine metabolites. A necessary requirement of cyclosporine drug monitoring assays is to measure the levels of parent cyclosporine drug and metabolite with immunosuppressive and toxic activity. There is a need for improved methods of monitoring levels of CSA and/or CSA metabolites and derivatives. Web site: http://www.delphion.com/details?pn=US06686454__ •

Apparatus for measurement and control of the content of glucose, lactate or other metabolites in biological fluids Inventor(s): Poscia; Alessandro (Orvieto, IT), Varalli; Maurizio Claudio (Milan, IT) Assignee(s): Menarini Industrie Farmaceutiche Riunite S.r.L. (Firenze, IL) Patent Number: 6,618,603 Date filed: May 7, 2001 Abstract: An apparatus for the continuous measurement of glucose and lactate in interstitial fluids including a glucose measurement cell, an A/D conversion block, a memory block and a bi-directional communication between the interface block and an external calculation unit. Excerpt(s): This invention relates generally to the field of measurement transducers, and more specifically, to electronic circuits for glucose content measurement instruments for personal independent use. Still more particularly, the invention relates to an apparatus for improved safety, flexibility of use, and improved measurement performance, in the near-continual determination of glucose or other molecules in extracellular fluids. The medical literature indicates the need to have dedicated instruments permitting almost continual measurement of the concentration in a patient's blood of certain specific molecules, such as glucose, lactate and others. Many such instruments dedicated to these measurements have been developed. One of the most serious drawbacks of prior devices has been the excessive invasiveness of known methods of measurement, which involve the need for direct access to a patient's blood vessels. Web site: http://www.delphion.com/details?pn=US06618603__

•

Bioactive tetracyclic diterpene compounds and methods of preparation and use thereof Inventor(s): Roncal; Tomas (San Sebastian, ES), Sterner; Olov (Malmoe, SE), Ugalde; Unai (Hondarribia, ES) Assignee(s): Universidad del Pais Vasco/Euskal Herriko Unibersitatea (Leioa, ES) Patent Number: 6,682,914 Date filed: October 31, 2001 Abstract: Newly-isolated and purified metabolites which are effective in regulating the development of at least one filamentous fungal microorganism species are disclosed. These compounds, which are referred to as conidiogenol and conidiogenone, may be

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used to induce conidiation in and/or to inhibit the growth of populations of such fungal species. The compounds are preferably produced by culture of the fungal species Penicillium cyclopium, and may be subsequently recovered from the culture medium and purified. Methods of using and methods of producing these compounds are also disclosed. Excerpt(s): The present invention relates broadly to the isolation, identification and use of natural products. More particularly, this invention relates to substantially pure forms of two related biologically active diterpenoid compounds that are useful to regulate the development of microorganisms. Specifically, these substances may be used to induce conidiation in, and thereby also to inhibit the growth of, such microorganisms. The continuous deposition of new cell wall and plasma membrane material at a fixed cellular site (termed "apical extension") is a successful growth pattern which is widely observed in prokaryotic and eukaryotic organisms (Heath, 1990). The derived tubular structure (the hypha) offers great practical advantages for the colonization of solid substrates, as well as the undertaking of fungal infection. It acts as a device providing sheer physical force combined with a versatile arsenal of apically secreted enzymes directed at the hydrolysis of biopolymers and other bioconversions. However, apical extension growth is unsuitable for dispersive purposes or resistance to unfavorable environmental conditions, and filamentous microorganisms have evolved alternative morphogenetic programs to generate cell forms which cater to these requirements: spores (Smith and Berry 1974). The formation of conidia or asexual spores among filamentous fungi is a complex process in which a succession of precisely regulated cellular events take place in tight coordination. Environmental or endogenous stimuli are thought to trigger a set of genetically determined programs which lead to the cessation of apical growth, and to the development of reproductive asexual structures which finally result in the formation of conidia. Web site: http://www.delphion.com/details?pn=US06682914__ •

Bioreactive allosteric polynucleotides Inventor(s): Breaker; Ronald R. (Guilford, CT) Assignee(s): Yale University (New Haven, CT) Patent Number: 6,630,306 Date filed: May 4, 2001 Abstract: Polynucleotides having allosteric properties that modify a function or configuration of the polynucleotide with a chemical effector and/or physical signal are employed primarily as biosensors and/or enzymes for diagostic and catalytic purposes. In some preferred embodiments, the polynucleotides are DNA enzymes that are used in solution/suspension or attached to a solid support as biosensors to detect the presence or absence of a compound, its concentration, or physical change in a sample by observation of self-catalysis. Chemical effectors include organic compounds such as amino acids, amino acid derivatives, peptides, nucleosides, nucleotides, steroids, and mixtures of these with each other and with metal ions, cellular metabolites or blood components obtained from biological samples, steroids, pharmaceuticals, pesticides, herbicides, food toxins, and the like. Physical signals include radiation, temperature changes, and combinations thereof. Excerpt(s): This invention relates primarily to functional DNA polynucleotides that exhibit allosteric properties, and to catalytic RNA and DNA polynucleotides that have

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catalytic properties with rates that can be controlled by a chemical effector, a physical signal, or combinations thereof. Bioreactive allosteric polynucleotides of the invention are useful in a variety of applications, particularly as biosensors. Biosensors are widely used in medicine, veterinary medicine, industry, and environmental science, especially for diagnostic purposes. Biosensors are typically composed of a biological compound (sensor material) that is coupled to a transducer, in order to produce a quantitative readout of the agent or conditions under analysis. Usually, the biological component of the biosensor is a macromolecule, often subject to a conformational change upon recognition and binding of its corresponding ligand. In nature, this effect may immediately initiate a signal process (e.g., ion channel function in nerve cells). Included in the group of `affinity sensors` are lectins, antibodies, receptors, and oligonucleotides. In biosensors, ligand binding to the affinity sensor is detected by optoelectronic devices, potentiometric electrodes, field effect transistors (FETs), or the like. Alternatively, the specificity and catalytic power of proteins have been harnessed to create biosensors that operate via enzyme function. Likewise, proteins have been used as immobilized catalysts for various industrial applications. The catalytic activity of purified enzymes or even whole organelles, microorganisms or tissues can be monitored by potentiometric or amperometric electrodes, FETs, or thermistors. The majority of biosensors that are commercially available are based on enzymes, of which the oxidoreductases and lyases are of great interest. It is nearly exclusively the reactants of the reactions catalyzed by these enzymes for which transducers are available. These transducers include potentiometric electrodes, FETs, pH- and O.sub.2 -sensitive probes, and amperometric electrodes for H.sub.2 O.sub.2 and redox mediators. For example, the oxidoreductases, a group of enzymes that catalyze the transfer of redox equivalents, can be monitored by detectors that are sensitive to H.sub.2 O.sub.2 or O.sub.2 concentrations. Web site: http://www.delphion.com/details?pn=US06630306__ •

Engineering of metabolic control Inventor(s): Liao; James C. (Los Angeles, CA) Assignee(s): Food Industry Research and Development Institute (CN) Patent Number: 6,706,516 Date filed: July 27, 2000 Abstract: The invention features a method of producing heterologous molecules in cells under the regulatory control of a metabolite and metabolic flux. The method can enhance the synthesis of heterologous polypeptides and metabolites. Excerpt(s): The use of recombinant DNA technology has allowed the engineering of host cells to produce desired compounds, such as polypeptides and secondary metabolites. The large scale production of polypeptides in engineered cells allows for the production of proteins with pharmaceutical uses and enzymes with industrial uses. Secondary metabolites are products derived from nature that have long been known for their biological and medicinal importance. Because of the structural complexity inherent in such molecules, traditional chemical synthesis often requires extensive effort and the use of expensive precursors and cofactors to prepare the compound. In recent years, the expression of heterologous proteins in cells has facilitated the engineering of heterologous biosynthetic pathways in microorganisms to produce metabolites from inexpensive starting materials. In this manner, a variety of compounds have been produced, including polyketides,.beta.-lactam antibiotics, monoterpenes, steroids, and aromatics. The invention is based, in part, on the discovery that production of

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heterologous polypeptides and metabolites can be enhanced by the regulated expression of the polypeptide (e.g., a biosynthetic enzyme) using a promoter which is regulated by the concentrations of a second metabolite, e.g. acetyl phosphate. The term "heterologous" refers to a polypeptide or metabolite which is introduced by artifice. A heterologous polypeptide or metabolite can be identical to endogenous entity that is naturally present. The term "metabolite" refers to a organic compound which is the product of one or more biochemical reactions A metabolite may itself be a precursor for other reactions. A secondary metabolite is a metabolite derived from another. Accordingly, in one aspect, the invention features a bacterial host cell containing a nucleic acid sequence comprising a promoter and a nucleic acid sequence encoding a heterologous polypeptide. Examples of bacterial host cells include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, Agrobacterium tumefaciens, Thermus thermophilus, and Rhizobium leguminosarum cells. The nucleic acid sequence is operably linked to the promoter which is controlled by a response regulator protein. In other words, the nucleic acid sequence is linked to the promoter sequence in a manner which allows for expression of the nucleotide sequence in vitro and in vivo. "Promoter" refers to any DNA fragment which directs transcription of genetic material. The promoter is controlled by a response regulator protein, for example, ntrC, phoB, phoP, ompR, cheY, creB, or torR, of E. coli or its homologs from other bacterial species. Further, the response regulator protein can be another member of the cluster orthologous group (COG) COG0745 as defined by http//www.ncbi.nlm.nih.gov/COG/(Tatusov et al. Nucleic Acids Res. (2000); 28:33-36). In one implementation, the promoter is bound by E. coli ntrC. The term "ntrC" refers to both the E. coli ntrC protein (SWISSPROT: P06713, http://www.expasy.ch/) and its homologs in other bacteria as appropriate. As used herein, "bound" refers to a physical association with a equilibrium binding constant (K.sub.D) of less than 100 nM, preferably less than 1 nM. An example of the promoter is the E. coli glnAp.sub.2 promoter, e.g. a region between positions about 93 and about 323 in the published DNA sequence, GenBank accession no. M10421(Reitzer & Magasanik (1985) Proc Nat Acad Sci USA 82:1979-1983). This region includes untranslated sequences from the glnA gene. Further, a translational fusion can be constructed between coding sequences for glnA and coding sequences for the heterologous polypeptide. Web site: http://www.delphion.com/details?pn=US06706516__ •

Felbamate derived compounds Inventor(s): Macdonald; Timothy L. (Charlottesville, VA) Assignee(s): University of Virginia Patent Foundation (Charlottesville, VA) Patent Number: 6,599,935 Date filed: December 17, 2001 Abstract: The present invention relates to novel felbamate derivatives and their use to treat neurological diseases such as epilepsy and to treat tissue damage resulting form ischemic events. The felbamate derivatives are modified to prevent the formation of metabolites that are believed responsible for the toxicity associated with felbamate therapy. Excerpt(s): The present invention is directed to novel derivatives of 2-phenyl-1,3propanediol dicarbamate (felbamate), and the use of such derivatives as therapeutic agents. More particularly, compositions comprising the present felbamate derivatives can be administered for reducing the incidence and severity of epileptic seizures and for

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preventing and treating hypoxic damage resulting from an ischemic event. Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a known pharmaceutical compound having been described in U.S. Pat. Nos. 2,884,444 and 4,868,327, the disclosures of which are expressly incorporated herein. Felbamate is a modulator of NMDA (N-methyl-Daspartate) receptor function, and a glycine site antagonist but also has other reported mechanisms of actions. Felbamate has also been reported to interact at the AMPA/kainate receptor, facilitate the function of the GABA receptor, and modulate Na.sup.+ channel conductance. Felbamate has also been demonstrated to decrease delayed neuronal cell death after kainic acid induced status epilepticus in animals. Glycine or d-serine were able to functionally reverse the anticonvulsant and ischemic protective effect of felbamate. Web site: http://www.delphion.com/details?pn=US06599935__ •

Fluorescent hplc assay for 20-hete and other p-450 metabolites of arachidonic acid Inventor(s): Maier; Kristopher G. (Milwaukee, WI), Roman; Richard J. (Brookfield, WI) Assignee(s): MCW Research Foundation (Milwauke, WI) Patent Number: 6,764,855 Date filed: February 14, 2003 Abstract: The present invention provides a fluorescent HPLC assay for detecting the presence and/or measuring the level of 20-hydroxyeicosatetraenoic acid (20-HETE) and other P-450 metabolites of arachidonic acid in a sample. P-450 metabolites of arachidonic acid are first extracted from the sample and then labeled with 2-(2,3naphthalimino)ethyl trifluoromethanesulfonate. The labeling reaction is catalyzed by N,N-diisopropylethylamine. Next, the labeled P-450 metabolites are separated on a 4.5.times.250-mm, 5.mu.M particle size C18 reverse-phase HPLC column using a mobile phase of methanol:water:acetic acid (82:18:0.1, v/v/v) and an isocratic elution at a rate of about 1.3 ml per minute. Fluorescence intensities of the column eluent are monitored by a fluorescence detector. Quantitation of P-450 metabolites in a sample can be made by using an internal standard. Excerpt(s): Not applicable. A variety of diseases such as salt sensitive hypertension, toxemia of pregnancy, asthma, hepatorenal syndrome, diabetes and subarachnoid hemorrhage are associated with abnormalities in arachidonic acid ("AA") metabolism. Recent studies have indicated that AA is primarily metabolized in the brain, kidney, lung, and vasculature by cytochrome P-450 enzymes to epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (diHETEs), and 19and 20hydroxyeicosatetraenoic acids (19- and 20-HETE). McGiff J C and Quilley J, Am J Physiol Regulatory Integrative Comp Physiol 277: R607-R623 (1999); Roman R J and Alonso-Galicia M, News Physiol Sci 14: 238-242 (1999). 20-HETE and EETs are biologically active and have been implicated as paracrine factors and/or second messengers in the regulation of vascular tone, sodium and water excretion in the kidney, and airway resistance. McGiff J C and Quilley J, Am J Physiol Regulatory Integrative Comp Physiol 277: R607-R623 (1999); Roman R J and Alonso-Galicia M, News Physiol Sci 14: 238-242 (1999). Despite the importance of P-450 metabolites of AA, very little is known about the regulation of the concentrations of these mediators in tissue and biological fluids. Part of the problem has been the lack of a sensitive, inexpensive, and high-throughput assay to measure the endogenous concentration of these compounds. To date, gas chromatography-mass spectroscopy (GC-MS) with selective ion monitoring and one report of a fluorescent enzyme based immunoassay

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("EIA") for EETs have been the only methods available to measure the concentration of P-450 metabolites of AA in biological samples. Capdevila J H et al. J Biol Chem 267: 21720-21726(1992); Catella F et al., Proc Natl Acad Sci USA 87: 5893-5897 (1990); Prakash C et al., Biochem Biophys Res Commun 185: 728-733 (1992); Schwartzman M L et al., Biochem Biophys Res Commun 180: 445-449 (1991); Toto R et al., Biochem Biophys Acta 191: 132-134 (1987). The EIA requires a specific antibody that is no longer generally available and, therefore, the assay cannot be reproduced in other labs. GC-MS has been successfully used to measure 20-HETE and EETs in the urine of humans and rats, and the reported concentration of these mediators is in the range of 0.5-5 ng/ml. The urinary excretion of EETs has been reported to increase in rats fed a high-salt diet and in patients with toxemia of pregnancy. Capdevila J H et al., J Biol Chem 267: 21720-21726 (1992); Oyekan A O et al., J Clin Invest 104:1131-1137(1999); Catella F et al., Proc Natl Acad Sci USA 87: 5893-5897 (1990). Moreover, the urinary excretion of 20-HETE is elevated in patients with hepatorenal syndrome and in DOCA-salt hypertensive rats. Sacerdoti D et al., J Clin Invest 100: 1264-1270 (1997); Oyekan A O et al., Am J Physiol Regulatory Integrative Comp Physiol 176: R766-R775 (1999). Although GC-MS is a reliable method for the measurement of P-450 metabolites of AA, the high cost for the purchase and maintenance of the instrumentation and difficulties in preparing the samples for analysis have limited the use of this technique. Indeed, the preparation of urine samples for GC-MS involves an organic extraction of the lipid fraction, separation of the EETs or HETEs fractions by thin-layer chromatography and reverse-phase HPLC, derivatization of the samples to the methyl or pentabenzylfluoro esters, and conversion of these esters to trimethylsilyl derivatives. Toto R et al., Biochem Biophys Acta 191: 132134 (1987). It also requires the synthesis and addition of a deuterated internal standard to the samples to correct for variable extraction and derivatization efficiencies. The extensive sample preparation reduces sample recoveries and the detection limits of this technique to the nanogram range. Oyekan A O et al., J Clin Invest 104: 1131-1137 (1999); Schwartzman M L et al., Biochem Biophys Res Commun 180: 445-449 (1991); Toto R et al. Biochem Biophys Acta 191: 132-134 (1987). GC-MS is also limited to the measurement of a single compound at a time. Web site: http://www.delphion.com/details?pn=US06764855__ •

Formulation and method for increasing the essential oil content in aromatic crops Inventor(s): Kalra; Alok (Uttar Pradesh, IN), Katiyar; Neetu (Uttar Pradesh, IN), Khanuja; Suman Preet Singh (Uttar Pradesh, IN), Kumar; Sushil (Uttar Pradesh, IN) Assignee(s): Council of Scientific and Industrial Research (New Delhi, IN) Patent Number: 6,720,289 Date filed: November 9, 2001 Abstract: The present invention provides a formulation for increasing the synthesis and accumulation of essential oil in aromatic plants and other plants. The formulation disclosed herein comprises a resistance inducer, such as an isomer of amino butyric acid or another amino acid, which is capable of increasing the synthesis of essential oil in an aromatic plant. The formulation may further comprise secondary metabolites as well as a carrier. Aromatic plants that may be used in the present invention include, but are not limited to, rose-scented geranium (Pelargonium graveolens) and menthol mint (Mentha arvensis). The present invention also provides a method of increasing the essential oil content in aromatic crops and other plants.

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Excerpt(s): The present invention relates to a formulation and a method useful for increasing the essential oil content of aromatic crops. In particular, this invention relates to a formulation comprising an amino acid, such as an isomer of amino butyric acid, wherein the formulation is capable of increasing or enhancing the essential oil content in aromatic plants. The concept of inducing resistance in plants in laboratories, glasshouse studies, and in the field has been demonstrated using abiotic and biotic elicitors, which may include complex carbohydrates, various amino and fatty acids, derivatives of salicylic, nicotinic and jasmonic acids, ethylene, glycoproteins, and the like. (Lyon et al., Plant Pathology, 44:407-27 (1995)). Such elicitors have also been shown to induce other biochemical changes, which affect plants and plant cell systems, such as photosynthesis (Pancheva et al., Journal of Plant Physiology 149:57-63 (1996)), anthocyanin accumulation (Berglund et al., Journal of Plant Physiology, 141:596-600 (1993)) and flowering (Krajncic and Nemec, Journal of Plant Physiology, 146:754-756 (1995)). These findings indicate that elicitors act as signal molecules for gene expression in plants. However, compounds or chemicals (such as elicitors) capable of enhancing the yields of secondary metabolites (such as essential oil) in aromatic plants, in vivo, are not presently known in the art. Web site: http://www.delphion.com/details?pn=US06720289__ •

Health supplements containing phyto-oestrogens, analogues or metabolites thereof Inventor(s): Kelly; Graham Edmund (Northbridge, AU) Assignee(s): Novogen Research Pty. Ltd. (AU) Patent Number: 6,642,212 Date filed: October 19, 1999 Abstract: Compositions enriched with natural phyto-oestrogens or analogues thereof selected from Genistein, Diadzein, Formononectin and Biochanin A. These compositions may be used as food additives, tablets or capsules for promoting health in cases of cancer, pre-menstrual syndrome, menopause or hypercholesterolaemia. Excerpt(s): This invention relates to natural products containing phyto-oestrogens, or phyto-oestrogen metabolites, which have various beneficial physiological effects in man, and which have a variety of uses, such as to promote good health and as a dietary additive, for example. The particular product in accordance with the invention is an extract of certain plants with the particular purpose of enrichment for phyto-oestrogens, both in their natural state and their closely related derivatives and metabolites. Plants which are used as foodstuffs or medicinal herbs contain a wide variety of chemicals which are assimilated into the body following ingestion. Some of these chemicals are important nutrients for man and animals (e.g. fats, carbohydrates, proteins, vitamins, minerals) while others have none, or little or no known nutritional value. The phytooestrogens hitherto have fallen into this latter category of no known nutritional value. Web site: http://www.delphion.com/details?pn=US06642212__

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Integrated assay for organ function, drugs and/or one or more metabolites Inventor(s): Burd; John F. (5659 Glenstone Way, San Diego, CA 92121), Edelman; Steven V. (UCSD Veterans Administration Medical Center, Department of, San Diego, CA 92161) Assignee(s): none reported Patent Number: 6,627,153 Date filed: August 31, 2001 Abstract: A test device that assesses the concentration of an organ marker, a drug marker and a metabolite associated with the drug/organ interaction. Excerpt(s): This invention relates to an integrated assay system, more specifically, to assessing the effectiveness of a drug and the organ function of a patient by measuring the concentrations of an organ marker, a drug and/or one or more metabolites with an integrated test system. Many drugs are currently available to treat diseases such as diabetes mellitus, cancer, hypertension, seizure disorders and infection. However, a number of these drugs can be dangerous and have been shown to result in organ damage in certain patients. On occasion, permanent organ damage can go undetected because potential drug side effects are not monitored effectively. Such organ damage may eventually require an organ transplant or even lead to death. For example, the drug troglitazone helps diabetes patients to control abnormally high blood glucose levels. Most patients tolerate this drug well and develop no lasting harmful side effects. Others tolerate the drug initially, but suddenly develop liver disease. Fortunately, for most of these patients, organ damage can abate or disappear when the drug is discontinued. However, some patients can develop permanent liver damage, which may result in death or require a transplant, especially if the patient's liver function is not being monitored regularly. Accordingly, liver function tests are strongly recommended before and periodically during treatment with troglitazone. Web site: http://www.delphion.com/details?pn=US06627153__

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Method for chemoprevention of prostate cancer Inventor(s): Raghow; Sharan (Collierville, TN), Steiner; Mitchell S. (Germantown, TN) Assignee(s): The University of Tennessee Research Corporation (Knoxville, TN) Patent Number: 6,632,447 Date filed: November 8, 2000 Abstract: This invention relates to the chemoprevention of prostate cancer and, more particularly, to a method of suppressing or inhibiting latent prostate cancer comprising administering to a mammalian subject a chemopreventive agent and analogs and metabolites thereof. The chemopreventive agent prevents, prevents recurrence of, suppresses or inhibit prostate carcinogenesis; and treats prostate cancer. Excerpt(s): Prostate cancer is one of the most frequently occurring cancers among men in the United States, with hundreds of thousands of new cases diagnosed each year. Unfortunately, over sixty percent of newly diagnosed cases of prostate cancer are found to be pathologically advanced, with no cure and a dismal prognosis. One approach to this problem is to find prostate cancer earlier through screening programs and thereby reduce the number of advanced prostate cancer patients. Another strategy, however, is to develop drugs to prevent prostate cancer. One third of all men over 50 years of age

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have a latent form of prostate cancer that may be activated into the life-threatening clinical prostate cancer form. The frequency of latent prostate tumors has been shown to increase substantially with each decade of life from the 50s (5.3-14%) to the 90s (40-80%). The number of people with latent prostate cancer is the same across all cultures, ethnic groups, and races, yet the frequency of clinically aggressive cancer is markedly different. This suggests that environmental factors may play a role in activating latent prostate cancer. Thus, the development of chemoprevention strategies against prostate cancer may have the greatest overall impact both medically and economically against prostate cancer. Toremifene is an example of a triphenylalkene compound described in U.S. Pat. Nos. 4,696,949 and 5,491,173 to Toivola et al., the disclosures of which are incorporated herein by reference. The parenteral and topical administration to mammalian subjects of formulations containing toremifene are described in U.S. Pat. No. 5,571,534 to Jalonen et al. and in U.S. Pat. No. 5,605,700 to DeGregorio et al., the disclosures of which are incorporated herein by reference. Web site: http://www.delphion.com/details?pn=US06632447__ •

Method for cultivation of filamentous fungi Inventor(s): Huang; Ting-Kuo (Chang-He, TW), Wang; Pei-Ming (Kaohsiung, TW), Wu; Wen-Teng (Hsinchu, TW), Yuan; Gwo-Fang (Hsinchu, TW) Assignee(s): Food Industry Research & Development Institute (Hsinchu, TW) Patent Number: 6,746,862 Date filed: July 7, 2000 Abstract: The invention discloses a method for cultivation of filamentous fungi using a suspended nutritionally solid substrate, the method including the steps of: (a) preparing a medium comprising a nutritionally solid substrate; and (b) inoculating an inoculum into the medium comprising the nutritionally solid substrate in a bioreactor to carry out fermentation. The present invention combines the properties of solid-state culture and submerged culture. In addition, the present invention may employ an air-lift bioreactor with a net draft tube and the fed-batch process to elevate the yields of filamentous fungi and metabolites thereof. Excerpt(s): The present invention relates to a method for cultivation of filamentous fungi, and more particularly to a method for cultivation of filamentous fungi by using suspended nutritionally solid substrates. Generally, the method for fermentation of filamentous fungi can include the use of solid-state culture or submerged culture. The conventional method for the most part uses solid-state culture. One example of producing metabolites from Monascus species is directly inoculating Monascus species into solid nutritional medium such as grain medium, for example rice or wheat. Then, fermentation is carried out. The mycelia of Monascus species penetrate into the surface of the solid nutritional medium and grow during the period of fermentation. The pigments produced are absorbed so that the color of the medium turns purple. In addition, the mycelia also penetrate inside the grain particles. This phenomenon facilitates the production of pigments. In 1991, Johns and Stuar employed Carrageenan particles consisting of synthetic medium to simulate grain in culture (Johns and Stuar, (1991) J. Industrial Microbiology, 8:23-28). However, due to reasons such as structure, nutrition components, etc, the synthetic medium is not suitable for Monascus species in the production based on solid-state culture. Generally, to adequately make use of medium and maintain optimal temperature and humidity, the operation procedures of conventional solid-state culture are complex and time-consuming. Moreover, some

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problems such as the restriction of oxygen transfer, contamination, etc., also make the scale-up difficult. Furthermore, because of the disadvantages of solid-state culture described above, the quality and quantity of the products are usually unstable. To solve this problem, many studies have developed submerged culture to carry out the fermentation. In 1982, Lin and Lizuka employed saccharide and cereal meals as a carbon source to solve the problems of scale-up and operation control (Lin and Lizuka, (1982) Appl. Environ. Microbiology, 43:671-676). However, the yield of the pigments is significantly reduced using this method. In 1984, Evans and Wang employed algin (an inert substance in which no nutrient is contained) to immobilize Monascus species and then carry out submerged culture. The result showed the phenomenon of mycelia attachment conduces the production of the pigments (Evans and Wang, (1984) Applied and Environmental Microbiology 47(6): 1323-1326). In 1990, Mak et. al. introduced roller bottle culture, which has the properties of high oxygen mass transfer and low shear stress to provide an environment for mycelia attachment, and used glucose as a carbon source to carry out the cultivation of Monascus species (Mak et. al., (1990) Enzyme Microbiol. Technol., 12:965-968). However, due to the nature of the roller bottle, the scale of the production is too small using this method. In 1995, Lee et. al. used topioca starch as a carbon source and pointed out that a high initial starch concentration in the medium is not suitable for practical use due to high viscosity of the medium (Lee et. al., (1995) J. Fermentation of Bioengineering, 79(5): 516-518). They proposed a solid-liquid state culture with gelatinized starch block provided at the bottom and a dilute soluble starch at the upper part of the reactor. The cultivation was carried out in a stirred-tank bioreactor. However, their proposed approach might have scale-up problem since the interface area to volume ratio is small for a large-scale system. Web site: http://www.delphion.com/details?pn=US06746862__ •

Method for detecting the presence of microbes and determining their physiological status Inventor(s): Lloyd; Christopher R. (North Logan, UT), Powers; Linda S. (Logan, UT) Assignee(s): Microbiosystems, Limited Partnership (Cheyenne, WY) Patent Number: 6,750,006 Date filed: January 22, 2002 Abstract: Method and apparatus for the detection of microbes in liquids, in air and on non-living surfaces in which samples are exposed to electromagnetic radiation of specific energies capable of exciting various metabolites, cofactors and cellular and spore components, with the microbial cells to be sampled (and more specifically the excited metabolites, cofactors and or other cellular components) contained therein emit fluorescence that can be measured. The signal from the background and scattered excitation signals is removed from the fluorescence signals of the microbial components, the relative fluorescent signals of the intrinsic microbial components are required to lie within physiological ranges, and the amplitude of the background-corrected fluorescence signals used to enumerate the microbe content in the sample. Excerpt(s): This invention relates to a method and apparatus for sensing the presence of microbes (bacteria, fungi, protozoa, rickettsiae and or other microorganisms) and spores on non-living surfaces, in air and in liquids. It is of course elementary that all microbial cells produce energy for their cellular activity through respiration. As cellular respiration occurs in living cells, pyridine nucleotides are reduced, flavins are oxidized, and other coenzymes and metabolites are produced. Alternatively, spores are found to

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be abundant with a calcium dipicolinic acid complex (a fluorescent compound otherwise rare in nature). The oxidation state of pyridine nucleotides, flavins and other cofactors, and/or the presence of calcium dipicolinate, can be simultaneously elucidated by concurrent excitation of each component with the appropriate electromagnetic radiation followed by detection of the characteristic radiation emitted by these individual fluorophores. Simultaneous excitation of a sample with multiple energies characteristic of the excitation for fluorescent cellular and endospore components with the subsequent collection and detection of emitted and reflected/scattered light energies (both associated with and independent of the fluorophores, respectively) is fundamental for the detection of microbes in a sample or on a non-living surface by the method described herein. The detection of respiring cells in real world samples is made more reliable by the aforementioned method for two reasons. First, the simultaneous excitation of microbes by multiple excitation energies and ensuing coincident detection of numerous fluorescence signals reduces the chance of interference, as the probability of an interference source duplicating the characteristics of numerous fluorophores is extremely small. Second, the relative quantities of the intrinsic metabolites, and thus of the resulting fluorescent signals, have been found to fall within defined physiological ranges. Analysis of the signals is achieved with a method capable of two things: (1) separating the detected fluorescent signals originating from any microbes present from interferences or background signals and or scattered excitation signals, and (2) a requirement that the intensities of the signals from microbial metabolites, microbial components and spore components fall within physiological ranges. Thus, the basis for the detection of microbes in a sample is comprised of the following steps: first, excitation of a sample simultaneously with multiple excitation energies characteristic of cellular metabolites, microbial components, and spore components; second, the subsequent collection of the numerous individual fluorescence signals (associated with the maxima and minima of the emissions of these excited metabolites); and finally, analysis of the collected signals with a method capable of removing background fluorescence and comparing the relative signal magnitudes of metabolites to known physiological ranges. Web site: http://www.delphion.com/details?pn=US06750006__ •

Method for measuring the magnetic resonance (NMR) by steady state signals (SSFP) Inventor(s): Hennig; Jurgen (Freiburg, DE), Scheffler; Klaus (Basel, CH), Speck; Oliver (Freiburg, DE) Assignee(s): Universitatsklinikum Freiburg (DE) Patent Number: 6,677,750 Date filed: August 2, 2002 Abstract: A method of magnetic resonance (NMR) for spatially resolved measurement of the distribution of NMR signals of metabolites (CSI) with low signal intensity, wherein on a spin ensemble, a sequence of radio frequency (RF) pulses is applied which are mutually offset by a time interval of a repetition time TR and magnetic gradient fields are switched of which at least one causes spatial encoding of the excited spins, is characterized in that the repetition time TR between the exciting RF pulses is selected to be at the most in the magnitude transverse relaxation time T2* of the spins to be excited, preferably approximately T2*/10 and that the magnetic gradient fields are selected such that their action integral is completely balanced over a repetition period of a time period TR such that NMR signal production is carried out according to the principle of steady

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state free precession (SSFP). This new method permits utilization of the advantages of SSFP methods also for spectroscopic recordings, in particular for chemical shift imaging. Excerpt(s): This application claims Paris Convention priority of DE 101 38 961.2-33 filed on Aug. 8, 2001, the entire disclosure of which is hereby incorporated by reference. The invention concerns a nuclear magnetic resonance (NMR) method for spatially resolved measurement of the distribution of NMR signals of metabolites (CSI) with low signal intensity, wherein a sequence of radio frequency (RE) pulses, which are mutually offset at a time interval of a repetition time TR, is applied to a spin ensemble and magnetic gradient fields are switched, of which at least one causing encoding of the excited spins. A method of this type is known e.g. from the publication by T. R. Brown et al. "NMR chemical shift imaging in three dimensions", Proc. Natl. Avad. Sci. USA, Vol. 79, 35233526 (1982). Web site: http://www.delphion.com/details?pn=US06677750__ •

Method of reducing or preventing malodour Inventor(s): Behan; John M. (Kent, GB), Minhas; Tony (Kent, GB), Wilson; Craig S. (Kent, GB) Assignee(s): Quest International B.V. (Naarden, NL) Patent Number: 6,737,395 Date filed: January 5, 2001 Abstract: A method for reducing or preventing body malodour by topically applying to human skin perfumery materials capable of inhibiting the production of malodorous metabolites caused by micro-organisms comprising corynebacteria. The perfumery materials are capable of inactivating corynebacteria capable of catabolising fatty acids. Excerpt(s): This invention relates to perfume components, mixtures thereof and perfume compositions, to personal products and detergent products containing such perfumes, and to a method and the use of such perfumes and products to deliver a deodorant effect. In particular, it relates to perfume components, mixtures thereof, and perfume compositions for inhibiting the production of odorous metabolites by topically applying to human skin perfumery components capable of inhibiting the production of body malodour caused by micro-organisms comprising corynebacteria, preferably by selectively inhibiting those corynebacteria capable of catabolising fatty acids. It is well known that freshly secreted sweat is odourless and that body malodour is the result of a biotransformation of the sweat by microorganisms living on the surface of the skin to produce volatile odoriferous compounds. Web site: http://www.delphion.com/details?pn=US06737395__

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Methods of treating or preventing neuropathic pain using sibutramine metabolites Inventor(s): Fang; Qun Kevin (Wellesley, MA), Han; Zhengxu (Shrewsbury, MA), Krishnamurthy; Dhileepkumar (Westboro, MA), Senanayake; Chrisantha Hugh (Shrewsbury, MA) Assignee(s): Sepracor, Inc. (Marlborough, MA) Patent Number: 6,710,087 Date filed: June 4, 2002

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Abstract: Methods of making and using racemic and optically pure metabolites of sibutramine, and pharmaceutically acceptable salts, solvates, and clathrates thereof, are disclosed. Pharmaceutical compositions and dosage forms are also disclosed which comprise a dopamine reuptake inhibitor, such as a racemic or optically pure sibutramine metabolite, and optionally an additional pharmacologically active compound. Excerpt(s): The invention relates to compositions comprising dopamine reuptake inhibitors, including racemic and optically pure metabolites of sibutramine, and to methods of making and using the same. Sibutramine, chemically named [N-1-[1-(4chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine, is a neuronal monoamine reuptake inhibitor which was originally disclosed in U.S. Pat. Nos. 4,746,680 and 4,806,570. Sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, e.g., Buckett et al, Prog. Neuro-psychopharm. & Biol. Psychiat., 12:575-584, 1988; King et al., J. Clin. Pharm., 26:607-611 (1989). Racemic sibutramine is sold as a hydrochloride monohydrate under the tradename MERIDIA.RTM., and is indicated for the treatment of obesity. Physician's Desk Reference.RTM. 1494-1498 (53.sup.rd ed., 1999). The treatment of obesity using racemic sibutramine is disclosed, for example, in U.S. Pat. No. 5,436,272. Web site: http://www.delphion.com/details?pn=US06710087__ •

MICROBIAL CULTURE LIQUORS CONTAINING MICROORGANISMS DIFFERING IN CHARACTERISTICS AND LIVING IN SYMBIOSIS AND METABOLITES THEREOF, CARRIERS AND ADSORBENTS CONTAINING THE ACTIVE COMPONENTS OF THE CULTURE LIQUORS AND UTILIZATION OF THE SAME Inventor(s): Nakamura; Keijiro (Hino, JP) Assignee(s): Orient Green Co., Ltd. (Tokyo, JP) Patent Number: 6,649,397 Date filed: January 5, 2001 Abstract: Solutions containing microorganisms differing in characteristics from each other and living in symbiosis with each other and enzymes characterized by containing aerobic microorganisms, anaerobic microorganisms and at least one basidiomycete belonging to the family Pleurotaceae living in symbiosis, metabolites thereof and enzymes; carriers obtained by adsorbing the components of the above solutions onto finely ground carbonaceous materials; and porous materials obtained by adsorbing the components of the above solutions onto porous materials. Because of having various effects of absorbing, adsorbing and decomposing harmful matters, deodorizing, decolorizing, etc., these materials are applicable to various uses in the fields of agriculture and environment. Excerpt(s): The present invention relates to microbe cultures, a process for producing the same, and utilization thereof. More particularly, the invention relates to microbe cultures containing anaerobic and aerobic microbes, which cannot hitherto live in symbiosis with each other, living in symbiosis with each other, and enzymes, which are metabolites of these microbes, the process for producing the same, carriers and absorbing materials containing the active ingredients of the culture and their applications to agricultural and environmental fields. In recent years, applications of microbes to agricultural and environmental fields have received considerable attention

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from ecological viewpoint. Attempts have been made to apply soil improving materials based on microbe technologies to soil which has become exhausted due to the use of a large amount of agricultural chemicals, and dormant soil in crop rotation. Web site: http://www.delphion.com/details?pn=US06649397__ •

Molecular constructs with a carcinoembryonic antigen (CEA) transcriptional regulatory sequence Inventor(s): Huber; Brian (Durham, NC), Richards; Cynthia A. (Durham, NC) Assignee(s): SmithKline Beecham Corporation (Philadelphia, PA) Patent Number: 6,699,690 Date filed: September 6, 2001 Abstract: Novel molecular chimaeras produced by recombinant DNA techniques are described. They comprise a target-tissue specific transcriptional regulatory sequence (TRS) linked and controlling the expression of a heterologous enzyme, for example Varicella Zoster Virus Thymidine Kinase (VZV TK) or non-mammaliam Cytosine Deaminase (CD). A molecular chimaera is packaged into a synthetic retroviral particle that is capable of infecting mammalian tissue. This, in turn, may be administered to a host, and the TRS will be selectively transcriptionally activated in the target tissue (for example cancerous cells). Administration of compounds that are selectively metabolised by the enzyme produce cytotoxic or cytostatic metabolites in situ thereby selectively killing or arresting the growth of the target cells. Excerpt(s): The present invention relates to molecular chimaeras in infective virions: methods of their construction; pharmaceutical formulations containing them; their use in therapy, particularly virus-directed enzyme prodrug therapy, particularly in the treatment of cancers, and more particularly in the treatment of hepatocellular and colorectal carcinomas; and the use of agents which can be catalysed by a heterologous enzyme to cytotoxic or cytostatic metabolites, such as purine arabinosides and substituted pyrimidines and cytosines in virus-directed enzyme prodrug therapy in a host (e.g., mammal or human). Cancer of all forms is one of the major causes of morbidity throughout the world. Research in cancer chemotherapy has produced a variety of antitumour agents with differing degrees of efficacy. Standard clinically used agents include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cisplatin, vincristine and vinblastine. However, these presently available antitumour agents are known to have various disadvantages such as toxicity to healthy cells and resistance of certain tumour types. Other forms of therapy, such as surgery, are known. However it is appreciated by those skilled in the art that novel approaches and entities for cancer therapy are still needed. Hepatocellular carcinoma (HCC) is one of the major malignant diseases in the world today; the greatest incidence being in Japan, China, other parts of Asia, and sub-Saharan Africa. Recent evidence suggests that the incidence of hepatocellular carcinoma in Europe and North America is increasing. The disease is estimated to be responsible for or involved in up to approximately 1,250,000 deaths a year, making it one of the world's major malignant diseases. Web site: http://www.delphion.com/details?pn=US06699690__

Patents 183

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Multi-channel non-invasive tissue oximeter Inventor(s): Barrett; Bruce J. (Birmingham, MI), Gonopolsky; Oleg (West Bloomfield, MI), Scheuing; Richard S. (Rochester Hills, MI) Assignee(s): Somanetics Corporation (Troy, MI) Patent Number: 6,615,065 Date filed: July 12, 2001 Abstract: A method and apparatus for spectrophotometric in vivo monitoring of blood metabolites such as hemoglobin oxygen concentration at a plurality of different areas or regions on the same organ or test site on an ongoing basis, by applying a plurality of spectrophotometric sensors to a test subject at each of a corresponding plurality of testing sites and coupling each such sensor to a control and processing station, operating each of said sensors to spectrophotometrically irradiate a particular region within the test subject; detecting and receiving the light energy resulting from said spectrophotometric irradiation for each such region and conveying corresponding signals to said control and processing station, analyzing said conveyed signals to determine preselected blood metabolite data, and visually displaying the data so determined for each of a plurality of said areas or regions in a comparative manner. Excerpt(s): This invention relates generally to in vivo spectrophotometric examination and monitoring of selected blood metabolites or constituents in human and/or other living subjects, e.g., medical patients, and more particularly to spectrophotometric oximetry, by transmitting selected wavelengths (spectra) of light into a given area of the test subject, receiving the resulting light as it leaves the subject at predetermined locations, and analyzing the received light to determine the desired constituent data based on the spectral absorption which has occurred, from which metabolic information such as blood oxygen saturation may be computed for the particular volume of tissue through which the light spectra have passed. A considerable amount of scientific data and writings, as well as prior patents, now exist which is/are based on research and clinical studies done in the above-noted area of investigation, validating the underlying technology and describing or commenting on various attributes and proposed or actual applications of such technology. One such application and field of use is the widespread clinical usage of pulse oximeters as of the present point in time, which typically utilize sensors applied to body extremities such as fingers, toes, earlobes, etc., where arterial vasculature is in close proximity, from which arterial hemoglobin oxygenation may be determined non-invasively. A further and important extension of such technology is disclosed and discussed in U.S. Pat. No. 5,902,235, which is related to and commonly owned with the present application and directed to a non-invasive spectrophotometric cerebral oximeter, by which blood oxygen saturation in the brain may be non-invasively determined through the use of an optical sensor having light emitters and detectors that is applied to the forehead of the patient. Earlier patents commonly owned with the '235 patent and the present one pertaining to various attributes of and applications for the underlying technology include U.S. Pat. Nos. 5,139,025; 5,217,013; 5,465,714; 5,482,034; and 5,584,296. The cerebral oximeter of the aforementioned '235 patent has proved to be an effective and highly desirable clinical instrument, since it provides uniquely important medical information with respect to brain condition (hemoglobin oxygen saturation within the brain, which is directly indicative of the single most basic and important life parameter, i.e. brain vitality). This information was not previously available, despite its great importance, since there really is no detectable arterial pulse within brain tissue itself with respect to which pulse oximetry could be utilized even if it could be effectively utilized in such an interior location (which is very doubtful), and

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this determination therefore requires a substantially different kind of apparatus and determination analysis. In addition, there are a number of uniquely complicating factors, including the fact that there is both arterial and venous vasculature present in the skin and underlying tissue through which the examining light spectra must pass during both entry to and exit from the brain, and this would distort and/or obscure the brain examination data if excluded in some way. Furthermore, the overall blood supply within the skull and the brain itself consists of a composite of arterial, venous, and capillary blood, as well as some pooled blood, and each of these are differently oxygenated. In addition, the absorption and scatter effects on the examination light spectra are much greater in the brain and its environment than in ordinary tissue, and this tends to result in extremely low-level electrical signal outputs from the detectors for analysis, producing difficult signal-to-noise problems. Web site: http://www.delphion.com/details?pn=US06615065__ •

Prevention of cancer Inventor(s): Raskov; Hans Henrik (Kildegardsvej 31a, DK-2900 Hellerup, DK) Assignee(s): Colotech A/S (Kobenhavn K, DK), Raskov; Hans Henrik (Frederiksberg C, DK) Patent Number: 6,703,380 Date filed: April 5, 2001 Abstract: The present invention relates to a method for the prevention of cancer or the initiation and/or progression of cancer in a human comprising administration to the human a combination dosage of a cyclooxygenase (COX) inhibitor, a vitamin D.sub.3 including analogues and metabolites thereof and calcium. In a further embodiment the invention relates to the use of the combination dosage for the preparation of a medicament and to such pharmaceutical preparations. In a further aspect the invention relates to a method for reducing the effective dosage of ASA in a chemoprofylactive treatment of colorectal cancer in a human by co-administration with a non toxic dosage of a vitamin D.sub.3 including analogues and metabolites thereof and Ca in the form of a combination dosage. Excerpt(s): The present invention relates to the chemoprophylaxis of colorectal cancer with combinations of a cyclooxygenase (COX) inhibitor, vitamin D.sub.3 including analogues and metabolites thereof and/or calcium. In a further aspect the invention relates to a method for reducing the effective dosage of ASA in a chemoprofylactive treatment of colorectal cancer in a human by co-administration with a non toxic dosage of a vitamin D.sub.3 including analogues and metabolites thereof and Ca in the form of a combination dosage. In a still further embodiment the invention relates to the use of a cyclooxygenase (COX) inhibitor, a vitamin D.sub.3 and calcium together with a pharmaceutically acceptable carrier for the preparation of a medicament for preventing the initiation and/or progression of colorectal cancer in a human. The invention also relates to such a pharmaceutical medicament. Colorectal cancer (CRC) is one of the leading cancer forms in the Western world (1.3 million per year and over 600,000 annual deaths). In Denmark, the incidence is approximately 65 per 100,000 inhabitants and correlates to age. Concurrently with a fall in tobacco smoking in Western industrial countries and an increased life expectancy, CRC is expected to become the most frequent solid cancer over the next decades. The great majority of CRC cases are sporadic cancers, for which it is not possible to establish a genetic disposition. Effective

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CRC prevention in well-defined risk groups would have a significant effect on population health. Web site: http://www.delphion.com/details?pn=US06703380__ •

Repinotan kit Inventor(s): Kroll; Werner (Solingen, DE), Rodriguez; Maria-Luisa (Erkrath, DE), Rombout; Ferdinand (Klimmen, NL), Schohe-Loop; Rudolf (Wuppertal, DE), Sennhenn; Bernd (Leverkusen, DE), Weber; Horst (Troisdorf, DE) Assignee(s): Bayer Aktiengesellschaft (Leverkusen, DE) Patent Number: 6,605,255 Date filed: November 16, 2001 Excerpt(s): The invention relates to a kit comprising a pharmaceutical composition containing repinotan or a physiologically acceptable salt of repinotan, and a means for the determination of the concentration of repinotan or its metabolites in body fluids, and also new pharmaceutical compositions containing repinotan or a physiologically acceptable salt of repinotan, and processes for their preparation. For the acute treatment of neurodegenerative diseases such as stroke and cranio-cerebral trauma, which frequently lead to neurological and functional long-term deficits in these patients, up to now no treatment principle has yet been accepted worldwide as effective. Apart from the use of thrombolytics (for example t-PA) in the first 3 hours after an ischaemic stroke or the use of nimodipine in patients having a traumatic subarachnoid haemorrhage, there are still no medicinal approaches which adequately take into account the pathophysiological cascade. In DE-A-195 43 476, the suitability of repinotan and its salts for the treatment of craniocerebral trauma is described. Web site: http://www.delphion.com/details?pn=US06605255__

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Streptomyces strain with insecticidal activity and method of using as an insecticide Inventor(s): Baum; Nancy Ann (Davis, CA), Jimenez; Desmond Rito (Woodland, CA), Lehman; Lori Jo (Vacaville, CA), Manker; Denise Carol (Davis, CA), Marrone; Pamela Gail (Davis, CA), Orjala; Jimmy Ensio (Davis, CA) Assignee(s): AgraQuest, Inc. (Davis, CA) Patent Number: 6,682,925 Date filed: April 13, 2000 Abstract: A novel strain of Streptomyces galbus that produces metabolites and exhibits pesticidal activity is disclosed. In addition, a supernatant of the novel strain with pesticidal activity is disclosed. An ethyl acetate-soluble, small molecular weight, alkali stable, metabolite produced by the novel strain Streptomyces galbus with pesticidal activity against lepidopteran insects is provided. Also included are methods for fermenting the novel strain of Streptomyces galbus and increasing the bioactivity of the pesticidal activity. Also included are methods for protecting or treating plants from caterpillars comprising the step of applying to a plant an effective amount of the novel Streptomyces galbus strain, the metabolites produced by the strain, or a combination thereof.

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Excerpt(s): The present invention is in the field of biopesticides. More particularly, this invention relates to a novel strain of Streptomyces with insecticidal activity and methods of use thereof. Natural products are substances produced by microbes, plants, and other organisms. Microbial natural products offer an abundant source of chemical diversity. There is a long history of utilizing these natural products for pharmaceutical purposes. Despite the emphasis on natural products for human therapeutics, there are only a few natural product insecticides for agricultural use. The most successful microbial natural product insecticides are the Bacillus thuringiensis toxins, avermectin and the spinosyns. Bacillus thuringiensis (Bt) bacteria produce cytoplasmic protein crystals (.delta.-endotoxins) during sporulation which are the most important factor in insect pathogenesis (see, Ellar, D. J. (1997) "The structure and function of Bacillus thuringiensis.delta.-endotoxins and prospects for biopesticide improvement," In: Microbial Insecticides: Novelty or Necessity? The British Crop Protection Council Symposium Proceedings No. 68, Coventry, UK). The.delta.-endotoxins have been used in both spray preparations as well as `systemic` biopesticides through the introduction of the endotoxin genes into transgenic plants. The growth of the market for the spray preparations of Bt is estimated to be around 10% for 1997 through 2000, which will result in a market of $100-$130 million by 2000 (see, Lisansky, S. (1997) "Microbial biopesticides" In: Microbial Insecticides: Novelty or Necessity? The British Crop Protection Council Symposium Proceedings No. 68, Coventry, UK.). The main Bt transgenic crops are maize and cotton. The transgenic Bt maize market in the U.S. has grown from only 1.4% of the planted acreage in 1996 to 19.1% in 1998. The growth in Bt cotton has not been as drastic, increasing from 14.6% of the planted acreage in 1996 to 16.8% in 1998. The entire market is currently directed against lepidopteran pests. In 1999, the market for pesticides used against caterpillars in the US exceeded 400 million dollars US. The avermectins are produced by Streptomyces avermitilis during fermentation. Abamectin, one of the naturally occurring macrocyclic lactones, shows activity against mites, pear psylla and diamond back moth. Emamectin, a semi-synthetic analog of abamectin, shows activity against lepidopteran larvae. In invertebrates the avermectins induce the opening of a pre-synaptic chloride ion channel (not GABAactivated), leading to efflux of chloride ions, depolarization of the nerve terminal, and hence, to neurotransmitter release. See, Turner, M. J. and Schaeffer, J. M. (1989) "Mode of action of Ivermectin," In: Ivermectin and Abamectin, W. C. Campbell (Ed.) SpringerVerlag, N.Y. The use of avermectins in insect control had an estimated world market value of $80-$120 million in 1998. Web site: http://www.delphion.com/details?pn=US06682925__ •

Transdermally administered acetylcysteine as mucolytic agent Inventor(s): Hoeck; Ulla (Hillerod, DK), Kreilgard; Bo (Hillerod, DK), Nathansen; Christina (Hillerod, DK) Assignee(s): Pharmacia AB (Stockholm, SE) Patent Number: 6,620,428 Date filed: October 23, 1998 Abstract: Device for transdermal administration of N-Acetyl-L-cysteine, optionally encompassing salts, prodrugs and metabolites thereof, optionally together with pharmaceutically acceptable carrier(s) to a human being or an animal in order to achieve a mucolytic effect. Use of a mucolytic compound comprising N-Acetyl-L-cysteine, optionally encompassing salts, prodrugs and metabolites thereof, optionally together

Patents 187

with pharmaceutically acceptable carrier(s), for the manufacture of a composition for achieving a mucolytic effect in a human being or an animal. Method for achieving a mucolytic effect in a living body by transdermal administration of a compound comprising N-Acetyl-L-cysteine, optionally encompassing salts, prodrugs and metabolites thereof, optionally together with pharmaceutically acceptable carrier(s). Excerpt(s): N-Acetyl-L-cysteine, C.sub.5 H.sub.9 NO.sub.3 S, is an expectorant. Its synthesis was disclosed in Smith et al., J. Org. Chem., 1961;26:820. N-Acetyl-L-cysteine decreases the viscosity of mucous and purulent expectorate. The mucolytic effect after peroral administration in connection with bronchitis is though not well-documented. However, several investigations have proved effect just below the significance limit. Anyhow, the patients' wellbeing during treatment with N-Acetyl-L-cysteine is significant. N-Acetyl-L-cysteine is registered as a mucolytic agent for peroral administration under trade marks such as Fabrol.RTM., Inspir.RTM. and Mucomust.RTM. N-Acetyl-cysteine has a low bioavailability, only about 4-10%, when administered perorally, see Mack R. Holdiness, "Clinical Pharmacokinetics of NAcetylcysteine", Clin. Pharmacokinet., 1991;20(2):123-134. The following references confirm the low bioavailability of N-Acetyl-L-cysteine: L. Borgstrom et al., "Pharmacokinetics of N-Acetylcysteine in Man", Eur J Clin Pharmacol. 1986;31:217-222, L. Borgstrom et al., "Dose dependent pharmacokinetics of N-Acetylcysteine after oral dosing to man", Biopharmaceutics & Drug Disposition, 1990(II):131-136, B. Olsson et al., "Pharmacokinetics and Bioavailability of Reduced and Oxidized N-Acetylcysteine", Eur J Clin Pharamcol. 1988;34:77-82. Martindale, "The Extra Pharmacopoeia", London, 1993, recommends a peroral dosing of 200 mg three times daily to adults, 200 mg once daily for children up to 2 years and 200 mg twice daily for children aged 2 to 6 years. Deutsche Apotheker Zeitung; 34; 1990 indicates that the maximum plasma level is reached 2 to 3 hours after oral administration. The same reference indicates 4% bioavailability upon oral administration. Web site: http://www.delphion.com/details?pn=US06620428__ •

Use of lipoxygenase metabolite of arachidonic acid and its derivatives in capsaicinchannel agonist Inventor(s): Hwang; Sun Wook (Seoul, KR), Oh; Uhtaek (Eul-gi Apt., 615-102, Sanbon 2dong, Kunpo-si, 435-042, Kyunggi-do, KR) Assignee(s): Oh; Uhtaek (Kyunggi-do, KR) Patent Number: 6,673,840 Date filed: February 6, 2001 Abstract: Disclosed is the use of metabolites produced from arachiconic acid by the catalytic action of lipoxygenase as capsaicin-channel or- receptor agonists. The lipoxygenase metavolites of arachidonic acid and their derivatives can activate the capsaicin channel to excite pain nerves, causing serious pain. In contrast, the capsaicin channel activation of the pain nerves, so that an analgesic effects are brought about. The lipoxygenase metabolites of arachidonic acid can be used as an analgesic and in searching for and developing analgesics. Excerpt(s): This is a 371 of PCT/KR99/00421, filed Aug. 2, 1999. The present invention relates to the use of the lipoxygenase metabolites of arachidonic acid and their derivatives as capsaicin-channel or -receptor agonists. More particularly, the present invention relates to the metabolites produced from arachidonic acid by the catalytic

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action of lipoxygenase, which can be used as an analgesic which is superior in painrelieving efficacy and free of durg resistance and addition. Analgesics developed thus far are largely classified into two categories: narcotic and antiphlogistic. The former, exerting its pharmacological effects on the central nervous system, shows potent painalleviating activity with accompaniments of strong side effects including resistance and addiction. With an unclear explanation regarding their pharmaceutical mechanism, antiphlogistic analgesics are weaker in pain relief than narcotic analgesics as well as may cause gastric and liver troubles (Insel, 1996; Reisine and Pasternak, 1996). Web site: http://www.delphion.com/details?pn=US06673840__

Patent Applications on Metabolites 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 metabolites: •

Administration of estradiol metabolites for inhibition of drug-induced nephrotoxicity Inventor(s): Dubey, Raghvendra K.; (Glenshaw, PA), Jackson, Edwin K.; (Pittsburgh, PA), Tofovic, Stevan P.; (Pittsburgh, PA) Correspondence: Mary-Elizabeth Buckles; Reed Smith Llp; Suite 1100-East Tower; 1301 K Street, N.W.; Washington; DC; 20005-3317; US Patent Application Number: 20040082558 Date filed: August 4, 2003 Abstract: Methods and composition are provided for the treatment or prevention of drug-induced nephrotoxicity and related conditions. More particularly, this invention relates to compositions comprising estradiol metabolites, and prodrugs thereof, that may be incorporated in various controlled release formulations. Excerpt(s): This application claims priority from U.S. Provisional Application No. 60/400,060 filed Aug. 2, 2002. The present invention relates to methods and compositions using estradiol metabolites which may be incorporated into drug delivery compositions. More particularly, the present invention relates to the use of estradiol metabolites for the prevention or for the treatment of drug-induced nephrotoxicity. The estradiol metabolites include 2-hydroxyestradiol, 4-hydroxyestradiol, 2methoxyestradiol, and 4-methoxyestradiol, and prodrugs thereof. Chronic renal disease is characterized by accelerated arteriosclerosis and an excessive rate of cardiovascular morbidity and mortality. Linder, A. B., et al., N. Engl. J. Med. 290:697, (1974), the disclosure of which is incorporated herein by reference. Recent data indicate the progression of chronic renal disease occurs more rapidly and more frequently in men than in women and appears to occur independently of blood pressure or serum cholesterol levels. United States Renal Data System:1993 Annual Data Report, MD. U.S. Department of Health and Human Services, Public Health Services, National Institutes of Health, p. xvi (1993); Neugarten, J., et al., J. Am. Soc. Nephrol. 11:319 (2000); and Silbiger, S. R., et al., Am. J. Kid. Disease 25:515 (1995), the disclosures of which are incorporated herein by reference. The resistance of kidneys in women to the progression

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

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of renal disease has been frequently attributed to 17.beta.-estradiol, the main estrogenic steroid produced by the human ovary, Silbiger, S. R., et al., Am. J. Kid. Disease 25:515 (1995), the disclosure of which is incorporated herein by reference. However, the effects of compounds such as 17.beta.-estradiol on drug-induced nephrotoxicity are not known. In addition, because estrogenic activity of estradiol increases the risk of cancer in women, Manson, J. E., et al., N. Engl. J. Med. 345: 34 (2001), the disclosure of which is incorporated herein by reference, and is feminizing in men, Brawnstein, G. D., New England J. Med. 328:490 (1993), the disclosure of which is incorporated herein by reference, it would be of limited value as a treatment for nephrotoxicity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Analogs of indole-3-carbinol metabolites as chemotherapeutic and chemopreventive agents Inventor(s): Chao, Wan-Ru; (Sunnyvale, CA), Jong, Ling; (Sunnyvale, CA) Correspondence: Reed & Eberle Llp; 800 Menlo Avenue, Suite 210; Menlo Park; CA; 94025; US Patent Application Number: 20040043965 Date filed: August 20, 2002 Abstract: Novel compounds useful as chemotherapeutic and chemopreventive agents are provided. The compounds are analogs of indole-3-carbinol metabolites wherein the structures and substituents of the compounds are selected to enhance the compounds' overall efficacy, particularly with respect to therapeutic activity, oral bioavailability, long-term safety, patient tolerability, and therapeutic window. The compounds are useful not only in treatment of cancer but also in prevention of cancer. One preferred class of the novel compounds have the structure of formula (I) 1wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are defined herein. Pharmaceutical compositions are provided as well, as are methods of synthesis and use. Excerpt(s): This invention relates generally to compounds and compositions for the treatment of cancer and other hyperproliferative diseases. More particularly, the invention pertains to novel dietary indole analogs that are useful in treating a range of cancers, including estrogen-related cancers such as breast, uterine, cervical, ovarian, and endometrial cancers, and non-estrogen-related cancers such as prostate, colon, liver and lung cancers. Cancer is the second leading cause of death in the United States, exceeded only by heart disease. Drugs that are used to treat cancer tend to be toxic at their therapeutic dose levels, commonly causing severe and even life-threatening adverse effects. Current anticancer drugs must also be administered intravenously. Consequently, nearly all cancer chemotherapy must be administered in a hospital or clinic. An additional problem with most current cancer chemotherapy is that cancers frequently develop resistance to the drugs, so that recurrence of disease is common. For patients who have been diagnosed with cancer, cytotoxic chemotherapy is considered an essential part of the management of the disease, but resistance to chemotherapeutic drugs is unfortunately a common development in cancer. Although the mechanisms of resistance to chemotherapy are not fully understood, the cellular mechanisms thus far implicated in the development of drug resistance are the same as those that protect normal tissues from toxicity. Furthermore, the efficacy of cytotoxic chemotherapeutics is ultimately limited by their narrow therapeutic index. Therefore, it is unlikely that any breakthrough in the treatment of cancer will come about as a result of a cytotoxic

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approach. There is accordingly an urgent need for new noncytotoxic therapies that are safer and more effective than those currently available, and that, furthermore, will improve both survival rate and the quality of life for cancer survivors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Analogs of thalidomide as potential angiogenesis inhibitors Inventor(s): Eger, Kurt; (Leipzig, DE), Figg, William D.; (Fairfax, VA), Guetschow, Michael; (Bonn, DE), Hauschildt, Sunna; (Leipzig, DE), Hecker, Thomas; (Erfurt, DE), Teubert, Uwe; (Hameln, DE), Weiss, Michael; (Bethesda, MD) Correspondence: Klarquist Sparkman, Llp; 121 S.W. Salmon Street, Suite #1600; One World Trade Center; Portland; OR; 97204-2988; US Patent Application Number: 20040077685 Date filed: November 14, 2003 Abstract: A number of thalidomide metabolites having superior anti-angiogenic properties have now been isolated and identified In addition, thalidomide analogs that mimic the effects of the isolated and identified active thalidomide metabolites, and variations of such thalidomide analogs, have been developed. Such thalidomide analog compounds show enhanced potency in the inhibition of undesirable angiogenesis without the undesirable effects of administration of thalidomide. Excerpt(s): The present invention concerns anti-angiogenesis compositions and methods, and particularly thalidomide analogs that actively inhibit angiogenesis in humans and animals. Angiogenesis is the formation of new blood vessels from preexisting vessels. Angiogenesis is prominent in solid tumor formation and metastasis. A tumor requires formation of a network of blood vessels to sustain the nutrient and oxygen supply for continued growth. Some tumors in which angiogenesis is important include most solid tumors and benign tumors, such as acoustic neuroma, neurofibroma, trachoma, and pyogenic granulomas. Prevention of angiogenesis could halt the growth of these tumors and the resultant damage due to the presence of the tumor. It has been shown that there is a direct correlation between tumor microvessel density and the incidence of metastasis. Tumor cells themselves can produce factors that stimulate the proliferation of endothelial cells and new capillary growth. Angiogenesis is important in two stages of tumor metastasis. The first stage where angiogenesis stimulation is important is in the vascularization of the tumor, which allows tumor cells to enter the blood stream and to circulate throughout the body. After the tumor cells have left the primary site, and have settled into the secondary, metastasis site, angiogenesis must occur before the new tumor can grow and expand. Therefore, prevention of angiogenesis could lead to the prevention of metastasis of tumors and possibly contain the neoplastic growth at the primary site. These observations have led to the investigation of anti-angiogenic agents as possible therapeutic options for various cancers. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Broadspecturm 2-amino-benzoxazole sulfonamide hiv protease inhibitors Inventor(s): De Bethune, Marie-Pierre T.M.M.G; (Everberg, BE), De Rock, Herman Augustinus; (Arendonk, BE), Surleraux, Dominique Louis Nestor Ghislain; (Machelen, BE), Tahri, Abdellah; (Heverlee, BE), Vendeville, Sandrine Marie Helene; (Bruxelles, BE), Verschueren, Wim Gaston; (Berchem, BE) Correspondence: Philip S. Johnson; Johnson & Johnson; One Johnson & Johnson Plaza; New Brunswick; NJ; 08933-7003; US Patent Application Number: 20040106661 Date filed: October 9, 2003 Abstract: The present invention concerns the compounds having the formula 1N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein R.sub.1 and R.sub.8 each are H, optionally substituted C.sub.1-6alkyl, C.sub.26alkenyl, C.sub.3-7 cycloalkyl, aryl, Het.sup.1, Het.sup.2; R.sub.1 may also be a radical of formula (R.sub.11aR.sub.11b)NC(R.sub.10aR.sub.10b)CR.sub.9--; t is 0, 1 or 2; R.sub.2 is H or C.sub.1-6alkyl; L is --C(.dbd.O)--, --O--C(.dbd.O)--, --NR.sub.8--C(.dbd.O)--, -C.sub.1-6alkanediyl-C(.dbd.O- )--, --NR.sub.8--C.sub.1-6alkanediyl-C(.dbd.O)--, -S(.dbd.O).sub.2-, --O--S(.dbd.O).sub.2--, --NR.sub.9-S(.dbd.O).sub.2; R.sub.3 is C.sub.16alkyl, aryl, C.sub.3-7cycloalkyl, C.sub.3-7cycloalkylC.sub.1-4al- kyl, or arylC.sub.14alkyl; R.sub.4 is H, C.sub.1-4alkylOC(.dbd.O), carboxyl, aminoC(.dbd.O), mono- or di(C.sub.1-4alkyl)aminoC(.dbd.O), C.sub.3-7 cycloalkyl, C.sub.2-6alkenyl, C.sub.26alkynyl or optionally substituted C.sub.1-6alkyl; R.sub.5 and R.sub.6 are H or C.sub.16alkyl. It further relates to their use as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. It also concerns combinations thereof with another anti-retroviral agent, and to their use in assays as reference compounds or as reagents. Excerpt(s): The present invention relates to 2-amino-benzoxazole sulfonamides, their use as aspartic protease inhibitors, in particular as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. The present invention also concerns combinations of the present 2-aminobenzoxazole sulfonamides with another anti-retroviral agent. It further relates to their use in assays as reference compounds or as reagents. The virus causing the acquired immunodeficiency syndrome (AIDS) is known by different names, including T-lymphocyte virus III (HTLV-III) or lymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Up until now, two distinct families have been identified, i.e. HIV-I and HIV-2. Hereinafter, HIV will be used to generically denote these viruses. One of the critical pathways in a retroviral life cycle is the processing of polyprotein precursors by aspartic protease. For instance with the HIV virus the gag-pol protein is processed by HIV protease. The correct processing of the precursor polyproteins by the aspartic protease is required for the assembly of infectious virions, thus making the aspartic protease an attractive target for antiviral therapy. In particular for HIV treatment, the HIV protease is an attractive target. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy Inventor(s): Ebert, Charles D.; (Salt Lake City, UT), Sanders, Steven W.; (Salt Lake City, UT) Correspondence: Thorpe North & Western; P.O. Box 1219; Sandy; UT; 84091-1219; US Patent Application Number: 20040120996 Date filed: December 8, 2003 Abstract: The present invention provides compositions and methods for administering oxybutynin while minimizing the incidence and or severity of adverse drug experiences associated with oxybutynin therapy. In one aspect, these compositions and methods provide a lower plasma concentration of oxybutynin metabolites, such as Ndesethyloxybutynin, which is presumed to be contributing at least in part to some of the adverse drug experiences, while maintaining sufficient oxybutynin plasma concentration to benefit a subject with oxybutynin therapy. The invention also provides isomers of oxybutynin and its metabolites that meet these characteristics of minimized incidence and/or severity of adverse drug experiences, and maintenance of beneficial and effective therapy for overactive bladder. Excerpt(s): This patent application is a continuation of U.S. patent application Ser. No. 10/098,752, filed Mar. 15, 2002, which is a continuation of U.S. patent application Ser. No. 09/559,711, filed Apr. 26, 2000, each of which are incorporated herein by reference. The present invention relates to compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy. Accordingly, this invention covers the fields of pharmaceutical sciences, medicine and other health sciences. Oral oxybutynin is currently used for treating various forms of overactive bladder and urinary incontinence. Particularly, oxybutynin effectively treats neurogenically caused bladder disorders. Relief from such disorders is attributed to the anticholinergic and antispasmodic action which oxybutynin imparts to the parasympathetic nervous system and the urinary bladder detrusor muscle. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compositions and methods for simultaneous detection of volatile sulfur compounds and polyamines Inventor(s): Pendergrass, James C.; (Lexington, KY) Correspondence: George David Mcclure JR.; P.O. Box 21902; Lexington; KY; 40622; US Patent Application Number: 20040076584 Date filed: October 18, 2002 Abstract: Disclosed are compositions and methods useful for the rapid and facile simultaneous detection of malodorous bacterial metabolites in samples of expired breath and other fluids. The invention enables estimation, by simple visual inspection and comparison against standards, of the concentration of polyamines and volatile sulfur compounds in the micromolar to millimolar range. Excerpt(s): The invention relates to, among other fields, the field of diagnostic tests to detect the presence of pathogenic microorganisms. In normal circumstances many microorganisms live on or in humans without causing harm to these humans. However, an increased number of certain microorganisms can be associated with a disease state.

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Particularly problematic is an increase in the number of microorganisms that produce significant concentrations of chemicals that arc toxic to humans. Such toxins include: volatile sulfur compounds (VSCs), such as hydrogen sulfide, methyl mercaptan, dimethyl disulfide, and dimethyl sulfide; and polyamines, such as putrescine and cadaverine. Higher concentrations of volatile sulfur compounds and of polyamines are associated with certain disease states and with socially stigmatized conditions, such as halitosis, or bad breath. It would be desirable to enable facile simultaneous detection of volatile sulfur compounds and polyamines in order to facilitate detection of the presence of potentially pathogenic microorganisms and of disease states and conditions with which these microorganisms are associated. The principal VSCs produced by oral bacteria are hydrogen sulfide (H.sub.2S) and methylmercaptan (CH.sub.3SH). H.sub.2S is produced by the bacterial enzyme L-cysteine desulthydrase, which degrades the amino acid L-cysteine to produce H.sub.2S, ammonium and 2-ketopropanate. The other major VSC, CH.sub.3SH, is produced by the action of the bacterial enzyme L-methionine gamma lyase, which breaks down the amino acid L-methionine to produce CH.sub.3SH, ammonium and 2-ketobutyrate. H.sub.2S levels have been reported to occur at levels as high as 2 mM in the gingival crevice of persons with severe periodontal disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Consumable product containing probiotics Inventor(s): Bengtsson-Riveros, Annmarie; (St-Legier, CH), Cavadini, Christoph; (Le Mont-Pelerin, CH), Darbyshire, John; (Tolochenaz, CH), De Reu, Johannes; (Lienden, NL), Knauf, Hermann; (Lisiuex, FR), Wood, Robert Dustan; (Quarante, FR) Correspondence: Bell, Boyd & Lloyd Llc; P. O. Box 1135; Chicago; IL; 60690-1135; US Patent Application Number: 20040115308 Date filed: February 2, 2004 Abstract: The present invention relates to any kinds of consumable products enriched with probiotics and a method for obtaining them. After production of probiotic biomass, the probiotics are applied to the product. Also metabolites obtained from a fermentation product may be directly applied to a consumable product. Excerpt(s): The present invention relates to a consumable product containing probiotics and to a process for obtaining it. Probiotic micro-organisms are micro-organisms which beneficially affect a host by improving its intestinal microbial balance. In general, it is believed that these bacteria inhibit or influence the growth and/or metabolism of pathogenic bacteria in the intestinal tract. It is also assumed that via probiotic microorganisms the immune function of the host is activated. For this reason, there have been many different approaches to include probiotic micro-organisms into food-stuffs. WO98/10666 (SOCIETE DES PRODUITS NESTLE S.A.) discloses a process for manufacturing a dehydrated food composition containing live probiotic acid bacteria, in which a food composition and a culture of probiotic lactic acid bacteria sensitive to oxygen are sprayed conjointly under a stream of hot air. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Dental implement and method for tooth surface inspection Inventor(s): de Josselin de Jong, Elbert; (Amsterdam, NL), van der Veen, Monique; (Amsterdam, NL), Waller, Elbert; (Amsterdam, NL) Correspondence: Woodard, Emhardt, Naughton, Moriarty And Mcnett; Bank One Center/tower; 111 Monument Circle, Suite 3700; Indianapolis; IN; 46204-5137; US Patent Application Number: 20040023184 Date filed: July 31, 2002 Abstract: Described are dental implements useful for inspecting tooth surfaces for abnormalities such as caries or plaque. Preferred implements of the invention include light emitting diodes mounted on an implement body having a mirror for insertion into a user's mouth. Such implements also have on-board batteries mounted in chambers in the implement handle, and a switch for energizing and de-energizing the LED with the battery. Also described are methods for examining tooth surfaces for abnormal conditions indicative of plaque involving illuminating surfaces with radiation at a wavelength in the range of 390-450 nm wherein the radiation is effective to cause detectable fluorescence emissions from bacterial metabolites known to be associated with plaque-containing surfaces, and detecting the emissions. Excerpt(s): The present invention relates generally to devices and methods for inspecting tooth surfaces, and in particular to such devices and methods involving the detection of differential fluorescence emissions from abnormal and healthy tooth surfaces. As further background, various devices and methods have been proposed that involve using fluorescence emissions to detect caries or other abnormal conditions. For example, U.S. Pat. No. 3,711,700 relates to a disclosing light for inspecting tooth surfaces. The disclosing light is designed for use in conjunction with a fluorescent dye such as sodium fluorescein. The disclosing light includes a light source and a dichroic reflector behind the light source to reflect blue light forward and the remainder backward. A second dichroic filter is positioned in front of the light source and transmits blue light and reflects back infrared radiation. A mirror reflects yellow light to the observer and transmits other wavelengths. U.S. Pat. No. 4,266,535 discloses a diagnostic lamp for use in conjunction with a fluorescent dye to inspect tooth surfaces. The lamp includes an incandescent bulb light source used in conjunction with a lens to supply a divergent beam of rays. A blue filter with an applied dichroic filter is used to filter the rays, which are made to impinge upon the fluorescent dye. The resulting fluorescence can be viewed in a folding, adjustable mirror. U.S. Pat. No. 5,957,687 discloses another diagnostic unit including a filtered light source and a mirror contained in a housing. Filtered light is concentrated in the blue frequency range and causes fluorescent dye to fluoresce. This can then be viewed in the mirror. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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DNA sequences capable of expressing foreign proteins and metabolites in dicotyledonous plants and cell culture Inventor(s): Rodriguez, Raymond L.; (Davis, CA), Thomas, Bruce R.; (Davis, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20040077040 Date filed: October 18, 2002

Patents 195

Abstract: The present invention relates to a method for producing a gene product by expressing a gene encoding said gene product in angiosperm host cells, which method comprises: a) constructing a vector expressible in angiosperm host cells, said vector comprising a promoter region derived from an amylase gene selected from SBAmyA, SBAmyB, SBAmyC genes or SBAmyD of the sugar beet and a gene encoding a desired gene product; b) transforming a compatible angiospasm host cell with said vector; c) cultivating the resulting transformant host cell to a sugar-depleted or sugar-free condition to promote the expression of said gene under the control of such promoter region; and d) recovering the product of the expressed gene. The sugar beet gene when incorporated into a dicot seed or plant has improved biological properties. The gene sequences and the products thereof are claimed. Excerpt(s): This invention relates to specific DNA sequences which are capable of expressing foreign proteins and their metabolites in dicotyledonous plants and cell culture. Specifically, the present invention concerns the incorporation into a vector and expressing of the SBAmyB or SBAmyC gene of the sugar beet and recovering the product of the expressed gene. The incorporation of the sugar beet genes SBAmyB or SBAmyC for.alpha.-amylase have not yet been reported. The synthesis of.alpha.amylase and levels of their mRNa are greatly induced under sucrose starvation. An increase of.alpha.-amylase synthesis is assumed to accelerate hydrolysis of cellular starch as an energy source when exogenous carbon source is depleted. Under normal growth condition with an adequate supply of sugars in the medium, the expression of.alpha.-amylase genes is subject to metabolite repression. It was observed that.alpha.amylases synthesized by the cultured rice cells are secreted into the culture medium and can account for about 15-20% of the total proteins present in the medium during periods of sugar depletion. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Generating, viewing, interpreting, and utilizing a quantitative database of metabolites Inventor(s): Watkins, Steven M.; (Sacramento, CA) Correspondence: Klarquist Sparkman, Llp; 121 SW Salmon Street; Suite 1600; Portland; OR; 97204; US Patent Application Number: 20040143461 Date filed: January 5, 2004 Abstract: This disclosure provides methods for the creation of a quantitative database of metabolites, particularly lipid metabolites, using chromatographic technology; methods for assembling that information into a visual format for interpretation, and methods of this information to identify and understand metabolome-wide effects, for instance those effects influenced by pharmaceuticals, genes, toxins, diet or the environment. Also provided are metabolite databases, such as lipid metabolite databases, that are stored on a computer readable medium, which include quantitative measurements of a plurality of metabolites. Excerpt(s): This is a continuation of PCT/IUS02/21426, filed Jul. 5, 2002 (published in English under PCT Article 21(2)), which in turn claims the benefit of U.S. Provisional Application No. 60/303,704, filed Jul. 6, 2001. The referenced applications are incorporated herein in their entirety. This disclosure relates to ways of quantifying metabolites and collecting quantitative data on metabolites, a database of quantified

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metabolite profiles, and methods of mining and visualizing selected subsets thereof. The recent explosion of data acquisition and analysis technology, termed informatics, promises to revolutionize predictive and diagnostic medicine. The information readily available to doctors and scientists today dwarfs that of even a few years ago, and will expand at an even more accelerated rate in the next few years. Managing this information and applying it to useful purpose are formidable challenges. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Mammalian metabolites of a tachykinin receptor antagonist Inventor(s): Chiu, Shuet-Hing Lee; (Westfield, NJ), Huskey, Su-er Wu; (Westfield, NJ) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20040023960 Date filed: April 24, 2003 Abstract: This invention is concerned with mammalian metabolites of the compound 2(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)-phe- nyl-4-(3-(5-oxo1H,4H-1,2,4-triazolo)methylmorpholine which is a tachykinin receptor antagonist that is useful in the prevention and treatment of certain disorders, including emesis and psychiatric disorders such as depression and anxiety. Excerpt(s): Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3), respectively. Evidence has been reviewed for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Chrohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyperreflexia. It has furthermore been suggested that tachykinin receptor antagonists have utility in the following disorders: anxiety, depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorder related to immune enhancement or suppression such as systemic lupus erythmatosus, ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Medicaments for treating dementia Inventor(s): Borbe, Harald; (Mainz, DE), Hager, Klaus; (Hannover, DE), Kenklies, Marlene; (Hannover, DE), Lobisch, Michael; (Reichelsheim/Blofeld, DE), Marahrens, Andreas; (Isernhagen, DE), Munch, Gerald; (Leipzig, DE), Peukert, Manfred; (Oberursel/Ts, DE), Wessel, Klaus; (Bad Vilbel, DE) Correspondence: Burns Doane Swecker & Mathis L L P; Post Office Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20040024048 Date filed: May 20, 2003 Abstract: The invention relates to the use of.alpha.-lipoic acid in reduced or oxidized form or derivatives thereof with intact dithiolane structure in the form of enantiomers or pharmaceutically acceptable salts, amides, esters, thioesters, ethers or metabolites for the adjuvant therapy of dementias. Excerpt(s): Loske C, Neumann A, Cunningham A M, Nichol K, Schinzel R, Riederer P, Munch G. Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. J Neural Transm, 219-229, 1998, Hagen T M, Russel T, Ingersoll T, Lykkesfeldt J, Liu J, Wehr C M, Vinarsky V, Batholomew J C, Ames B N. R(+)-alpha-lipoic acid supplemented old rats have improved mitochondrial function, decreased oxidative damage and increased metabolic rate. FASEB J 13: 411-418, 1999 and Summary of product characteristics for Thioctacid, ASTA Medica 1999. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Metabolites of prinomastat and their synthesis Inventor(s): Ouellette, Michael A.; (San Diego, CA), Potts, Barbara C.M.; (Escondido, CA), Srirangam, Jayaram K.; (San Diego, CA), Tibbetts, Anthony R.; (San Diego, CA), Zhang, Kanyin E.; (San Diego, CA) Correspondence: Agouron Pharmaceuticals, INC.; 10350 North Torrey Pines Road; LA Jolla; CA; 92037; US Patent Application Number: 20040053922 Date filed: June 10, 2003 Abstract: Metabolites of a matrix metalloproteinase inhibitor prinomastat and their synthesis. These metabolites are: (3S)-N-hydroxy4-(4-((1-oxy-pyrid-4-yl)oxy)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide (M6); (3S)2,2-dimethyl-1,1-dioxo-4-[4-(1-oxy-pyridin-4-yloxy)-benzenesul- fonyl]-thiomorpholine3-carboxylic acid amide (M7); (3S)-2,2-dimethyl-4-[4-(1-oxypyridin-4-yloxy)benzenesulfonyl]-thiomorpho- line-3-carboxylic acid amide (M8); (3S)-2,2-dimethyl-1,1dioxo-4-[4-(pyrid- in-4-yloxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid amide (M2); and (3S)-2,2-dimethyl-4-[4-(pyridin-4yloxy)-benzenesulfonyl)-thiomorphpli- ne-3carboxylic acid amide (M3). Excerpt(s): The present patent application claims priority to U.S. Serial No. 60/387,548, filed Jun. 10, 2003, which is hereby incorporated by reference in its entirety for all purposes. This invention relates to metabolites of (3S)-N-hydroxy-4-(4-(pyrid- -4-yloxy)benzenesuffonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carbo- xamide, a matrix metalloproteinase inhibitor having the generic name Prinomistat, and to their synthesis. Matrix metalloproteinases ("MMPs") are a family of enzymes, including, collagenases,

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gelatinases, matrilysin, and stromelysins, that are involved in the degradation and remodeling of connective tissues. These enzymes are contained in a number of cell types that are found in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells and metastatic tumor cells. They also share a number of properties, including zinc and calcium dependence, secretion as zymogens, and, 40-50% amino acid sequence homology. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method and apparatus for detection of vulnerable atherosclerotic plaque Inventor(s): Casscells, S. Ward III; (Houston, TX), Guo, Bujin; (Houston, TX), Naghavi, Morteza; (Houston, TX), Willerson, James T.; (Houston, TX) Correspondence: Stradling Yocco Carlson & Rauth; Suite 1600; 660 Newport Center Drive; P.O. Box 7680; Newport Beach; CA; 92660; US Patent Application Number: 20040111016 Date filed: August 12, 2003 Abstract: Methods for the detection of inflammation associated with vulnerable atherosclerotic plaque to prevent heart attack and stroke are disclosed. The methods are also applicable to detection of infection, cancer, wounds or auto-immune disease in the body. Certain embodiments of the new methods provide a way of predicting the level of vulnerability of an atherosclerotic plaque to rupture or thrombus formation by assessing via fiber optic NIR spectrophotometry the status of two or more parameters associated with inflamed atherosclerotic plaque in a vessel of a living patient. From these measurements such conditions as low pH, hypoxia, low glucose, oxidative stress or compounds abundant in vulnerable plaque such as oxidized LDL cholesterol and oxidized metabolites of NO, significant active macrophage population, thin plaque cap, as well as senescence and/or apoptosis of smooth muscle or endothelial cells are determined with the assistance of a suitably programmed microprocessor. By considering together the status of some or all of these conditions with respect to successive sites along a vessel wall, particular plaques which are at significant risk of rupturing or thrombosing can be distinguished from "normal" vessel wall and from "intermediate" and relatively stable or "lower risk" plaques. Sites having more of the indicator conditions would be considered most in need of prompt intervention, and certain combinations of parameter levels would be suggestive of relatively stable plaque.Also disclosed is a multi-parameter catheter and analytical processing assembly for use in the methods. Excerpt(s): The present application is a continuation-in-part of U.S. patent application Ser. No. 08/717,449 filed Sep. 20, 1996. The present invention generally relates to methods of diagnosing and treating inflammation, particularly inflamed atherosclerotic plaque at risk of rupture or thrombosis. More particularly, the methods of the invention pertain to the simultaneous detection of two or more chemical parameters associated with inflammation and/or active cellular metabolism in plaque. The invention also relates to multi-parameter catheter assemblies for irradiating sites along a blood vessel wall with near-infrared and visible wavelength radiation and for receiving and analyzing the reflected radiation to qualitatively or quantitatively determine the status of each such parameter. Atherosclerotic coronary artery disease is the leading cause of death in industrialized countries. Typically, patients who have died of coronary disease may exhibit as many as several dozen atherosclerotic plaques in the arterial tree. Plaque, a thickening in the arterial vessel wall, results from the accumulation of cholesterol,

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proliferation of smooth muscle cells, secretion of a collagenous extracellular matrix by the cells, and accumulation of inflammatory cells and, eventually, hemorrhage, thrombosis and calcification. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method for diagnosing lactose intolerance and diagnostic kit for performing the method Inventor(s): Aygen, Sitke; (Koln, DE) Correspondence: Jacobson Holman Pllc; 400 Seventh Street N.W.; Suite 600; Washington; DC; 20004; US Patent Application Number: 20040087837 Date filed: March 19, 2003 Abstract: The method for diagnosing lactose intolerance in patients by the oral administration of defined amounts of lactose, followed by assaying metabolites of lactose, is performed in a way where the lactose administered contains 99%.sup.13Clabeled lactose, preferably from 5 to 30 mg, and after the administration of the lactose, the, content of.sup.13C-labeled lactose is determined in a serum sample taken at a defined time after the administration. A diagnostic kit for performing the method consists of a capsule with from 5 to 30 mg of 99%.sup.13C-labeled lactose, a patient instruction manual, a blood sampling device, sample containers for collecting the blood sample, and optionally a spatula and sample container for a stool specimen. Excerpt(s): The present invention relates to a method for diagnosing lactose intolerance in patients by the oral administration of defined amounts of lactose, followed by assaying metabolites of lactose, and a diagnostic kit for performing the method. Lactose intolerance is a universally very frequent phenomenon and results in a more or less severe digestive disorder from milk and dairy products in the afflicted persons. Lactose intolerance is generally based on the absence of the enzyme lactase for whose formation a gene on chromosome 2 is responsible. This gene determines the time from which humans no longer produce lactase. Depending on the ethnic origin, this can be the case sooner or later. In earlier times of evolution, humans, like many other mammals, lost the enzyme always when they were no longer fed with breast milk (cf. Pharm. Ztg. No. 9, 145th annual volume, Mar. 2, 2000). Today, the H.sub.2 breath test is employed most frequently for diagnosing lactose intolerance since it is simple and telling. Thus, the patient drinks a solution of 50 g lactose in water. The hydrogen subsequently exhaled is then measured repeatedly by gas chromatography over 4 hours. Thus, not only qualitative, but also quantitative information about the lactase deficiency is obtained. Lactose intolerance is now considered a disease which can be treated only symptomatically to date. However, in the meantime, there has been found a possibility of ingesting the enzyme lactase in the form of capsules, tablets or solution and thus compensating the lactase deficiency. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods and agents for treating cardiovascular diseases Inventor(s): Borlak, Jurgen; (Lehrte, DE), Thum, Thomas; (Hannover, DE) Correspondence: Kurt Briscoe; Norris, Mclaughlin & Marcus, P.A.; 220 East 42nd Street, 30th Floor; New York; NY; 10017; US Patent Application Number: 20040110733 Date filed: December 4, 2002 Abstract: This invention relates to a method and an agent for treating cardiovascular diseases, especially cardiac hypertrophy, wherein said method and agent consist in increasing testosterone concentration in pathological tissues to normal levels or inhibiting and/or eliminating metabolites from testosterone metabolism.The testosterone concentration in pathological tissues can be increased to normal levels by administering at least one substance from the following groups:testosterone;substances with effects similar to those of testosterone;testosterone mimetics;substances that enhance testosterone synthesis;substances that inhibit testosterone metabolism.Metabolites from testosterone metabolism can be inhibited and/or eliminated by administering at least one substance from the following groups:substances that bind to the androgen receptor, causing the receptor levels to be regulated and thus normalized;substances that bind to the androgen receptor, regulating the androgen receptor-mediated gene expression by inhibiting it, as is observed in cardiac hypertrophy.Areas of application are medicine and pharmaceuticals industry. Excerpt(s): This invention relates to methods and agents for treating cardiovascular diseases, especially cardiac hypertrophy. Areas of application are medicine and pharmaceuticals industry. Both spermatogenesis and androgen secretion are controlled by hormones of the anterior lobe of the pituitary gland; together with androgens folliclestimulating hormones (FSHs) promote spermatogenesis by supporting the function of Sertoli cells. Luteinizing hormones (LHs) affect the Leydig cells and stimulates androgen release. These secreted androgens have an inhibiting effect both on the release of FSHs and on that of LHs. The relatively slight inhibiting effect of these androgens is supported by estradiol, which is synthesized in the testis and converted from testosterone in the peripheral tissues. Injections of testosterone into the hypothalamus cause testicular atrophy and a decrease in secretion of a joint releasing hormone for FSH and LH. Androgen release is strongly inhibited by estrogens and, to a lesser extent, by progestogens. Via a feedback mechanism, they inhibit the release of gonadotropic hormones. Lack of FSHs thus leads to an interruption of spermatogenesis, and deficiency of LHs stops androgens secretion. In other words, administration of estrogens to men has an effect similar to that of surgical castration, only that it is caused by hormones. In order to avoid the effects of androgens, chemically synthesized antiandrogens are used as receptor blocker. Due to their structure, which is similar to that of testosterone, they can bind to the androgen receptor, inhibiting the signal transduction mediated by the androgen receptor. Known blockers are cyproteron and cyproteron acetate. Under the influence of antiandrogens, development of the seminal duct and its accessory glands as well as the penis is inhibited. In addition, differentiation of the normal phenotype into the male phenotype in the hypothalamus is blocked. In adult animals, antiandrogens inhibit spermatogenesis as well as seminal vesicle and cause prostate and oil gland atrophy. Furthermore, antiandrogens increase secretion of FSH- and LH-releasing hormones and thus also release of FSHs and LHs. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods for conducting metabolic analyses Inventor(s): Schneider, Luke V.; (Half Moon Bay, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20040091943 Date filed: October 17, 2003 Abstract: The present invention provides methods and apparatus for purifying metabolites of interest and conducting metabolic analyses. The methods generally involve determining metabolic flux values for a plurality of target analytes by monitoring the relative isotope abundance of a stable isotope in a substrate labeled with the stable isotope and/or one or more target metabolites formed through metabolism of the labeled substrate. Certain methods utilize multiple electrophoretic methods to separate the target analytes from other components within the sample being analyzed. The methods can be used in a variety of applications including screens to identify metabolites that are correlated with certain diseases and diagnostic screens for identifying individuals having, or susceptible to, a disease. Excerpt(s): This application claims the benefit of U.S. provisional application No. 60/130,238, filed Apr. 20, 1999. This application is also related to U.S. provisional application No. 60/075,715 filed Feb. 24, 1998; copending U.S. patent application Ser. No. 09/513,486, filed Feb. 25, 2000, entitled "Protein Separation Via Multidimensional Electrophoresis," and having attorney docket number 020444-000200US; copending U.S. patent application Ser. No. 09/513,395, filed Feb. 25, 2000, entitled "Methods for Protein Sequencing," and having attorney docket number 020444-000300US; copending U.S. application Ser. No. 09/513,907, filed Feb. 25, 2000, entitled "Polypeptide Fingerprinting Methods and Bioinformatics Database System," and having attorney docket number 020444-000100US; copending U.S. patent application Ser. No. ______, filed Apr. 19, 2000, entitled "Labeling of Protein Samples", and having attorney docket number 020444000500US; and copending PCT application ______, filed Apr. 19, 2000, entitled "Polypeptide Fingerprinting Methods, Metabolic Profiling, and Bioinformatics Database," and having attorney docket number 020444-000600PC. All of these applications are incorporated by reference in their entirety for all purposes. This invention relates to the field of metabolism and separation technology, including methods for separating and analyzing metabolites and making correlations between certain metabolites or metabolic conditions and cellular states. One goal in biochemical research is to develop correlations between the presence, absence, concentration, conversion rates, or transport rates of certain molecules within cells, tissues and particular cell or tissue states (e.g., disease states, particular developmental stages, states resulting from exposure to certain environmental stimuli and states associated with therapeutic treatments). Such correlations have the potential to provide significant insight into the mechanism of disease, cellular development and differentiation, as well as in the identification of new therapeutics, drug targets and/or disease markers. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods of optimizing drug therapeutic efficacy for treatment of immune-mediated gastrointestinal disorders Inventor(s): Seidman, Ernest G.; (Luc, CA), Theoret, Yves; (Montreal, CA) Correspondence: Cathryn Campbell; Mcdermott, Will & Emery; 7th Floor; 4370 LA Jolla Village Drive; San Diego; CA; 92122; US Patent Application Number: 20040097527 Date filed: November 6, 2003 Abstract: The present invention provides a method of optimizing therapeutic efficacy and reducing toxicity associated with 6-mercaptopurine drug treatment of an immunemediated gastrointestinal disorder such as inflammatory bowel disease. The method of the invention includes the step of determining the level of one or more 6mercaptopurine metabolites in the patient having an immune-mediated gastrointestinal disorder. Excerpt(s): This application claims the benefit of priority of provisional application serial No. 60/101,714, filed Sep. 24, 1998, which is incorporated herein by reference. The present invention relates generally to autoimmunity and immune-mediated gastrointestinal disorders such as inflammatory bowel disease and more specifically to methods for optimizing treatment of immune-mediated gastrointestinal disorders. Immune-mediated gastrointestinal disorders encompass a wide range of debilitating gastrointestinal diseases of various etiologies. One such immune-mediated gastrointestinal disorder, inflammatory bowel disease (IBD), is the collective term used to describe two gastrointestinal disorders of unknown etiology: Crohn's disease (CD) and ulcerative colitis (UC). The course and prognosis of IBD, which occurs world-wide and is reported to afflict as many as two million people, varies widely. Onset of IBD is predominantly in young adulthood with diarrhea, abdominal pain, and fever the three most common presenting symptoms. The diarrhea may range from mild to severe and in ulcerative colitis often is accompanied by bleeding. Anemia and weight loss are additional common signs of IBD. Ten percent to fifteen percent of all patients wits IBD will require surgery over a ten year period. In addition, patients with IBD are at increased risk for the development of intestinal cancer. Reports of an increasing occurrence of psychological problems, including anxiety and depression, are perhaps not surprising symptoms of what is often a debilitating disease that strikes people in the prime of life. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods of preparing didesmethylsibutramine and other sibutramine derivatives Inventor(s): Han, Zhengxu; (Shrewsbury, MA), Krishnamurthy, Dhileepkumar; (Westborough, MA), Pflum, Derek; (Northville, MI), Senanayake, Chris Hugh; (Shrewsbury, MA) Correspondence: Jones Day; 51 Louisiana Aveue, N.W; Washington; DC; 20001-2113; US Patent Application Number: 20040087660 Date filed: August 20, 2003 Abstract: This invention encompasses novel methods of preparing sibutramine and sibutramine derivatives, and stereomerically pure sibutramine derivatives in particular. Examples of sibutramine derivatives include, but are not limited to, sibutramine

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metabolites such as desmethylsibutramine and didesmethylsibutramine. The invention further encompasses novel compounds useful in the synthesis of sibutramine derivatives. Excerpt(s): This application claims priority to U.S. Provisional Application No. 60/283,371, filed Apr. 13, 2001, the entirety of which is incorporated herein by reference. This invention relates to methods of synthesizing sibutramine derivatives, which include sibutramine metabolites such as, but not limited to, desmethylsibutramine and didesmethylsibutramine. Sibutramine is a neuronal monoamine reuptake inhibitor, which has the chemical name [N-1-[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine. Originally disclosed in U.S. Pat. Nos. 4,746,680 and 4,806,570, sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, e.g., Buckett et al., Prog. Neuro-psychopharm. & Biol. Psychiat., 12:575-584, 1988; King et al., J. Clin. Pharm., 26:607-611 (1989). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of treating or preventing restless leg syndrome using sibutramine metabolites Inventor(s): Fang, Qun K.; (Wellesley, MA), Jerussi, Thomas P.; (Framingham, MA), Senanayake, Chrisantha H.; (Shrewsbury, MA) Correspondence: Jones Day; 51 Louisiana Aveue, N.W; Washington; DC; 20001-2113; US Patent Application Number: 20040067957 Date filed: September 22, 2003 Abstract: Methods are disclosed for the treatment and prevention of disorders and conditions such as, but are not limited to: eating disorders; weight gain; obesity; irritable bowel syndrome; obsessive-compulsive disorders; platelet adhesion; apnea; affective disorders such as attention deficit disorders, depression, and anxiety; male and female sexual function disorders; restless leg syndrome; osteoarthritis; substance abuse including nicotine and cocaine addiction; narcolepsy; pain such as neuropathic pain, diabetic neuropathy, and chronic pain; migraines; cerebral function disorders; chronic disorders such as premenstrual syndrome; and incontinence.Pharmaceutical compositions and dosage forms are also disclosed which comprise a racemic or optically pure sibutramine metabolite and an optional additional pharmacologically active compound. Excerpt(s): This application is a continuation-in-part of U.S. application Ser. No. 09/662,135, filed Sep. 14, 2000, which is a continuation-in-part of U.S. application Ser. No. 09/372,158, filed Aug. 11, 1999, both of which are incorporated herein by reference in their entireties. The invention relates to methods of using and compositions comprising dopamine reuptake inhibitors such as racemic and optically pure metabolites of sibutramine, optionally in combination with other pharmacologically active compounds. Sibutramine, chemically named [N-1-[1-(4-chlorophenyl)cyclobutyl]3- -methylbutyl]-N,N-dimethylamine, is a neuronal monoamine reuptake inhibitor which was originally disclosed in U.S. Pat. Nos. 4,746,680 and 4,806,570. Sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, e.g., Buckett et al., Prog. Neuro-psychopharm. & Biol. Psychiat., 12:575-584, 1988; King et al., J. Clin. Pharm., 26:607-611 (1989). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Monoterpene as a chemopreventive agent for regression of mammalian nervous system cell tumors, use of monoterpene for causing regression and inhibition of nervous system cell tumors, and method for administration of monoterpene perillyl alcohol Inventor(s): Alves Brown, Gilda; (Rio de Janeiro, BR), Da Costa Carvalho, Maria da Gloria; (Rio de Janeiro, BR), Da Fonseca Quirico Dos Santos, Thereza; (Rio de Janeiro, BR), Pereira Da Fonseca, Clovis Orlando; (Rio de Janeiro, BR) Correspondence: Jacobson Holman Pllc; 400 Seventh Street N.W.; Suite 600; Washington; DC; 20004; US Patent Application Number: 20040087651 Date filed: December 13, 2002 Abstract: The present invention refers to a composition based on monoterpenes with chemopreventive and chemotherapeutic effects in malignant neoplasias of humans and animals containing from 0,03% to 30% of monoterpenes and 99,97% of solvents. Another objective of the present invention is an application of monoterpenes in inhibition of cell growth and metastasis control of primary tumors being applied in vitro and in vivo gliomas cell lines C6 and U 87 and A172. Further another objective of the present invention refers to a specific methods for applying the composition with chemopreventive and chemotherapeutic effects in humans and animals showing malignant neoplasias by inhalation and nebulization treatment, oral and intratumoral, followed or not by radiotherapy with dilutions from 0,03% to 30% of the monoterpene perillyl or its derived metabolites diluted in the solvents specified by the usual techniques. Excerpt(s): The present invention relates to treatment for mammalian nervous system cell tumors. In particular, the present invention relates to using of monoterpene perillyl alcohol to inhibit tumor formation and to cause tumor regression. The progress in treating most common solid malignancies has slowed due at least in part to the lack of new effective agents. This has led to a new emphasis on cancer prevention and on developing therapeutic agents with novel mechanisms. Recent data suggest that monoterpenes, a class of non-toxic compounds that act through novel mechanism, may be useful for both chemoprevention and treatment of cancer. These compounds have been shown to exert chemopreventive and chemotherapeutic activities in several tumor models and represent a new class of cancer therapeutic agents. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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N-aryl diazaspiracyclic compounds and methods of preparation and use thereof Inventor(s): Bhatti, Balwinder S.; (Winston-Salem, NC), Miller, Craig Harrison; (Winston-Salem, NC), Schmitt, Jeffrey Daniel; (Winston-Salem, NH) Correspondence: Womble Carlyle Sandridge & Rice, Pllc; P.O. Box 7037; Atlanta; GA; 30357-0037; US Patent Application Number: 20040067930 Date filed: June 27, 2003 Abstract: Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are N-aryl

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diazaspirocyclic compounds, bridged analogs of N-heteroaryl diazaspirocyclic compounds, or prodrugs or metabolites of these compounds. The aryl group can be a five- or six-membered heterocyclic ring (heteroaryl). The compounds and compositions can be used to treat and/or prevent a wide variety of conditions or disorders, particularly those disorders characterized by dysfunction of nicotinic cholinergic neurotransmission, including disorders involving neuromodulation of neurotransmitter release, such as dopamine release. CNS disorders, which are characterized by an alteration in normal neurotransmitter release, are another example of disorders that can be treated and/or prevented. The compounds and compositions can also be used to alleviate pain. The compounds can: (i) alter the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) when employed in effective amounts, not result in appreciable adverse side effects (e.g., side effects such as significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle). Excerpt(s): This document claims priority to and the benefit of the filing date of copending provisional application entitled "N-Aryl Diazaspiracyclic Compounds and Methods of Preparation and Use Thereof" assigned serial No. 60/394,337, and filed Jul. 5, 2002, which is hereby incorporated by reference. The present invention relates to pharmaceutical compositions incorporating compounds capable of affecting nicotinic cholinergic receptors, for example, as modulators of specific nicotinic receptor subtypes. The present invention also relates to methods for treating a wide variety of conditions and disorders, particularly those associated with dysfunction of the central and autonomic nervous systems. Nicotine exhibits a variety of pharmacological effects (Pullan et al., N. Engl. J. Med. 330:811-815 (1994)), some of which are due to neurotransmitter release (See, for example, Sjak-shie et al., Brain Res. 624:295 (1993), where neuroprotective effects of nicotine are proposed). For example, acetylcholine, dopamine, norepinephrine, serotonin and glutamate are released by neurons upon administration of nicotine (Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313 (1991) and Vizi, Br. J. Pharmacol. 47:765 (1973), (Hall et al., Biochem. Pharmacol. 21:1829 (1972), (Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977)), and Toth et al., Neurochem Res. 17:265 (1992)). Confirmatory reports and additional recent studies show that nicotine administration modulates glutamate, nitric oxide, GABA, takykinins, cytokines and peptides in the central nervous system (CNS) (reviewed in Brioni et al., Adv. Pharmacol. 37:153 (1997)). Nicotine also reportedly potentiates the pharmacological behavior of certain pharmaceutical compositions used to treat certain disorders. See, for example, Sanberg et al., Pharmacol. Biochem. & Behavior 46:303 (1993); Harsing et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings from Intl. Symp. Nic. S40 (1994). Various additional beneficial pharmacological effects of nicotine have been proposed. See, for example, Decina et al., Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry 21:301 (1988); Pomerleau et al., Addictive Behaviors 9:265 (1984); Onaivi et al., Life Sci. 54(3):193 (1994); Tripathi et al., J. Pharmacol. Exp. Ther. 221:91(1982) and Hamon, Trends in Pharmacol. Res.15:36 (1994). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Nitrosated and nitrosylated nebivolol and its metabolites, compositions and methods of use Inventor(s): Garvey, David S.; (Dover, MA) Correspondence: Edward D Grieff; Hale & Dorr Llp; 1455 Pennsylvania Ave, NW; Washington; DC; 20004; US Patent Application Number: 20040132805 Date filed: October 29, 2003 Abstract: The invention describes novel nitrosated and/or nitrosylated nebivolol, novel nitrosated and/or nitrosylated metabolites of nebivolol and novel compositions comprising at least one nitrosated and/or nitrosylated nebivolol and/or at least one nitrosated and/or nitrosylated metabolite of nebivolol, and, optionally, at least one nitric oxide donor and/or at least one antioxidant or a pharmaceutically acceptable salt thereof, and/or at least one compound used to treat cardiovascular diseases or a pharmaceutically acceptable salt thereof, and/or at least one nitrosated compound used to treat cardiovascular diseases. The invention also provides novel compositions comprising nebivolol and/or at least one metabolite of nebivolol and at least one nitric oxide donor, and, optionally, at least one antioxidant or a pharmaceutically acceptable salt thereof, and/or at least one compound used to treat cardiovascular diseases or a pharmaceutically acceptable salt thereof, and/or at least one nitrosated compound used to treat cardiovascular diseases. The compounds and compositions of the invention can also be bound to a matrix. The nitric oxide donor is a compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and may preferably be isosorbide dinitrate and/or isosorbide mononitrate. The antioxidant may preferably be a hydralazine compound or a pharmaceutically acceptable salt thereof. The invention also provides methods for treating and/or preventing vascular diseases characterized by nitric oxide insufficiency; and for treating and/or preventing Raynaud's syndrome; and for treating and/or preventing cardiovascular diseases or disorders. Excerpt(s): This application claims priority to U.S. Provisional Application No. 60/287,725 filed May 2, 2001. The decline in cardiovascular morbidity and mortality in the United States over the past three decades has been the result of significant advances in research on cardiovascular disease mechanisms and therapeutic strategies. The incidence and prevalence of myocardial infarction and death from myocardial infarction, as well as that from cerebrovascular accident, have decreased significantly over this period largely owing to advances in prevention, early diagnosis, and treatment of these very common diseases. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Non-invasive measurement of analytes Inventor(s): Lambert, Christopher Robert; (Hudson, MA), Workman, Jerome James JR.; (Brookline, MA) Correspondence: Mintz, Levin, Cohn, Ferris, Glovsky; And Popeo, P.C.; One Financial Center; Boston; MA; 02111; US Patent Application Number: 20040106163 Date filed: July 10, 2003

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Abstract: This invention provides devices, compositions and methods for determining the concentration of one or more metabolites or analytes in a biological sample, including cells, tissues, organs, organisms, and biological fluids. In particular, this invention provides materials, apparatus, and methods for several non-invasive techniques for the determination of in vivo blood glucose concentration levels based upon the in vivo measurement of one or more analytes or parameters found in skin. Excerpt(s): This invention is a continuation in part of U.S. Ser. No. 10/______, filed on Jul. 9, 2003 and claims priority to the U.S. provisional patent application serial No. 60/425,488, filed Nov. 12, 2002, and serial No. 60/438,837, filed Jan. 9, 2003, each of which is incorporated by reference in its entirety. This invention provides devices, compositions and methods for determining the concentration of one or more analytes in a biological sample, including cells, tissues, organs, organisms, and biological fluids. In particular, this invention provides materials, apparatus, and methods for several noninvasive techniques for the determination of in vivo blood glucose concentration levels based upon the in vivo measurement of one or more analytes or parameters found in skin. Identifying and understanding the risk factors associated with diabetes is invaluable for the development and evaluation of effective intervention strategies. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

P450rai-2(p450 cytochrome 26b),encoding nucleic acid molecules and methods and uses thereof Inventor(s): Jones, Glenville; (Kingston Ontario, CA), Petkovich, Martin P.; (Kingston Ontario, CA), Ramshaw, Heather; (Napanee Ontario, CA), White, Jay A.; (Ontario, CA) Correspondence: Bereskin And Parr; Scotia Plaza; 40 King Street West-Suite 4000 Box 401; Toronto; ON; M5h 3y2; CA Patent Application Number: 20040131617 Date filed: November 13, 2003 Abstract: The present invention provides a novel all-trans-RA inducible all-trans-RA metabolizing cytochrome P450, P450RAI-2, that is predominantly expressed in the brain, cerebellum in particular. It is also expressed in normal and tumour lung tissue and in breast cancer cells and may have a correlation with lung and breast cancer. Human P450RAI-2 show 42% amino acid identity to human P450RAI-1 and when transfected into COS-1 cells causes the rapid conversion of all-trans-RA into more polar metabolites including the inactive products 4-oxo-RA, 4-OH-RA and 18-OH-RA. P450RAI-2, as with P450RAI-1, is also inducible in certain cultured cell lines exposed to all-trans-RA. Methods for and uses of the new polynucleotide, polypeptide, fragments thereof and inhibitors thereof, include the treatment of dermatological disorders, cancer and certain brain disorders. Excerpt(s): This application claims priority from Patent Cooperation Treaty patent application No. PCT/CA 00/01493 filed Dec. 15, 2000, which is incorporated herein by reference. As Dec. 15, 2001 falls on a Saturday, this application is being filed on the next available business day, Monday Dec. 17, 2001, in accordance with Article 4 of the Stockholm Act of the Paris Convention for the Prtoection of Industrial Property and Article 18 of the Patent Cooperation Treaty. The present invention relates to a novel gene encoding a polypeptide that is a member of the cytochrome P450 family. More particularly the present invention relates to a polynucleotide encoding the novel polypeptide, to an antisense polynucleotide thereof and to fragments thereof. The

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invention further relates to the novel cytochrome P450 as well as to vectors, host cells and antibodies to the polypeptide and the recombinant methods for producing the same. Uses and methods relating to any of the foregoing are also included within the scope of the invention. The cytochromes P450 comprise a large gene superfamily that encodes over 500 distinct heme-thiolate proteins that catalyze the oxidation of drugs and numerous other compounds in the body [Nelson et al., (1996); Guengerich (1991)]. Since there are at least 500 different cytochrome P450 enzymes, it is of considerable interest in the pharmaceutical and other fields to identify which of these enzymes are most important in the metabolism of individual compounds. There are now numerous examples of adverse drug-drug interactions and side effects that can now be understood in terms of the cytochrome P450 enzymes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Polyamine-mediated transfection Inventor(s): Bennett, Michael; (El Sobrante, CA), Lizarzaburu, Mike E.; (San Mateo, CA), Nantz, Michael H.; (Davis, CA), Niedzinski, Edmund J.; (Vacaville, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20040077888 Date filed: May 30, 2003 Abstract: The present invention provides cationic lipids and methods that facilitate nucleic acid delivery and which also yield biologically benign metabolites following transfection. The compounds are lipidic polyamines that use a pentaerythritol scaffold to link different hydrophobic and DNA-binding domains. Excerpt(s): This application claims priority to U.S. Provisional Patent Application Nos. 60/385,234 and 60/384,514, both filed on May 31, 2002, the disclosures of which are hereby incorporated by reference in their entireties for all purposes. The development of new cationic lipids as vehicles for the intracellular delivery of gene pharmaceuticals continues to be a promising field of research (see, Miller, A. D., Angew. Chem. Int. Ed., 37:1768-1785 (1998)). Since Felgner's first report (see, Feigner et al., Proc. Natl. Acad. Sci. USA., 84:7413-7417 (1987)) of cationic lipid-mediated DNA delivery, dramatic improvements in lipid-based gene delivery systems have led to numerous clinical applications (see, Martin, P., J. Gene Med., 3:91-92 (2001)). Despite recent successes in non-viral gene therapy, cytotoxicity and low transfection activity continue to plague most lipid-based gene delivery systems (see, Byk et al., European Opin. Ther. Patents, 8:1125-1141 (1998)). Overcoming these obstacles is crucial for successful application of this technology, particularly in cases that involve repeat dosing. One particular approach to ameliorate the effects of lipid-associated cytotoxicity is the design and synthesis of degradable cationic lipids. Lipids may be engineered to degrade in response to a number of physiological conditions, such as changes in pH (see, Zhu et al, J. Am. Chem. Soc., 122:2645-2646 (2000); Gerasimov et al., Biochim. Biophys. Acta., 1324:200214 (1997)) or enzymatic activity (see, Litzinger et al., Biochim. Biophys. Acta., 1113:201227 (1992)). A cationic lipid that slowly degrades to non-toxic metabolites after facilitating the cellular incorporation of DNA would avoid the potential side effects that might result from the cumulative concentration of intracellular cationic lipids. The development of cationic lipids that both facilitate DNA delivery and also yield biologically benign metabolites following DNA transfection would thus be advantageous (see, Byk et al., J. Med. Chem., 43:4377-4387 (2000); Tang et al., Biochem.

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Biophys. Res. Commun., 242:141-145, (1998)). Previous research has explored the relationship between the chemical structure of cationic lipids and the influences on nonviral gene transfection (see, Wu et al., Bioconjugate Chem., 12:251-257 (2001); Bennett et al., J. Med. Chem., 40:4069-4078 (1997)). In one such study, pentaerythritol derivatives containing.alpha.-ammonium ester headgroups exhibited low cytotoxicity in transfection experiments (see, Aberle et al., Biochemistry, 37:6533-6540). As postulated, the metabolism of these compounds was accelerated by facile hydrolysis of the.alpha.ammonium esters, giving rise to non-toxic metabolites. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Polyhydroxyalkanoate production from polyols Inventor(s): Peoples, Oliver P.; (Arlington, MA), Skraly, Frank A.; (Somerville, MA) 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: 20040023347 Date filed: May 21, 2003 Abstract: Organisms are provided which express enzymes such as glycerol dehydratase, diol dehydratase, acyl-CoA transferase, acyl-CoA synthetase.beta.-ketothiolase, acetoacetyl-CoA reductase, PHA synthase, glycerol-3-phosphate dehydrogenase and glycerol-3-phosphatase, which are useful for the production of PHAs. In some cases one or more of these genes are native to the host organism and the remainder are provided from transgenes. These organisms produce poly (3-hydroxyalkanoate) homopolymers or co-polymers incorporating 3-hydroxypropionate or 3-hydroxyvalerate monomers wherein the 3-hydroxypropionate and 3-hydroxyvalreate units are derived from the enzyme catalysed conversion of diols. Suitable diols that can be used include 1,2propanediol, 1,3 propanediol and glycerol. Biochemical pathways for obtaining the glycerol from normal cellular metabolites are also described. The PHA polymers are readily recovered and industrially useful as polymers or as starting materials for a range of chemical intermediates including 1,3-propanediol, 3-hydroxypropionaldehyde, acrylics, malonic acid, esters and amines. Excerpt(s): Priority is claimed to U.S. provisional application Serial No. 60/095,329 filed Aug. 4, 1998. This is generally in the field of production of polyhydroxyalkanoates by genetic engineering of bacterial enzymes. Numerous microorganisms have the ability to accumulate intracellular reserves of poly [(R)-3-hydroxyalkanoate] (PHA) polymers. PHAs are biodegradable and biocompatible thermoplastic materials with a broad range of industrial and biomedical applications (Williams and Peoples, 1996, CHEMTECH 26: 38-44). PHAs can be produced using a number of different fermentation process and recovered using a range of extraction techniques (reviewed by Braunegg et al. 1998, J. Biotechnol. 65: 127-161; Choi and Lee, 1999). Plant crops are also being genetically engineered to produce these polymers offering a cost structure in line with the vegetable oils and direct price competitiveness with petroleum-based polymers (Williams and Peoples 1996, CHEMTECH 26:38-44; Poirier, Y. 1999, Plant Biotechnology pp. 181-185). PHAs are formed by the action of a PHA synthase enzyme. As the polymer chains grow, they form insoluble granules. The PHAs can then be recovered and then converted into chemicals or converted into chemicals during the recovery process (Martin et al. PCT WO 97/15681). Therefore, in addition to their utility as polymers, the PHAs represent a unique mechanism for storing new chemistries in both microbial and plant crop systems.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Product and method for treating joint disorders in vertebrates Inventor(s): Chrisope, Gerald L.; (Boulder, CO), Rose, Rebecca; (Longmont, CO) Correspondence: Sheridan Ross PC; 1560 Broadway; Suite 1200; Denver; CO; 80202 Patent Application Number: 20040161480 Date filed: February 9, 2004 Abstract: A compound and method of using such compound is disclosed that, when administered to an animal, is capable of arresting the inflammatory response in affected tissues and facilitates the repair and maintenance of damaged tissues in the joints of vertebrates. The combination of natural physiological metabolites and herbal phytochemicals is used to treat connective tissue diseases, the composition preferably orally administered. One embodiment of the composition includes chondroitin sulfate and glucosamine that, when ingested by a vertebrate, suppresses the degradation of connective tissue by an autoimmune response. A preferred composition of the present invention includes a palatability agent, an herbal phytochemical, and a metabolic precursor that synergistically acts to increase blood circulation, thereby enhancing transport of the phytochemical and metabolic precursors to an affected site whereby deleterious inflammatory byproducts are removed. Excerpt(s): This is a Continuation application of pending application Ser. No. 10/042,815, filed Jan. 8, 2002, which is a continuation of Ser. No. 09/341,000 filed Jun. 28, 1999 (now U.S. Pat. No. 6,344,220), which is a continuation of Ser. No. 08/813,560, filed Mar. 7, 1997 (now U.S. Pat. No. 5,916,565), which claims priority from U.S. Provisional Patent Application No. 60/013,025, filed Mar. 8, 1996. The present invention is directed to compounds, and methods using such compounds, that when administered to an animal, arrest the inflammatory response in affected tissues and facilitate repair and maintenance of damaged tissues in the joints of vertebrates. In healthy conditions, articular cartilage forms a smooth surface between articulating bone ends to reduce the friction caused by movement. This friction is further reduced by the synovial fluid. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Sanitary article for an organism state analysis and a method of an organism state analysis Inventor(s): Bykhovsky, Dmitry Yurievich; (Moscow, RU), Dostoinov, Ilya Andreevich; (Moscow, RU), Kuznetsov, Valery Lvovich; (Moscow, RU), Pastukhov, Viktor Andreevich; (Moscow, RU) Correspondence: William Collard; Collard & Roe, P.C.; 1077 Northern Boulevard; Roslyn; NY; 11576; US Patent Application Number: 20040133090 Date filed: October 31, 2003 Excerpt(s): The invention relates to the medicine and can be used for the prophylaxis and diagnostics of a number of disorders in human organism and also for the revealing of some states accompanied by the changes in the content of diagnostically important metabolites in biological liquids. Among these disorders are diabetes mellitus,

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ketonuria, L-uria, microalbuminuria, proteinuria, the disorders of protein, fat and carbohydrate metabolism and such states as pregnancy. In spite of the presence of a wide range of diagnostic means and methods until the present time the methods and means of early detection of the unfavourable changes in the organism are very essential. Besides, under certain diseases it is desirable to carry out the continuous monitoring of the content of the reference (signal) metabolites in biological liquid without the constant service of a physician. It is especially important for such patients as infants or the patients having chronic diseases and hard to move (lying patients). The difficulties of taking necessary samples of biological liquid and solid secretions in such cases are well known. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Substituted felbamate derived compounds Inventor(s): Macdonald, Timothy L.; (Charlottesville, VA) Correspondence: University OF Virginia Patent Foundation; 1224 West Main Street, Suite 1-110; Charlottesville; VA; 22903; US Patent Application Number: 20040023986 Date filed: April 25, 2003 Abstract: The present invention relates to novel felbamate derivatives and their use to threat neurological diseases such as epilepsy and neuropathic pain, and to treat tissue damage resulting form ischemic events. The felbamate derivatives are modified to prevent the formation of metabolites that are believed responsible for the toxicity associated with felbamate therapy. Excerpt(s): This application claims priority under 35 U.S.C.sctn.119(e) to provisional patent application No. 60/243,023 filed Oct. 25, 2000 and 60/243,024 filed Oct. 25, 2000, the disclosures of which are incorporated herein. The present invention is directed to novel derivatives of 2-phenyl-1,3-propanediol dicarbamate (felbamate), and the use of such derivatives as therapeutic agents. More particularly, compositions comprising the present felbamate derivatives can be administered for treating a variety of neurological related maladies such as reducing the incidence and severity of epileptic seizures and for preventing and treating hypoxic damage resulting from an ischemnic event. Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a known pharmaceutical compound having been described in U.S. Pat. Nos. 2,884,444 and 4,868,327, the disclosures of which are expressly incorporated herein. Felbamate is a modulator of NMDA (N-methyl-D-aspartate) receptor function, and a glycine site antagonist but also has other reported mechanisms of actions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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System and method for metabolyte neuronal network analysis Inventor(s): Evans, Daron G.; (Dallas, TX) Correspondence: Chalker Flores, Llp; 12700 Park Central, STE. 455; Dallas; TX; 75251; US Patent Application Number: 20040106169 Date filed: February 20, 2003

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Abstract: The present invention provides a system and method for testing the neuronal effects of a compound and its metabolites. The system (100) includes a microelectrode array (102), a data capture unit (108) communicably coupled to the microelectrode array (104), a processor (110) communicably coupled to the data capture unit (108) and one or more input/output devices (112) communicably coupled to the processor (110). The microelectrode array (102) is capable of supporting genetically modified neuronal cells (104) and measuring neuronal activity. The testing medium containing the compound and the metabolites is extracted from hepatocyte cells (106). The method (400) determines the effects of the metabolites of a sample compound on neuronal cells by exposing a sample compound to hepatocyte cells (406), extracting medium from the exposed cells (408) and exposing the extracted medium to neuronal cells on a microelectrode array (410). The effects of a sample compound and its metabolites versus the effects of a sample compound alone can be determined from a comparison of the data (406). Excerpt(s): The present invention relates in general to the field of action potential analysis, and more particularly, to the use of advanced neuronal networks detection techniques for the detailed analysis of neuronal signal transduction pathways and their use for large-scale reproducible analysis. This application claims priority to U.S. Provisional Patent Application Serial No. 60/430,409, filed Dec. 2, 2002. Without limiting the scope of the invention, the background of the invention is described in connection with the recording and analysis of neuronal action potentials using substrate integrated, thin film electrodes, as an example. The first recordings of neuronal action potentials using substrate integrated, thin film electrodes were made as early as 1977 (Gross, et al. 1977). Subsequent research has led to multi-channel investigations of network dynamics and their applications. Indium-tin oxide was introduced later as a viable microelectrode material and was designed and tested for recording in life support chambers (Gross and Schwalm, 1995). These networks were used to explore stimulation of networks through the recording electrodes (Gross et al., 1994). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment for inhibiting neoplastic lesions Inventor(s): Shanahan-Prendergast, Elizabeth; (County Kildare, IE) Correspondence: Hoffmann & Baron, Llp; 6900 Jericho Turnpike; Syosset; NY; 11791; US Patent Application Number: 20040092583 Date filed: January 2, 2004 Abstract: The invention discloses the use of incensole and/or furanogermacrens, derivatives metabolites and precursors thereof in the treatment of neoplasia, particularly resistant neoplasia and immunodysregulatory disorders. These compounds can be administered alone or in combination with conventional chemotherapeutic, antirival, anti-parasite agents, radiation and/or surgery. Excerpt(s): The present invention relates to a method for the selective inhibition of neoplastic cells, for example for the treatment, inhibition or prevention of precancerous lesions, tumours, cancer growth or other neoplasias in mammals. This invention also relates to the use of the compounds of the present invention including incensole and/or furanogermacren, derivatives, metabolites, analogues, mimic molecules and to compositions containing the compounds of the present invention including incensole and/or furanogermacren, derivatives, metabolites, analogues, mimic molecules. Cancer

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develops from changes in the DNA, or genetic material, of the body's cells, causing them to develop into precancerous lesions. Such lesions exhibit a strong tendency to develop into malignant tumours, or cancer. Such lesions include lesions of the breast (that can develop into breast cancer), lesions of the skin (that can develop into malignant melanoma or basal cell carcinoma), colonic adenomatous polyps (that can develop into colon cancer), and other such neoplasms. Cancer may take years to develop. The process typically begins with some disruption to the DNA of a cell, the genetic code that directs the life of the cell. Many things, such as diet, tobacco, sun exposure or certain chemicals can cause such disruptions. Some cells will enter a precancerous phase, known as dysplasia. Some cells will also enter the state of carcinoma in situ, in which the cancer cells are restricted to a microscopic site and do not pose a great threat. Eventually, unless the body's own immune system takes care of the wayward cells either on its own or by being enhanced by specific chemicals, a tumour will develop. It may take as long as 30 years for a tumour to go through the entire process and become large enough to produce clinical symptoms. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Ultrashort acting hypnotic barbiturates Inventor(s): Druzgala, Pascal; (Santa Rosa, CA), Milner, Peter G.; (Los Altos Hills, CA) Correspondence: Saliwanchik Lloyd & Saliwanchik; A Professional Association; 2421 N.W. 41st Street; Suite A-1; Gainesville; FL; 32606-6669; US Patent Application Number: 20040167143 Date filed: January 23, 2004 Abstract: The subject invention concerns novel compounds that are useful as ultrashort acting hypnotic barbiturates. Specifically exemplified are derivatives of barbituric and thiobarbituric acids. They are rapidly metabolized by blood and tissue enzymes to form polar metabolites with no hypnotic activity and which are rapidly eliminated. Excerpt(s): This application is a continuation of co-pending application U.S. Ser. No. 10/145,601, filed May 13, 2002; which is a continuation of application U.S. Ser. No. 09/841,738, filed Apr. 24, 2001, now U.S. Pat. No. 6,387,914. This application also claims the benefit of U.S. Provisional Application No. 60/199,144, filed Apr. 24, 2000. The principal use of a sedative-hypnotic drug is to produce drowsiness and to promote sleep. Since sedative-hypnotic drugs usually have the capacity of producing widespread depression of the CNS, these drugs are employed for various reasons, including as antiepileptic, muscle relaxants, antianxiety drugs, and even to produce amnesia or general anesthesia. Throughout the world, more prescriptions are written for sedativehypnotic-antianxiety drugs than for any other class of drugs. Barbiturates have enjoyed a long period of extensive use as sedative-hypnotic drugs. However, except for a few specialized uses, they have been largely replaced by the somewhat safer benzodiazepines. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of genes encoding membrane transporter pumps to stimulate the production of secondary metabolites in biological cells Inventor(s): Goossens, Alain; (Lokeren, BE), Inze, Dirk Gustaaf; (Moorsel-Aalst, BE) Correspondence: Trask Britt; P.O. Box 2550; Salt Lake City; UT; 84110; US Patent Application Number: 20040064849 Date filed: September 18, 2003 Abstract: The invention relates to the field of secondary metabolite production in plants and plant cell cultures. More specifically, the invention relates to the use of transporters and more particularly ABC-transporters to enhance the production and/or secretion of secondary metabolites in plants and plant cell cultures. Excerpt(s): This application is a continuation of PCT International Patent Application No. PCT/EP/02/04322, filed on Apr. 18, 2002, designating the United States of America, and published, in English, as PCT International Publication No. WO 02/083888 A2 on Oct. 24, 2002, the contents of the entirety of which is incorporated by this reference. The invention relates generally to biotechnology, and more specifically to the field of secondary metabolite production in plants and plant cell cultures. Particularly, the invention relates to the use of transporters and more particularly ABCtransporters to enhance the production and/or secretion of secondary metabolites in plants and plant cell cultures. Higher plants are able to produce a large number of small-molecularweight compounds with very complex structures. These compounds, called "secondary metabolites", can play a role in the resistance against pests and diseases, attraction of pollinators and interaction with symbiotic microorganisms. Besides the importance for the plant itself, secondary metabolites are of great commercial interest because they determine the quality of food (color, taste, and aroma) and ornamental plants (flower color, smell). A number of secondary metabolites isolated from plants are commercially available as fine chemicals, for example, drugs, dyes, flavours, fragrances and even pesticides. In addition, various health improving effects and disease preventing activities of secondary metabolites have been discovered, such as anti-oxidative and antimetastatic-lowering properties (e.g., vinblastine, taxol). 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 metabolites, 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 “metabolites” (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 metabolites. You can also use this procedure to view pending patent applications concerning metabolites. 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 METABOLITES Overview This chapter provides bibliographic book references relating to metabolites. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on metabolites include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “metabolites” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on metabolites: •

Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment Source: Malden, MA: Blackwell Science, Inc. 1999. 568 p. Contact: Available from Blackwell Science, Inc. 350 Main Street, Malden, MA 02148. (800) 215-1000 or (781)-388-8250. Fax (781) 388-8270. E-mail: [email protected]. Website: www.blackwellscience.com. PRICE: $125.00 plus shipping and handling. ISBN: 0632043423. Summary: Cirrhosis (liver scarring) is a very prevalent disease and ascites (fluid accumulation) is the most frequent complication. The development of ascites in cirrhosis is the consequence of the simultaneous occurrence of very complex processes leading to impairment in hepatic, circulatory, and renal function. The textbook offers 32 chapters on the pathogenesis, diagnosis and treatment of ascites and renal dysfunction in liver disease. Topics include historical notes on ascites in cirrhosis; characteristics of ascites;

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clinical disorders of renal function in cirrhosis with ascites; clinical disorders of renal function in acute liver failure; renal dysfunction and postoperative renal failure in obstructive jaundice; spontaneous bacterial peritonitis; the etiology, diagnosis, and management of noncirrhotic ascites; extracellular fluid volume homeostasis; physiology of the renal circulation; physiology of the gastrointestinal and liver circulation; the renin angiotensin aldosterone system in cirrhosis; the sympathetic nervous system in cirrhosis; arginine vasopressin in cirrhosis; atrial natriuretic peptide and other natriuretic factors in cirrhosis; arachidonic acid metabolites and the kidney in cirrhosis; nitric oxide and systemic and renal hemodynamic disturbances in cirrhosis; endothelin and systemic, renal, and hepatic hemodynamic disturbances in cirrhosis; the systemic circulation in cirrhosis; the splanchnic circulation in cirrhosis; alterations of hepatic and splanchnic microvascular exchange in cirrhosis (local factors in the formation of ascites); experimental models in the investigation of portal hypertension; renal dysfunction and ascites in carbon tetrachloride induced cirrhosis in rates; bacterial infection of the ascitic fluid in rates with carbon tetrachloride induced cirrhosis; the arterial vasodilation hypothesis of ascites formation in cirrhosis; prognosis of cirrhosis with ascites; the medical treatment of ascites in cirrhosis; treatment of ascites by paracentesis; the treatment of refractory ascites in cirrhosis; the treatment of hepatorenal syndrome in cirrhosis; drug induced renal failure in cirrhosis; liver transplantation in cirrhotic patients with ascites; and the treatment and prophylaxis of spontaneous bacterial peritonitis. Each chapter is written by experts in the field and includes extensive references. The text concludes with a subject index.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “metabolites” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “metabolites” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “metabolites” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): •

A novel method for the determination of sildenafil (Viagra) and its metabolite (UK103,320) in postmortem specimens using LC/MS/MS and LC/MS/MS/MS final report (SuDoc TD 4.210:00/20) by Russell J. Lewis; ISBN: B000113JSS; http://www.amazon.com/exec/obidos/ASIN/B000113JSS/icongroupinterna

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Alternaria: Biology, Plant Diseases and Metabolites (Topics in Secondary Metabolism, Vol 3) by J. Chelkowski, A. Visconti; ISBN: 0444889981; http://www.amazon.com/exec/obidos/ASIN/0444889981/icongroupinterna

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Amines and Their Metabolites (Neuromethods 2 Series I Neurochemistry) by Alan A. Boulton, et al; ISBN: 0896030768; http://www.amazon.com/exec/obidos/ASIN/0896030768/icongroupinterna

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Analysis for Drugs and Metabolites Including Anti-Infective Agents (Methodological Surveys in Biochemistry and Analysis, Vol 20) by Eric Reid, Ian D. Wilson; ISBN: 0851869564; http://www.amazon.com/exec/obidos/ASIN/0851869564/icongroupinterna

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Analysis of drugs and metabolites by gas chromatography--mass spectrometry by Benjamin J Gudzinowicz; ISBN: 0824765761; http://www.amazon.com/exec/obidos/ASIN/0824765761/icongroupinterna

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Analysis of Phenolic Plant Metabolites (Methods in Ecology) by Peter G. Waterman, et al; ISBN: 0632029692; http://www.amazon.com/exec/obidos/ASIN/0632029692/icongroupinterna

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Arachidonic Acid Metabolites (Atherosclerosis Reviews) by Ruth Johnsson Hegyeli; ISBN: 0881671312; http://www.amazon.com/exec/obidos/ASIN/0881671312/icongroupinterna

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Bioactive Metabolites from Microorganisms: Selected Papers from the 2nd International Symposium on New Bioactive Metabolites from Microorganisms, Ge by M.E. Bushell, U. Grafe; ISBN: 0444880518; http://www.amazon.com/exec/obidos/ASIN/0444880518/icongroupinterna

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Bioactive Secondary Metabolite of Microorganisms (Progress in Industrial Microbiology, Vol 30) by Vladimir Betina; ISBN: 0444987037; http://www.amazon.com/exec/obidos/ASIN/0444987037/icongroupinterna

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Bioanalytical Approaches for Drugs, Including Anti-Asthmatics and Metabolites (Methodological Surveys in Biochemistry and Analysis, Volume 22) by Eric Reid, Ian D. Wilson; ISBN: 0851862365; http://www.amazon.com/exec/obidos/ASIN/0851862365/icongroupinterna

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Biogenic Monoamines and Their Metabolites in the Urine, Plasma, and Cerebrospinal Fluid of Normal, Psychiatric, and Neurological Subjects by Bruce A. Davis; ISBN: 0849346118; http://www.amazon.com/exec/obidos/ASIN/0849346118/icongroupinterna

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Biosynthesis of Secondary Metabolites - Second Edition by R.B. Herbert; ISBN: 0412277204; http://www.amazon.com/exec/obidos/ASIN/0412277204/icongroupinterna

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Central cardiovascular and thermal effects of arachidonic acid and some of its metabolites in rats (Acta Universitatis Ouluensis) by Anna-Leena Sirén; ISBN: 9514213556; http://www.amazon.com/exec/obidos/ASIN/9514213556/icongroupinterna

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Clinical Pharmacokinetics of Sulfonamides and Their Metabolites (Antibiotics and Chemotherapy, Vol 37) by Tom B. Vree; ISBN: 3805545118; http://www.amazon.com/exec/obidos/ASIN/3805545118/icongroupinterna

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Comprehensive Natural Products Chemistry : Polyketides and Other Secondary Metabolites Including Fatty Acids and Their Derivatives by Ushio Sankawa, et al; ISBN: 0080431534; http://www.amazon.com/exec/obidos/ASIN/0080431534/icongroupinterna

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Consideration of the target organ toxicity of trichloroethylene in terms of metabolite toxicity and pharmacokinetics (SuDoc EP 1.23/6:600/J-92/238) by Ivan W. F. Davidson; ISBN: B00010H1MY; http://www.amazon.com/exec/obidos/ASIN/B00010H1MY/icongroupinterna

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CRC Handbook of Bioactive Microbial Metabolites (Vol 3) by Janos Berdy; ISBN: 0849334829; http://www.amazon.com/exec/obidos/ASIN/0849334829/icongroupinterna

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Developments in Industrial Microbiology: Microbial Metabolites (Developments in Industrial Microbiology) by Nashm Claude, et al; ISBN: 0697166880; http://www.amazon.com/exec/obidos/ASIN/0697166880/icongroupinterna

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Drug Metabolite Isolation and Determination (Subseries A, Analysis) by Eric Reid; ISBN: 0306412659; http://www.amazon.com/exec/obidos/ASIN/0306412659/icongroupinterna

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Energy-Related Metabolites During & After Myocardial Ischemia and Retroperfusion of the Coronary Sinus: An Experimental Study in the Pig With the Microdialysis Technique and Extracorporeal Circulation by Vitas Zemgulis; ISBN: 915545108X; http://www.amazon.com/exec/obidos/ASIN/915545108X/icongroupinterna

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Functions of Plant Secondary Metabolites and Their Exploitation in Biotechnology (Annual Plant Reviews, Vol 3) by Michael Wink; ISBN: 0849340861; http://www.amazon.com/exec/obidos/ASIN/0849340861/icongroupinterna

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Handbook of Neurochemistry: Alternations of Metabolites in the Nervous System by Abel Lajtha; ISBN: 030641743X; http://www.amazon.com/exec/obidos/ASIN/030641743X/icongroupinterna

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Health Aspects of Nitrate and Its Metabolites (Particularly Nitrite): Proceedings; ISBN: 9287127921; http://www.amazon.com/exec/obidos/ASIN/9287127921/icongroupinterna

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Herbicide Metabolites in Surface Water and Groundwater: Developed from a Symposium Sponsored by the Division of Agrochemicals and the Division of Envi. 209th National meeting (Acs Symposium Series) by M. T. Meyer, E. M. Thurman; ISBN: 0841234051; http://www.amazon.com/exec/obidos/ASIN/0841234051/icongroupinterna

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Herbivores: Their Interactions with Secondary Plant Metabolites : Ecological and Evolutionary Processes by Gerald A. Rosenthal, et al; ISBN: 0125971842; http://www.amazon.com/exec/obidos/ASIN/0125971842/icongroupinterna

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Human Metabolism of Alcohol: Regulation, Enzymology, and Metabolites of Ethanol by Kathryn E., Ph.D. Crow, Richard D.,Ph.D., D. Phil. Batt; ISBN: 0849345227; http://www.amazon.com/exec/obidos/ASIN/0849345227/icongroupinterna

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Imaging of Energy Metabolites (Atp, Glucose and Lactate) in Tissue Sections: A Bioluminescent Technique by Paschen; ISBN: 0895743116; http://www.amazon.com/exec/obidos/ASIN/0895743116/icongroupinterna

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Immunochemical Detection of Pesticides and Their Metabolites in the Water Cycle: Research Report (Research Report / Deutsche Forschungsgemeinschaft,) by Bertold Hock, Niebner Reinhard; ISBN: 3527271376; http://www.amazon.com/exec/obidos/ASIN/3527271376/icongroupinterna

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Long-Term Clinical Pharmacokinetic Study of Tacrolimus & Mycophenolic Acid & Metabolites in De Novo Renal Allograft Recipients (Acta Biomedica Lovaniensia, 294) by Dirk Kuypers; ISBN: 9058673243; http://www.amazon.com/exec/obidos/ASIN/9058673243/icongroupinterna

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Mass Spectra of Drugs, Pharmaceuticals and Metabolites (SpecData) by Rolf Kuehnle; ISBN: 0471440442; http://www.amazon.com/exec/obidos/ASIN/0471440442/icongroupinterna

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Methods of Enzymatic Analysis, 3.eE, Vol. 6, Metabolites 1: Carbohydrates by H.U. Bergmeyer, J. Bermeyer; ISBN: 3527260463; http://www.amazon.com/exec/obidos/ASIN/3527260463/icongroupinterna

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Methods of Enzymatic Analysis, Metabolites 3: Lipids, Amino Acids and Related Compounds (Methods of Enzymatic Analysis Vol. 8) by H.U. Bergmeyer, et al; ISBN: 352726048X; http://www.amazon.com/exec/obidos/ASIN/352726048X/icongroupinterna

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Methods of Enzymatic Analysis: Metabolites 2 : Tri- And Dicarboxylic Acids, Purines, Pyrimidines. by Hans Ulrich Bergmeyer; ISBN: 0895732378; http://www.amazon.com/exec/obidos/ASIN/0895732378/icongroupinterna

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Methoxyacetaldehyde, an intermediate metabolite of 2-methoxyethanol, is immunosuppressive in the rat (SuDoc EP 1.23/6:600/J-94/037) by Ralph J. Smialowicz; ISBN: B00010IOXO; http://www.amazon.com/exec/obidos/ASIN/B00010IOXO/icongroupinterna

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Pesticides and their metabolites in selected surface-water public supplies in New York State, 1999 (SuDoc I 19.42/4:00-4119) by U.S. Geological Survey; ISBN: B000114GJE; http://www.amazon.com/exec/obidos/ASIN/B000114GJE/icongroupinterna

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Pesticides and their metabolites in three small public water-supply reservoir systems, western New York, 1998-99 (SuDoc I 19.42/4:99-4278) by Patrick J. Phillips; ISBN: B000113FP0; http://www.amazon.com/exec/obidos/ASIN/B000113FP0/icongroupinterna

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Plant Tissue Culture: An Alternative for Production of Useful Metabolites (Agricultural Services Bulletin , No 108) by Masanaru Misawa; ISBN: 9251033919; http://www.amazon.com/exec/obidos/ASIN/9251033919/icongroupinterna

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Prostaglandins and Arachidonate Metabolites : Volume 86: Prostglandins and Arachidonate Metabolites (Methods in Enzymology) by Sidney P. Colowick, William E. Lands; ISBN: 0121819868; http://www.amazon.com/exec/obidos/ASIN/0121819868/icongroupinterna

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Regulation of Secondary Metabolite Formation by Horst Kleinkauf, Hans Von Dohren; ISBN: 3110103478; http://www.amazon.com/exec/obidos/ASIN/3110103478/icongroupinterna

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Regulation of Secondary Metabolite Formation: Proceedings of the Sixteenth Workshop Conference Hoechst, Gracht Castle, 12-16 May 1985 by Workshop Conference Hoechst 1985 Gracht Castle), et al; ISBN: 0895734990; http://www.amazon.com/exec/obidos/ASIN/0895734990/icongroupinterna

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Role of metabolites in aviation forensic toxicology final report (SuDoc TD 4.210:95/26) by Arvind K. Chaturvedi; ISBN: B00010QLSY; http://www.amazon.com/exec/obidos/ASIN/B00010QLSY/icongroupinterna

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Secondary Metabolites : Their Function and Evolution - No. 171 (CIBA Foundation Symposia Series) by Derek Chadwick, Julie Whelan; ISBN: 047193447X; http://www.amazon.com/exec/obidos/ASIN/047193447X/icongroupinterna

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Stereochemical determination of selegiline metabolites in postmortem biological specimens (SuDoc TD 4.210:97/14) by Thomas C. Kupiec; ISBN: B00010Z1HG; http://www.amazon.com/exec/obidos/ASIN/B00010Z1HG/icongroupinterna

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The Impact of Substance P (Sp) N-Terminal Metabolite Sp1-7 in Opioid Tolerance and Withdrawal by Qin Zhou; ISBN: 9155451748; http://www.amazon.com/exec/obidos/ASIN/9155451748/icongroupinterna

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The Penicillin Fermentation: A Model for Secondary Metabolite Production by S. John Pirt; ISBN: 187468510X; http://www.amazon.com/exec/obidos/ASIN/187468510X/icongroupinterna

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The Polyketide Metabolites (Ellis Horwood Series in Organic Chemistry) by David O'Hagan; ISBN: 0136832695; http://www.amazon.com/exec/obidos/ASIN/0136832695/icongroupinterna

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

Nutrition in Chronic Renal Failure Source: in Johnson, R.J. and Feehally, J. Comprehensive Clinical Nephrology. 2nd ed. Orlando, FL: Mosby, Inc. 2003. p. 935-943. Contact: Available from Mosby, Inc. Order Fulfillment Department, 6277 Sea Harbor Drive, Orlando FL 32887. (800) 321-5068. Fax (800)874-6418. E-mail: [email protected] Website: www.elsevierhealth.com. PRICE: $199.00. ISBN: 723432589. Summary: Diet and nutrition play an integral role in the management of individuals with renal (kidney) disease. Abnormalities associated with chronic renal disease include retention of nitrogenous metabolites, a decreased ability to regulate levels of electrolytes and water, and certain vitamin deficiencies. Dietary intake can play a crucial role in managing these abnormalities. Interest in the nutritional status of patients with renal failure has increased with the understanding that poor nutrition predicts a poor outcome. This chapter on nutrition in chronic renal (kidney) failure (CRF) is from a comprehensive textbook that covers every clinical condition encountered in nephrology (the study of kidney disease). The author of this chapter discusses malnutrition, assessment of nutritional status, nutritional guidelines, monitoring and treatment, including the use of oral supplementation, tube feeding, supplementation of dialysate fluids, and appetite stimulants and growth factors. The author concludes that indices of malnutrition are powerful predictors of mortality in end stage renal disease (ESRD). The high prevalence of protein-energy malnutrition in this group is clearly related to multiple factors encountered both before and after renal replacement therapy (dialysis) has commenced. The chapter is clinically focused and extensively illustrated in full color. 8 figures. 4 tables. 28 references.

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Drug Metabolism in the Liver and Intestines Source: in Textbook of Gastroenterology. 4th ed. [2-volume set]. Hagerstown, MD: Lippincott Williams and Wilkins. 2003. p. 592-604. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-6423. Fax: (301) 223-2400. Website: www.lww.com. PRICE: $289.00. ISBN: 781728614. Summary: The absorption of drugs into the body most often involves passive diffusion through lipid membranes, usually via the digestive tract but occasionally through the skin or lungs. Most drugs that gain entry into the body would remain there for a very long time if it were not for the body's ability to convert (metabolize) drugs into more water-soluble and hence more readily excreted, metabolites. The liver is the major organ involved in drug metabolism. For some xenobiotics, the small intestine also plays a major role. This chapter on drug metabolism in the liver and intestines is from a lengthy, two-volume textbook that integrates the various demands of science, technology, expanding information, good judgment, and common sense into the diagnosis and management of gastrointestinal patients. Topics include general principles, the discovery of drug-metabolizing enzymes, P450s and drug metabolism, phase 2 enzymes, and the role of transporters. 4 figures. 3 tables. 139 references.

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Nutritional Management of Nondialyzed Patients with Chronic Renal Failure Source: in Kopple, J.D. and Massry, S.G. Nutritional Management of Renal Disease. Baltimore, MD: Williams and Wilkins. 1997. p. 479-531. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (800) 638-0672 or (410) 528-4223. Fax (800) 447-8438 or (410) 528-8550. PRICE: $99.00. ISBN: 068304740X. Summary: This chapter on the nutritional management of nondialyzed patients with chronic renal failure (CRF) is from a medical textbook on nutrition and metabolism of individuals with renal disease or renal failure. The author stresses that the patient with CRF has alterations in both the dietary requirements and tolerance for most nutrients. Causes of these disorders include decreased (or occasionally increased) urinary, intestinal, and dermal excretion and intestinal absorption. Causes may also include altered metabolism of individual nutrients or their metabolites or products. The author also notes that the nutritional status of the patient undergoing maintenance hemodialysis or peritoneal dialysis is a strong predictor of morbidity and mortality. Other topics include training and monitoring the patient undergoing dietary therapy; dietary therapy for patients who are not yet receiving dialysis therapy, including recommended nutrient intakes; management of the patient with diabetic nephropathy; nutritional management during catabolic stress; and the use of growth factors. Detailed guidelines are provided for patient care management. 4 figures. 3 tables. 270 references. (AA-M).

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Uremic Toxicity Source: in Kopple, J.D. and Massry, S.G. Nutritional Management of Renal Disease. Baltimore, MD: Williams and Wilkins. 1997. p. 97-190. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (800) 638-0672 or (410) 528-4223. Fax (800) 447-8438 or (410) 528-8550. PRICE: $99.00. ISBN: 068304740X.

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Summary: This chapter on uremic toxicity is from a medical textbook on nutrition and metabolism of individuals with renal disease or renal failure. The author defines uremia as a toxic syndrome caused by severe glomerular insufficiency, associated with disturbances in tubular and endocrine functions of the kidney. It is characterized by retention of toxic metabolites associated with changes in volume and electrolyte composition of the body fluids and excess or deficiency of various hormones. The longterm survival of patients with end-stage renal disease (ESRD) on maintenance hemodialysis is strong evidence that some of the most important uremic toxins are dialyzable. The author notes that in acute as well as in chronic renal failure, severe glomerular insufficiency is always associated with secondary disturbances in tubular functions, which may explain such aspects of uremia as hyperkalemia and metabolic acidosis. The author outlines the symptoms and signs of uremia, the toxic effects of uremic plasma or serum, factors that influence uremic toxicity, and the toxicity of specific substances in uremia. 1 table. 860 references. (AA-M). •

Role of the Chemistry Laboratory in the Clinical Study of Renal Disease Source: in Barakat, A.Y. Renal Disease in Children: Clinical Evaluation and Diagnosis. Secaucus, NJ: Springer-Verlag. 1990. p. 55-90. Contact: No longer available from publisher. Summary: This chapter, from an extensive desk reference book about the clinical evaluation and diagnosis of renal disease in children, discusses the role of the chemistry laboratory in the clinical study of renal disease. Eight sections cover: recent changes in laboratory technology; reference intervals; pediatric specimens; electrolytes, fluid, and acid-base balance; other inorganic analytes; glucose and metabolites; nitrogenous compounds; and proteins. The author notes that the improved accuracy of micromethods, such as the widespread use of enzymes as diagnostic reagents for more specific measurements of substrates like glucose and uric acid, has greatly reduced potential interferences from both drugs and endogenous metabolites. Current automation allows any laboratory, whether in a children's hospital or in a facility serving both adult and pediatric patients, to perform rapid, precise microchemical determinations. 22 references.

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Nutrition Support in Renal Failure Source: in American Dietetic Association. Manual of Clinical Dietetics. Chicago, IL: American Dietetic Association. 1996. p. 327-342. Contact: Available from American Dietetic Association. 216 West Jackson Boulevard, Chicago, IL 60606. (800) 877-1600 or (312) 899-0040. Fax (312) 899-4899. PRICE: $59.95 for members, $70.00 for nonmembers. ISBN: 0880911530. Summary: This section outlining guidelines for nutritional support in renal failure is from a manual that serves as a nutrition care guide for dietetics professionals, physicians, nurses, and other health professionals. The manual integrates current knowledge of nutrition, medical science, and food to set forth recommendations for healthy individuals and those for whom medical nutrition therapy (MNT) is indicated. The goal of nutrition support in renal failure is to achieve or maintain optimal nutritional status and preserve remaining kidney function through alterations in fluid, protein, and electrolyte intake. Nutrition support is used for patients with acute or chronic renal failure who are unable to meet nutrient requirements by oral intake. Impaired kidney function results in altered filtration, reabsorption, and excretion of metabolites and diminished urinary output. Hormonal function is also affected and

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may cause impaired vitamin D activation, impaired red blood cell synthesis, and glucose intolerance. The alterations differ with the cause of renal impairment; therefore, sodium, potassium, blood urea nitrogen (BUN), phosphate, urinary output, and the presence of acidosis must be monitored. The text notes the purpose, use, modifications, and adequacy of the diet. A separate section discusses enteral and parenteral nutrition, continuous arteriovenous hemofiltration, and the use of modified formulas (essential amino acids). 3 tables. 57 references. (AA-M). •

Use of Drugs in Uremia and Dialysis Source: in Suki, W.N.; Massry, S.G., eds. Therapy of Renal Diseases and Related Disorders, 2nd ed. Hingham, MA: Kluwer Academic Publishers. 1991. p. 853-865. Contact: Available from Kluwer Academic Publishers. P.O. Box 358, Accord Station, Hingham, MA 02018. (617) 871-6600. PRICE: $315. ISBN: 0792306767. Summary: To avoid toxicity from either parent drugs or active metabolites, the doses of many drugs must be adjusted downward in patients with decreased renal insufficiency. This chapter, from a medical text on the therapy of renal disease and related disorders, discusses the principles of drug dosing as a framework for dosing regimen adjustments in patients with renal insufficiency. The authors offer dosing guidelines for patients with various degrees of renal dysfunction, including dialysis. 2 figures. 4 tables. 23 references.

Directories In addition to the references and resources discussed earlier in this chapter, a number of directories relating to metabolites have been published that consolidate information across various sources. The Combined Health Information Database lists the following, which you may wish to consult in your local medical library:10 •

Dietary Supplements Resource List Source: Beltsville, MD: Food and Nutrition Information Center. 2000. 10 p. Contact: Available from Food and Nutrition Information Center. National Agricultural Library, U.S. Department of Agriculture, 10301 Baltimore Avenue, Room 304, Beltsville, MD 20705-2351. INTERNATIONAL: (301) 504-5719; TTY: (301) 504-6856; FAX: (301) 5046409; E-MAIL: [email protected]. PRICE: Free. Summary: This resource list, compiled by the National Agriculture Library, contains sources of information on the uses and risks of dietary supplements. The resources selected cover nutrition information on phytochemicals, vitamins, minerals, herbs,

10

You will need to limit your search to “Directory” and “metabolites” using the "Detailed Search" option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find directories, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Select your preferred language and the format option “Directory.” Type “metabolites” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months.

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botanicals, and other plant-derived substances; melatonin; amino acids; fatty acids; concentrates; and metabolites. Resources are listed in alphabetical order under the following headings: books, magazines/newsletters, and resources including web sites on the Internet. Contact information is provided for web sites and organizations.

225

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

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

Soy metabolite shows novel anti-androgen effects in rats Source: Reuters Medical News Date: April 14, 2004

•

Oral prednisone reduces exhaled inflammatory metabolites in asthmatic children Source: Reuters Medical News Date: June 23, 2003

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•

Progesterone metabolite reduces risk of preterm delivery in high-risk women Source: Reuters Medical News Date: June 11, 2003

•

Nicotine metabolite increases plasma levels of chemicals involved in aging Source: Reuters Medical News Date: October 31, 2002

•

Active nelfinavir metabolite present in plasma of treated HIV patients Source: Reuters Industry Breifing Date: April 09, 2001 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 “metabolites” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “metabolites” (or synonyms). If you know the name of a company that is relevant to metabolites, 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/.

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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 “metabolites” (or synonyms).

Academic Periodicals covering Metabolites Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to metabolites. In addition to these sources, you can search for articles covering metabolites 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 metabolites. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the U.S. Pharmacopeia (USP). Today, the USP is a nonprofit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at http://www.usp.org/. The USP currently provides standards for over 3,700 medications. The resulting USP DI Advice for the Patient can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration’s (FDA) Drug Approvals database, located at http://www.fda.gov/cder/da/da.htm. While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopeia (USP). Below, we have compiled a list of medications associated with metabolites. If you would like more information on a particular medication, the provided hyperlinks will direct you to ample documentation (e.g. typical dosage, side effects, drug-interaction risks, etc.). The

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following drugs have been mentioned in the Pharmacopeia and other sources as being potentially applicable to metabolites: Capecitabine •

Systemic - U.S. Brands: Xeloda http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203548.html

Cladribine •

Systemic - U.S. Brands: Leustatin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202699.html

Cytarabine •

Systemic - U.S. Brands: Cytosar-U http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202177.html

Floxuridine •

Systemic - U.S. Brands: FUDR http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202241.html

Fludarabine •

Systemic - U.S. Brands: Fludara http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202630.html

Fluorouracil •

Systemic - U.S. Brands: Adrucil http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202245.html

•

Topical - U.S. Brands: Efudex; Fluoroplex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202246.html

Gemcitabine •

Systemic - U.S. Brands: Gemzar http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203038.html

Hydroxyurea •

Systemic - U.S. Brands: Droxia; Hydrea http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202291.html

Mercaptopurine •

Systemic - U.S. Brands: Purinethol http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202350.html

Methotrexate For Noncancerous Conditions •

Systemic - U.S. Brands: Folex; Folex PFS; Methotrexate LPF; Rheumatrex http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202356.html

Pentostatin •

Systemic - U.S. Brands: Nipent http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202650.html

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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.

233

APPENDICES

235

APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

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/

11

These publications are typically written by one or more of the various NIH Institutes.

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•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

•

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.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

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

12

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.

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•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “metabolites” (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 108459 261 227 186 1891 111024

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.18 Simply search by “metabolites” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

14

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

15

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

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Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

19 Adapted 20

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

241

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 metabolites 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 metabolites. 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 metabolites. 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 “metabolites”:

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Dietary Supplements http://www.nlm.nih.gov/medlineplus/dietarysupplements.html Environmental Health http://www.nlm.nih.gov/medlineplus/environmentalhealth.html Genetic Brain Disorders http://www.nlm.nih.gov/medlineplus/geneticbraindisorders.html Heart Failure http://www.nlm.nih.gov/medlineplus/heartfailure.html Leukodystrophies http://www.nlm.nih.gov/medlineplus/leukodystrophies.html Medicines http://www.nlm.nih.gov/medlineplus/medicines.html Metabolic Disorders http://www.nlm.nih.gov/medlineplus/metabolicdisorders.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 metabolites. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

•

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

•

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

•

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

Patient Resources

•

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 metabolites. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with metabolites. 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 metabolites. 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 “metabolites” (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 “metabolites”. 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

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option “Organization Resource Sheet.” Type “metabolites” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “metabolites” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.22

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

22

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)23: •

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

•

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

•

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

•

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/

23

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries

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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/

Finding Medical Libraries

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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

•

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

•

Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

•

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

•

Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

•

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

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

•

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

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

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

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

Basic Guidelines for Metabolites Metabolite Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002258.htm

•

Background Topics for Metabolites Metabolism Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002257.htm

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

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

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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

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

253

METABOLITES DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine: A dopaminergic neurotoxic compound which produces irreversible clinical, chemical, and pathological alterations that mimic those found in Parkinson disease. [NIH] Abacavir: A nucleoside analog reverse transcriptase inhibitor (NARTIs) developed by Glaxo Wellcome. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Abortion: 1. The premature expulsion from the uterus of the products of conception - of the embryo, or of a nonviable fetus. The four classic symptoms, usually present in each type of abortion, are uterine contractions, uterine haemorrhage, softening and dilatation of the cervix, and presentation or expulsion of all or part of the products of conception. 2. Premature stoppage of a natural or a pathological process. [EU] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetaminophen: Analgesic antipyretic derivative of acetanilide. It has weak antiinflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acidemia: Increased acidity of blood. [NIH] Acidity: The quality of being acid or sour; containing acid (hydrogen ions). [EU] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acoustic: Having to do with sound or hearing. [NIH] 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

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criteria for AIDS as defined by the CDC in 1993. [NIH] Acrylamide: A colorless, odorless, highly water soluble vinyl monomer formed from the hydration of acrylonitrile. It is primarily used in research laboratories for electrophoresis, chromatography, and electron microscopy and in the sewage and wastewater treatment industries. [NIH] Acrylonitrile: A highly poisonous compound used widely in the manufacture of plastics, adhesives and synthetic rubber. [NIH] Actin: Essential component of the cell skeleton. [NIH] Action Potentials: The electric response of a nerve or muscle to its stimulation. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [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] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Acylation: The addition of an organic acid radical into a molecule. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adduct: Complex formed when a carcinogen combines with DNA or a protein. [NIH] Adduction: The rotation of an eye toward the midline (nasally). [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA

Dictionary 255

and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Deaminase: An enzyme that catalyzes the hydrolysis of adenosine to inosine with the elimination of ammonia. Since there are wide tissue and species variations in the enzyme, it has been used as a tool in the study of human and animal genetics and in medical diagnosis. EC 3.5.4.4. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [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] Adjuvant Therapy: Treatment given after the primary treatment to increase the chances of a cure. Adjuvant therapy may include chemotherapy, radiation therapy, or hormone therapy. [NIH]

Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adsorption: The condensation of gases, liquids, or dissolved substances on the surfaces of solids. It includes adsorptive phenomena of bacteria and viruses as well as of tissues treated with exogenous drugs and chemicals. [NIH] Adsorptive: It captures volatile compounds by binding them to agents such as activated carbon or adsorptive resins. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

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

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stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Affinity Chromatography: In affinity chromatography, a ligand attached to a column binds specifically to the molecule to be purified. [NIH] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [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] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Airway Resistance: Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. [NIH] Alanine: A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldehyde Dehydrogenase: An enzyme that oxidizes an aldehyde in the presence of NAD+ and water to an acid and NADH. EC 1.2.1.3. Before 1978, it was classified as EC 1.1.1.70. [NIH]

Aldehydes: Organic compounds containing a carbonyl group in the form -CHO. [NIH] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [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]

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Alkylate: To treat with an alkylating agent. [EU] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]

Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. [NIH] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] 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] 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] Amebiasis: Infection with any of various amebae. It is an asymptomatic carrier state in most individuals, but diseases ranging from chronic, mild diarrhea to fulminant dysentery may occur. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino acid: 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] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnesia: Lack or loss of memory; inability to remember past experiences. [EU] Amnestic: Nominal aphasia; a difficulty in finding the right name for an object. [NIH]

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Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [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] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Amylase: An enzyme that helps the body digest starches. [NIH] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [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] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analytes: A component of a test sample the presence of which has to be demonstrated. The term "analyte" includes where appropriate formed from the analyte during the analyses. [NIH]

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] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgen-Binding Protein: Carrier proteins produced in the Sertoli cells of the testis, secreted into the seminiferous tubules, and transported via the efferent ducts to the epididymis. They participate in the transport of androgens. Androgen-binding protein has the same amino acid sequence as sex hormone binding-globulin. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Androgenic: Producing masculine characteristics. [EU] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance

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of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angiogenesis inhibitor: A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue to a solid tumor. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [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] Ankle: That part of the lower limb directly above the foot. [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] Anthelmintic: An agent that is destructive to worms. [EU] Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [NIH] Antiandrogens: Drugs used to block the production or interfere with the action of male sex hormones. [NIH] Antiangiogenesis: Prevention of the growth of new blood vessels. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH]

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Metabolites

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] Antidiabetic: An agent that prevents or alleviates diabetes. [EU] Antiepileptic: An agent that combats epilepsy. [EU] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] 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] Anti-infective: An agent that so acts. [EU] Anti-Infective Agents: Substances that prevent infectious agents or organisms from spreading or kill infectious agents in order to prevent the spread of infection. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimetastatic: Having to do with reducing inflammation. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antimycotic: Suppressing the growth of fungi. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]

Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiphlogistic: An agent that counteracts inflammation and fever. [EU] Antipruritic: Relieving or preventing itching. [EU] Antipsychotic: Effective in the treatment of psychosis. Antipsychotic drugs (called also neuroleptic drugs and major tranquilizers) are a chemically diverse (including phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines, and diphenylbutylpiperidines) but pharmacologically similar class of drugs used to treat schizophrenic, paranoid, schizoaffective, and other psychotic disorders; acute delirium and dementia, and manic episodes (during induction of lithium therapy); to control the

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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] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU] Antispasmodic: An agent that relieves spasm. [EU] Antitumour: Counteracting tumour formation. [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] Aorta: The main trunk of the systemic arteries. [NIH] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [NIH]

Apnea: A transient absence of spontaneous respiration. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Appetite Stimulants: Agents that are used to stimulate appetite. These drugs are frequently used to treat anorexia associated with cancer and AIDS. [NIH] Aqueous: Having to do with water. [NIH] Aqueous humor: Clear, watery fluid that flows between and nourishes the lens and the cornea; secreted by the ciliary processes. [NIH] Arachidonate 12-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in platelets. EC 1.13.11.31. [NIH] Arachidonate 15-Lipoxygenase: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in neutrophils and lymphocytes. EC 1.13.11.33. [NIH] Arachidonate Lipoxygenases: Enzymes catalyzing the oxidation of arachidonic acid to

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Metabolites

hydroperoxyarachidonates (HPETES). These products are then rapidly converted by a peroxidase to hydroxyeicosatetraenoic acids (HETES). The positional specificity of the enzyme reaction varies from tissue to tissue. The final lipoxygenase pathway leads to the leukotrienes. EC 1.13.11.- . [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arsenic trioxide: An anticancer drug that induces programmed cell death (apoptosis) in certain cancer cells. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriovenous: Both arterial and venous; pertaining to or affecting an artery and a vein. [EU] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Ascites: Accumulation or retention of free fluid within the peritoneal cavity. [NIH] Ascitic Fluid: The serous fluid which accumulates in the peritoneal cavity in ascites. [NIH] Ascorbic Acid: A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. [NIH] Aseptic: Free from infection or septic material; sterile. [EU] Aspartate: A synthetic amino acid. [NIH] Aspartic: The naturally occurring substance is L-aspartic acid. One of the acidic-amino-acids is obtained by the hydrolysis of proteins. [NIH] Aspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. [NIH] Aspergillosis: Infections with fungi of the genus Aspergillus. [NIH]

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Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Astringent: Causing contraction, usually locally after topical application. [EU] Astrocytes: The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood. [NIH] Atmospheric Pressure: The pressure at any point in an atmosphere due solely to the weight of the atmospheric gases above the point concerned. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] ATP: ATP an abbreviation for adenosine triphosphate, a compound which serves as a carrier of energy for cells. [NIH] Atrial: Pertaining to an atrium. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [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]

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Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Bacterial Physiology: Physiological processes and activities of bacteria. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Bacteriuria: The presence of bacteria in the urine with or without consequent urinary tract infection. Since bacteriuria is a clinical entity, the term does not preclude the use of urine/microbiology for technical discussions on the isolation and segregation of bacteria in the urine. [NIH] Barbiturate: A drug with sedative and hypnotic effects. Barbiturates have been used as sedatives and anesthetics, and they have been used to treat the convulsions associated with epilepsy. [NIH] Basal cell carcinoma: A type of skin cancer that arises from the basal cells, small round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Basal cells: Small, round cells found in the lower part (or base) of the epidermis, the outer layer of the skin. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basidiomycete: A major group of fungi whose diagnostic characteristic is the basidium; includes the rusts, "bracket" fungi, and toadstools. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign tumor: A noncancerous growth that does not invade nearby tissue or spread to other parts of the body. [NIH] Benzamides: Benzoic acid amides. [NIH] Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Benzo(a)pyrene: A potent mutagen and carcinogen. It is a public health concern because of its possible effects on industrial workers, as an environmental pollutant, an as a component

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of tobacco smoke. [NIH] Benzodiazepines: A two-ring heterocyclic compound consisting of a benzene ring fused to a diazepine ring. Permitted is any degree of hydrogenation, any substituents and any Hisomer. [NIH] Beta Rays: A stream of positive or negative electrons ejected with high energy from a disintegrating atomic nucleus; most biomedically used isotopes emit negative particles (electrons or negatrons, rather than positrons). Cathode rays are low-energy negative electrons produced in cathode ray tubes, also called television tubes or oscilloscopes. [NIH] Beta-Glucosidase: An enzyme that catalyzes the hydrolysis of terminal non-reducing residues in beta-D-glucosides with release of beta-glucose. EC 3.2.1.21. [NIH] Betahistine: N-Methyl-2-pyridineethanamine. A physiological histamine analog vasodilator agent that also acts as a histamine H1 receptor agonist. It is used in Meniere's disease and in vascular headaches but may exacerbate bronchial asthma and peptic ulcers. [NIH] Beta-Thromboglobulin: A platelet-specific protein which is released when platelets aggregate. Elevated plasma levels have been reported after deep venous thrombosis, preeclampsia, myocardial infarction with mural thrombosis, and myeloproliferative disorders. Measurement of beta-thromboglobulin in biological fluids by radioimmunoassay is used for the diagnosis and assessment of progress of thromboembolic disorders. [NIH] Bewilderment: Impairment or loss of will power. [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] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Bile Pigments: Pigments that give a characteristic color to bile including: bilirubin, biliverdine, and bilicyanin. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biochemical reactions: In living cells, chemical reactions that help sustain life and allow cells to grow. [NIH] Biodegradation: The series of processes by which living organisms degrade pollutant chemicals, organic wastes, pesticides, and implantable materials. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some

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cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] 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] Biomass: Total mass of all the organisms of a given type and/or in a given area. (From Concise Dictionary of Biology, 1990) It includes the yield of vegetative mass produced from any given crop. [NIH] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH] Biopolymers: Polymers, such as proteins, DNA, RNA, or polysaccharides formed by any living organism. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotic: Pertaining to living organisms in their ecological rather than their physiological relations. [NIH] Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alteration may be either nonsynthetic (oxidation-reduction, hydrolysis) or synthetic (glucuronide formation, sulfate conjugation, acetylation, methylation). This also includes metabolic detoxication and clearance. [NIH] Bladder: The organ that stores urine. [NIH] Blastomycosis: A fungal infection that may appear in two forms: 1) a primary lesion characterized by the formation of a small cutaneous nodule and small nodules along the lymphatics that may heal within several months; and 2) chronic granulomatous lesions characterized by thick crusts, warty growths, and unusual vascularity and infection in the middle or upper lobes of the lung. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example,

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in the forearm. [NIH] Blood urea: A waste product in the blood that comes from the breakdown of food protein. The kidneys filter blood to remove urea. As kidney function decreases, the BUN level increases. [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] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Cells: Cells contained in the bone marrow including fat cells, stromal cells, megakaryocytes, and the immediate precursors of most blood cells. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [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] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [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] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [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 Diseases: Pathologic conditions affecting the brain, which is composed of the intracranial components of the central nervous system. This includes (but is not limited to) the cerebral cortex; intracranial white matter; basal ganglia; thalamus; hypothalamus; brain stem; and cerebellum. [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] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU]

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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] Bronchial Hyperreactivity: Tendency of the smooth muscle of the tracheobronchial tree to contract more intensely in response to a given stimulus than it does in the response seen in normal individuals. This condition is present in virtually all symptomatic patients with asthma. The most prominent manifestation of this smooth muscle contraction is a decrease in airway caliber that can be readily measured in the pulmonary function laboratory. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Bronchus: A large air passage that leads from the trachea (windpipe) to the lung. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bupivacaine: A widely used local anesthetic agent. [NIH] Buprenorphine: A derivative of the opioid alkaloid thebaine that is a more potent and 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] Butylated Hydroxytoluene: Antioxidant used in foods, cosmetics, petroleum products, etc. It may inhibit some neoplasms and facilitate others. [NIH] Butyric Acid: A four carbon acid, CH3CH2CH2COOH, with an unpleasant odor that occurs in butter and animal fat as the glycerol ester. [NIH] Caco-2 Cells: Human colonic adenocarcinoma cells that are able to express differentiation features characteristic of mature intestinal cells, such as enterocytes or mucus cells. These cells are valuable in vitro tools for studies related to intestinal cell function and differentiation. [NIH] Cadaverine: A foul-smelling diamine formed by bacterial decarboxylation of lysine. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcineurin: A calcium- and calmodulin-binding protein present in highest concentrations in the central nervous system. Calcineurin is composed of two subunits. A catalytic subunit, calcineurin A, and a regulatory subunit, calcineurin B, with molecular weights of about 60

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kD and 19 kD, respectively. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including histones, myosin light chain, and the regulatory subunit of cAMP-dependent protein kinase. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes in T-lymphocytes that act by inhibiting T-cell activation. EC 3.1.3.-. [NIH] Calcitonin: A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. [NIH] Calcitonin Gene-Related Peptide: Calcitonin gene-related peptide. A 37-amino acid peptide derived from the calcitonin gene. It occurs as a result of alternative processing of mRNA from the calcitonin gene. The neuropeptide is widely distributed in neural tissue of the brain, gut, perivascular nerves, and other tissue. The peptide produces multiple biological effects and has both circulatory and neurotransmitter modes of action. In particular, it is a potent endogenous vasodilator. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Caloric intake: Refers to the number of calories (energy content) consumed. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Cannula: A tube for insertion into a duct or cavity; during insertion its lumen is usually occupied by a trocar. [EU] Capecitabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH]

Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Fragility: The lack of resistance, or susceptibility, of capillaries to damage or disruption under conditions of increased stress. [NIH] Capsaicin: Cytotoxic alkaloid from various species of Capsicum (pepper, paprika), of the Solanaceae. [NIH]

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Metabolites

Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboxy: Cannabinoid. [NIH] Carboxylic Acids: Organic compounds containing the carboxy group (-COOH). This group of compounds includes amino acids and fatty acids. Carboxylic acids can be saturated, unsaturated, or aromatic. [NIH] Carcinoembryonic Antigen: A glycoprotein that is secreted into the luminal surface of the epithelia in the gastrointestinal tract. It is found in the feces and pancreaticobiliary secretions and is used to monitor the respone to colon cancer treatment. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogenicity: The ability to cause cancer. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Carcinoma in Situ: A malignant tumor that has not yet invaded the basement membrane of the epithelial cell of origin and has not spread to other tissues. [NIH] Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiotoxic: Having a poisonous or deleterious effect upon the heart. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Carotenoids: Substance found in yellow and orange fruits and vegetables and in dark green, leafy vegetables. May reduce the risk of developing cancer. [NIH]

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Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Case report: A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin). [NIH] Case series: A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment. [NIH] Case-Control Studies: Studies which start with the identification of persons with a disease of interest and a control (comparison, referent) group without the disease. The relationship of an attribute to the disease is examined by comparing diseased and non-diseased persons with regard to the frequency or levels of the attribute in each group. [NIH] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Castration: Surgical removal or artificial destruction of gonads. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catechin: Extracted from Uncaria gambier, Acacia catechu and other plants; it stabilizes collagen and is therefore used in tanning and dyeing; it prevents capillary fragility and abnormal permeability, but was formerly used as an antidiarrheal. [NIH] Catechol: A chemical originally isolated from a type of mimosa tree. Catechol is used as an astringent, an antiseptic, and in photography, electroplating, and making other chemicals. It can also be man-made. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Cathode: An electrode, usually an incandescent filament of tungsten, which emits electrons in an X-ray tube. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Celecoxib: A drug that reduces pain. Celecoxib belongs to the family of drugs called

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nonsteroidal anti-inflammatory agents. It is being studied for cancer prevention. [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 Adhesion: Adherence of cells to surfaces or to other cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] 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] Cellular metabolism: The sum of all chemical changes that take place in a cell through which energy and basic components are provided for essential processes, including the synthesis of new molecules and the breakdown and removal of others. [NIH] Cellulose: A polysaccharide with glucose units linked as in cellobiose. It is the chief constituent of plant fibers, cotton being the purest natural form of the substance. As a raw material, it forms the basis for many derivatives used in chromatography, ion exchange materials, explosives manufacturing, and pharmaceutical preparations. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Central Nervous System Infections: Pathogenic infections of the brain, spinal cord, and meninges. DNA virus infections; RNA virus infections; bacterial infections; mycoplasma infections; Spirochaetales infections; fungal infections; protozoan infections; helminthiasis; and prion diseases may involve the central nervous system as a primary or secondary process. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebellum: Part of the metencephalon that lies in the posterior cranial fossa behind the brain stem. It is concerned with the coordination of movement. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU]

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Cerebral Arteries: The arteries supplying the cerebral cortex. [NIH] 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] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Cervical: Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck; cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the "neck") of the uterus. [NIH] Cervix: The lower, narrow end of the uterus that forms a canal between the uterus and vagina. [NIH] Chemical Warfare: Tactical warfare using incendiary mixtures, smokes, or irritant, burning, or asphyxiating gases. [NIH] Chemical Warfare Agents: Chemicals that are used to cause the disturbance, disease, or death of humans during war. [NIH] Chemoprevention: The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapeutics: Noun plural but singular or plural in constructions : chemotherapy. [EU]

Chemotherapy: Treatment with anticancer drugs. [NIH] Chimaera: Organism that contains a mixture of genetically different cells. [NIH] Chimera: An individual that contains cell populations derived from different zygotes. [NIH] Chloral Hydrate: A hypnotic and sedative used in the treatment of insomnia. The safety margin is too narrow for chloral hydrate to be used as a general anesthetic in humans, but it is commonly used for that purpose in animal experiments. It is no longer considered useful as an anti-anxiety medication. [NIH] Chloroform: A commonly used laboratory solvent. It was previously used as an anesthetic, but was banned from use in the U.S. due to its suspected carcinogenecity. [NIH] Chlorogenic Acid: A naturally occuring phenolic acid which is a carcinogenic inhibitor. It has also been shown to prevent paraquat-induced oxidative stress in rats. (From J Chromatogr A 1996;741(2):223-31; Biosci Biotechnol Biochem 1996;60(5):765-68). [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH]

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Metabolites

Chloroplasts: Plant cell inclusion bodies that contain the photosynthetic pigment chlorophyll, which is associated with the membrane of thylakoids. Chloroplasts occur in cells of leaves and young stems of higher plants. [NIH] Chloroquine: The prototypical antimalarial agent with a mechanism that is not well understood. It has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses. [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] Chondrocytes: Polymorphic cells that form cartilage. [NIH] Chondroitin sulfate: The major glycosaminoglycan (a type of sugar molecule) in cartilage. [NIH]

Choriocarcinoma: A malignant tumor of trophoblastic epithelium characterized by secretion of large amounts of chorionic gonadotropin. It usually originates from chorionic products of conception (i.e., hydatidiform mole, normal pregnancy, or following abortion), but can originate in a teratoma of the testis, mediastinum, or pineal gland. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Fatigue Syndrome: Fatigue caused by the combined effects of different types of prolonged fatigue. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Ciliary: Inflammation or infection of the glands of the margins of the eyelids. [NIH] Ciliary processes: The extensions or projections of the ciliary body that secrete aqueous humor. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by

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calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Clear cell carcinoma: A rare type of tumor of the female genital tract in which the inside of the cells looks clear when viewed under a microscope. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clone: The term "clone" has acquired a new meaning. It is applied specifically to the bits of inserted foreign DNA in the hybrid molecules of the population. Each inserted segment originally resided in the DNA of a complex genome amid millions of other DNA segment. [NIH]

Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clozapine: A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. [NIH] Coal Tar: A by-product of the destructive distillation of coal used as a topical antieczematic. It is an antipruritic and keratoplastic agent used also in the treatment of psoriasis and other skin conditions. Occupational exposure to soots, tars, and certain mineral oils is known to be carcinogenic according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985) (Merck Index, 11th ed). [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 mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. [NIH]

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Metabolites

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] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collagen disease: A term previously used to describe chronic diseases of the connective tissue (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. [NIH] Collagenases: Enzymes that catalyze the degradation of collagen by acting on the peptide bonds. EC 3.4.24.-. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Communis: Common tendon of the rectus group of muscles that surrounds the optic

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foramen and a portion of the superior orbital fissure, to the anterior margin of which it is attached at the spina recti lateralis. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Compulsions: In psychology, an irresistible urge, sometimes amounting to obsession to perform a particular act which usually is carried out against the performer's will or better judgment. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make 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] Computerized axial tomography: A series of detailed pictures of areas inside the body,

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Metabolites

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] Concentric: Having a common center of curvature or symmetry. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Cone: One of the special retinal receptor elements which are presumed to be primarily concerned with perception of light and color stimuli when the eye is adapted to light. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Conjunctivitis: Inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Connective Tissue Diseases: A heterogeneous group of disorders, some hereditary, others acquired, characterized by abnormal structure or function of one or more of the elements of connective tissue, i.e., collagen, elastin, or the mucopolysaccharides. [NIH] Connexins: A group of homologous proteins which form the intermembrane channels of gap junctions. The connexins are the products of an identified gene family which has both highly conserved and highly divergent regions. The variety contributes to the wide range of functional properties of gap junctions. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and

Dictionary 279

the proper method of treatment in a case. [NIH] Contact dermatitis: Inflammation of the skin with varying degrees of erythema, edema and vesinculation resulting from cutaneous contact with a foreign substance or other exposure. [NIH]

Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Continuous infusion: The administration of a fluid into a blood vessel, usually over a prolonged period of time. [NIH] Contractility: Capacity for becoming short in response to a suitable stimulus. [EU] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Conventional therapy: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment. [NIH] Conventional treatment: A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional therapy. [NIH] Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Disease: Disorder of cardiac function due to an imbalance between myocardial function and the capacity of the coronary vessels to supply sufficient flow for normal function. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Coronary Vessels: The veins and arteries of the heart. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the

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Metabolites

internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Cranial Nerves: Twelve pairs of nerves that carry general afferent, visceral afferent, special afferent, somatic efferent, and autonomic efferent fibers. [NIH] Craniocerebral Trauma: Traumatic injuries involving the cranium and intracranial structures (i.e., brain; cranial nerves; meninges; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage. [NIH] Creatine: An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. [NIH]

Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Croton Oil: Viscous, nauseating oil obtained from the shrub Croton tiglium (Euphorbaceae). It is a vesicant and skin irritant used as pharmacologic standard for skin inflammation and allergy and causes skin cancer. It was formerly used as an emetic and cathartic with frequent mortality. [NIH] Cruciferous vegetables: A family of vegetables that includes kale, collard greens, broccoli, cauliflower, cabbage, brussels sprouts, and turnip. These vegetables contain substances that may protect against cancer. [NIH] Cultured cell line: Cells of a single type that have been grown in the laboratory for several generations (cell divisions). [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curare: Plant extracts from several species, including Strychnos toxifera, S. castelnaei, S. crevauxii, and Chondodendron tomentosum, that produce paralysis of skeletal muscle and are used adjunctively with general anesthesia. These extracts are toxic and must be used with the administration of artificial respiration. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH] Cutaneous: Having to do with the skin. [NIH] Cyanobacteria: A subgroup of the oxygenic photosynthetic bacteria comprised of unicellular to multicellular photosynthetic bacteria possessing chlorophyll a and carrying out oxygenic photosynthesis. Cyanobacteria are the only known organisms capable of fixing both carbon dioxide (in the presence of light) and nitrogen. Formerly called blue-green algae, cyanobacteria were traditionally treated as algae. By the late 19th century, however, it was realized that the blue-green algae were unique and lacked the traditional nucleus and chloroplasts of the green and other algae. The comparison of nucleotide base sequence data

Dictionary 281

from 16S and 5S rRNA indicates that cyanobacteria represent a moderately deep phylogenetic unit within the gram-negative bacteria. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclins: Regulatory proteins that function in the cell cycle to activate maturation promoting factor. They complex with p34cdc2 (PROTEIN P34CDC2), the catalytic subunit of maturation-promoting factor, and modulate its protein kinase activity. Cyclins themselves have no enzymatic activity. [NIH] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] 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] Cyproterone: An anti-androgen that, in the form of its acetate, also has progestational properties. It is used in the treatment of hypersexuality in males, as a palliative in prostatic carcinoma, and, in combination with estrogen, for the therapy of severe acne and hirsutism in females. [NIH] Cystamine: A radiation-protective agent that interferes with sulfhydryl enzymes. It may also protect against carbon tetrachloride liver damage. [NIH] Cysteamine: A radiation-protective agent that oxidizes in air to form cystamine. It can be given intravenously or orally to treat radiation sickness. The bitartrate has been used for the oral treatment of nephropathic cystinosis. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cysteinyl: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cystitis: Inflammation of the urinary bladder. [EU] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it

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Metabolites

(phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]

Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxic chemotherapy: Anticancer drugs that kill cells, especially cancer cells. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Dacarbazine: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]

Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] 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] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal

Dictionary 283

of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Dermal: Pertaining to or coming from the skin. [NIH] Dermatitis: Any inflammation of the skin. [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] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [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] Dextromethorphan: The d-isomer of the codeine analog of levorphanol. Dextromethorphan shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is a NMDA receptor antagonist (receptors, N-methyl-D-aspartate) and acts as a non-competitive channel blocker. It is used widely as an antitussive agent, and is also used to study the involvement of glutamate receptors in neurotoxicity. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Ketoacidosis: Complication of diabetes resulting from severe insulin deficiency coupled with an absolute or relative increase in glucagon concentration. The metabolic acidosis is caused by the breakdown of adipose stores and resulting increased levels of free fatty acids. Glucagon accelerates the oxidation of the free fatty acids producing excess ketone bodies (ketosis). [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialysate: A cleansing liquid used in the two major forms of dialysis--hemodialysis and peritoneal dialysis. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU]

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Metabolites

Dichloroacetate: A derivative of acetic acid which increases the activity of pyruvate dehydrogenase and rate of lipogenesis. It is used in organic synthesis, pharmaceuticals, and medicine. [NIH] Diclofenac: A non-steroidal anti-inflammatory agent (NSAID) with antipyretic and analgesic actions. It is primarily available as the sodium salt, diclofenac sodium. [NIH] Diclofenac Sodium: The sodium form of diclofenac. It is used for its analgesic and antiinflammatory properties. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Dietetics: The study and regulation of the diet. [NIH] Diethylstilbestrol: DES. 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] 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] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilate: Relax; expand. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilator: A device used to stretch or enlarge an opening. [NIH] 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] Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Dipeptidases: Exopeptidases that specifically act on dipeptides. EC 3.4.13. [NIH] Dipeptides: Peptides composed of two amino acid units. [NIH] Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discriminant Analysis: A statistical analytic technique used with discrete dependent variables, concerned with separating sets of observed values and allocating new values. It is sometimes used instead of regression analysis. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or

Dictionary 285

more stimuli. [NIH] Disease Transmission: The transmission of infectious disease or pathogens. When transmission is within the same species, the mode can be horizontal (disease transmission, horizontal) or vertical (disease transmission, vertical). [NIH] Disease Transmission, Horizontal: The transmission of infectious disease or pathogens from one individual to another in the same generation. [NIH] Disease Transmission, Vertical: The transmission of infectious disease or pathogens from one generation to another. It includes transmission in utero or intrapartum by exposure to blood and secretions, and postpartum exposure via breastfeeding. [NIH] Disease Vectors: Invertebrates or non-human vertebrates which transmit infective organisms from one host to another. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] 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] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Disulphide: A covalent bridge formed by the oxidation of two cysteine residues to a cystine residue. The-S-S-bond is very strong and its presence confers additional stability. [NIH] Diuresis: Increased excretion of urine. [EU] Diuretic: A drug that increases the production of urine. [NIH] DNA Topoisomerase: An enzyme catalyzing ATP-independent breakage of single-stranded DNA, followed by passage and rejoining of another single-stranded DNA. This enzyme class brings about the conversion of one topological isomer of DNA into another, e.g., the relaxation of superhelical turns in DNA, the interconversion of simple and knotted rings of single-stranded DNA, and the intertwisting of single-stranded rings of complementary sequences. (From Enzyme Nomenclature, 1992) EC 5.99.1.2. [NIH] Dopamine: An endogenous catecholamine and prominent neurotransmitter in several systems of the brain. In the synthesis of catecholamines from tyrosine, it is the immediate precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of dopaminergic receptor subtypes mediate its action. Dopamine is used pharmacologically for its direct (beta adrenergic agonist) and indirect (adrenergic releasing) sympathomimetic effects including its actions as an inotropic agent and as a renal vasodilator. [NIH]

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Metabolites

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] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Dross: Residue remaining in an opium pipe which has been smoked; contains 50 % of the morphine present in the original drug. [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 Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyes: Chemical substances that are used to stain and color other materials. The coloring may or may not be permanent. Dyes can also be used as therapeutic agents and test reagents in medicine and scientific research. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eating Disorders: A group of disorders characterized by physiological and psychological disturbances in appetite or food intake. [NIH] Echocardiography: Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] 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] Egg Yolk: Cytoplasm stored in an egg that contains nutritional reserves for the developing embryo. It is rich in polysaccharides, lipids, and proteins. [NIH] Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that act near the site of synthesis without altering functions throughout the body. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Electrode: Component of the pacing system which is at the distal end of the lead. It is the interface with living cardiac tissue across which the stimulus is transmitted. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] 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] Electroplating: Coating with a metal or alloy by electrolysis. [NIH] Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Emaciation: Clinical manifestation of excessive leanness usually caused by disease or a lack of nutrition. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Embryo Transfer: Removal of a mammalian embryo from one environment and replacement in the same or a new environment. The embryo is usually in the pre-nidation phase, i.e., a blastocyst. The process includes embryo or blastocyst transplantation or transfer after in vitro fertilization and transfer of the inner cell mass of the blastocyst. It is not used for transfer of differentiated embryonic tissue, e.g., germ layer cells. [NIH] Emesis: Vomiting; an act of vomiting. Also used as a word termination, as in haematemesis. [EU]

Emollient: Softening or soothing; called also malactic. [EU] Empirical: A treatment based on an assumed diagnosis, prior to receiving confirmatory

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Metabolites

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] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] 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, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with

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the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancers: Transcriptional element in the virus genome. [NIH] Enkephalins: One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. [NIH] Enterocytes: Terminally differentiated cells comprising the majority of the external surface of the intestinal epithelium (see intestinal mucosa). Unlike goblet cells, they do not produce or secrete mucins, nor do they secrete cryptdins as do the paneth cells. [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]

Environmental Pollutants: Substances which pollute the environment. Use environmental pollutants in general or for which there is no specific heading. [NIH]

for

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Activation: Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1) activation by ions (activators); 2) activation by cofactors (coenzymes); and 3) conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophil: A polymorphonuclear leucocyte with large eosinophilic granules in its cytoplasm, which plays a role in hypersensitivity reactions. [NIH] 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] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] Epidermal Growth Factor: A 6 kD polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and epithelial cells. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidural: The space between the wall of the spinal canal and the covering of the spinal cord. An epidural injection is given into this space. [NIH]

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Metabolites

Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erectile: The inability to get or maintain an erection for satisfactory sexual intercourse. Also called impotence. [NIH] Erythema: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of causes. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythroleukemia: Cancer of the blood-forming tissues in which large numbers of immature, abnormal red blood cells are found in the blood and bone marrow. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen Antagonists: Compounds which inhibit or antagonize the action or biosynthesis of estrogen. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Estrogen receptor negative: ER-. Breast cancer cells that do not have a protein (receptor molecule) to which estrogen will attach. Breast cancer cells that are ER- do not need the hormone estrogen to grow and usually do not respond to hormone (antiestrogen) therapy that blocks these receptor sites. [NIH] Estrogen receptor positive: ER+. Breast cancer cells that have a protein (receptor molecule) to which estrogen will attach. Breast cancer cells that are ER+ need the hormone estrogen to grow and will usually respond to hormone (antiestrogen) therapy that blocks these receptor sites. [NIH] Estrone: 3-Hydroxyestra-1,3,5(10)-trien-17-one. A metabolite of estradiol but possessing less biological activity. It is found in the urine of pregnant women and mares, in the human placenta, and in the urine of bulls and stallions. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), estrone may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [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

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as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Ethylene Glycol: A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins. [NIH]

Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [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] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH] Excitatory Amino Acid Agonists: Drugs that bind to and activate excitatory amino acid receptors. [NIH] Exercise Test: Controlled physical activity, more strenuous than at rest, which is performed in order to allow assessment of physiological functions, particularly cardiovascular and pulmonary, but also aerobic capacity. Maximal (most intense) exercise is usually required but submaximal exercise is also used. The intensity of exercise is often graded, using criteria such as rate of work done, oxygen consumption, and heart rate. Physiological data obtained from an exercise test may be used for diagnosis, prognosis, and evaluation of disease severity, and to evaluate therapy. Data may also be used in prescribing exercise by determining a person's exercise capacity. [NIH] Exercise Tolerance: The exercise capacity of an individual as measured by endurance (maximal exercise duration and/or maximal attained work load) during an exercise test. [NIH]

Exhaustion: The feeling of weariness of mind and body. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expectorant: 1. Promoting the ejection, by spitting, of mucus or other fluids from the lungs and trachea. 2. An agent that promotes the ejection of mucus or exudate from the lungs, bronchi, and trachea; sometimes extended to all remedies that quiet cough (antitussives). [EU]

Expiration: The act of breathing out, or expelling air from the lungs. [EU]

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Metabolites

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 Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Matrix Proteins: Macromolecular organic compounds that contain carbon, hydrogen, oxygen, nitrogen, and usually, sulfur. These macromolecules (proteins) form an intricate meshwork in which cells are embedded to construct tissues. Variations in the relative types of macromolecules and their organization determine the type of extracellular matrix, each adapted to the functional requirements of the tissue. The two main classes of macromolecules that form the extracellular matrix are: glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen, elastin, fibronectins and laminin). [NIH] 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] Extravascular: Situated or occurring outside a vessel or the vessels. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fascioliasis: Helminth infection of the liver caused by species of Fasciola. [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fermentation: An enzyme-induced chemical change in organic compounds that takes place in the absence of oxygen. The change usually results in the production of ethanol or lactic acid, and the production of energy. [NIH] Fertilization in Vitro: Fertilization of an egg outside the body when the egg is normally fertilized in the body. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH]

Dictionary 293

Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibroblast Growth Factor: Peptide isolated from the pituitary gland and from the brain. It is a potent mitogen which stimulates growth of a variety of mesodermal cells including chondrocytes, granulosa, and endothelial cells. The peptide may be active in wound healing and animal limb regeneration. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] 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] Flatus: Gas passed through the rectum. [NIH] Flavoring Agents: Substances added to foods and medicine to improve the quality of taste. [NIH]

Fluid Therapy: Therapy whose basic objective is to restore the volume and composition of the body fluids to normal with respect to water-electrolyte balance. Fluids may be administered intravenously, orally, by intermittent gavage, or by hypodermoclysis. [NIH] Fluorescence: The property of emitting radiation while being irradiated. The radiation emitted is usually of longer wavelength than that incident or absorbed, e.g., a substance can be irradiated with invisible radiation and emit visible light. X-ray fluorescence is used in diagnosis. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Flutamide: An antiandrogen with about the same potency as cyproterone in rodent and canine species. [NIH] Fluvoxamine: A selective serotonin reuptake inhibitor. It is effective in the treatment of depression, obsessive-compulsive disorders, anxiety, panic disorders, and alcohol amnestic disorders. [NIH] 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] Food Additives: Substances which are of little or no nutritive value, but are used in the processing or storage of foods or animal feed, especially in the developed countries; includes antioxidants, food preservatives, food coloring agents, flavoring agents, anti-infective agents (both plain and local), vehicles, excipients and other similarly used substances. Many of the same substances are pharmaceutic aids when added to pharmaceuticals rather than to foods. [NIH]

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Metabolites

Food Coloring Agents: Natural or synthetic dyes used as coloring agents in processed foods. [NIH] Food Preservatives: Substances capable of inhibiting, retarding or arresting the process of fermentation, acidification or other deterioration of foods. [NIH] Foramen: A natural hole of perforation, especially one in a bone. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fossa: A cavity, depression, or pit. [NIH] Fractionation: Dividing the total dose of radiation therapy into several smaller, equal doses delivered over a period of several days. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] Friction: Surface resistance to the relative motion of one body against the rubbing, sliding, rolling, or flowing of another with which it is in contact. [NIH] Fungi: A kingdom of eukaryotic, heterotrophic organisms that live as saprobes or parasites, including mushrooms, yeasts, smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi refer to those that grow as multicelluar colonies (mushrooms and molds). [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Galactitol: A naturally occurring product of plants obtained following reduction of galactose. It appears as a white crystalline powder with a slight sweet taste. It may form in excess in the lens of the eye in galactosemia, a deficiency of galactokinase. [NIH] Galactokinase: An enzyme that catalyzes reversibly the formation of galactose 1-phosphate and ADP from ATP and D-galactose. Galactosamine can also act as the acceptor. A deficiency of this enzyme results in galactosemia. EC 2.7.1.6. [NIH] Galactosemia: Buildup of galactose in the blood. Caused by lack of one of the enzymes needed to break down galactose into glucose. [NIH] Gallate: Antioxidant present in tea. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of

Dictionary 295

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] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [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] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gelatinases: A class of enzymes that catalyzes the degradation of gelatin by acting on the peptide bonds. EC 3.4.24.-. [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] Gene Silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. [NIH] Gene Targeting: The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [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

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Metabolites

order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic Screening: Searching a population or individuals for persons possessing certain genotypes or karyotypes that: (1) are already associated with disease or predispose to disease; (2) may lead to disease in their descendants; or (3) produce other variations not known to be associated with disease. Genetic screening may be directed toward identifying phenotypic expression of genetic traits. It includes prenatal genetic screening. [NIH] Genetic Techniques: Chromosomal, biochemical, intracellular, and other methods used in the study of genetics. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genistein: An isoflavonoid derived from soy products. It inhibits protein-tyrosine kinase and topoisomerase-ii (dna topoisomerase (atp-hydrolysing)) activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 phase arrest in human and murine cell lines. [NIH] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational trophoblastic disease: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic tumor, gestational trophoblastic neoplasia, molar pregnancy, or choriocarcinoma. [NIH] Gestational trophoblastic neoplasia: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic disease, gestational trophoblastic tumor, molar pregnancy, or choriocarcinoma. [NIH] Gestational trophoblastic tumor: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic disease, gestational trophoblastic neoplasia, molar pregnancy, or choriocarcinoma. [NIH] Giardiasis: An infection of the small intestine caused by the flagellated protozoan Giardia lamblia. It is spread via contaminated food and water and by direct person-to-person contact. [NIH] Ginseng: An araliaceous genus of plants that contains a number of pharmacologically active agents used as stimulants, sedatives, and tonics, especially in traditional medicine. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glioma: A cancer of the brain that comes from glial, or supportive, cells. [NIH]

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Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomeruli: Plural of glomerulus. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]

Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glucosylceramides: Cerebrosides which contain as their polar head group a glucose moiety bound in glycosidic linkage to the hydroxyl group of ceramides. Their accumulation in tissue, due to a defect in beta-glucosidase, is the cause of Gaucher's disease. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glucuronides: Glycosides of glucuronic acid formed by the reaction of uridine diphosphate glucuronic acid with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and bilirubin metabolism to a more water-soluble compound that can be eliminated in the urine and bile. [NIH] Glucuronosyltransferase: A family of enzymes accepting a wide range of substrates, including phenols, alcohols, amines, and fatty acids. They function as drug-metabolizing enzymes that catalyze the conjugation of UDPglucuronic acid to a variety of endogenous and exogenous compounds. EC 2.4.1.17. [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

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Metabolites

the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosaminoglycan: A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye. [NIH] Glycoside: Any compound that contains a carbohydrate molecule (sugar), particularly any such natural product in plants, convertible, by hydrolytic cleavage, into sugar and a nonsugar component (aglycone), and named specifically for the sugar contained, as glucoside (glucose), pentoside (pentose), fructoside (fructose) etc. [EU] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosyltransferases: Enzymes that catalyze the transfer of glycosyl groups to an acceptor. Most often another carbohydrate molecule acts as an acceptor, but inorganic phosphate can also act as an acceptor, such as in the case of phosphorylases. Some of the enzymes in this group also catalyze hydrolysis, which can be regarded as transfer of a glycosyl group from the donor to water. Subclasses include the hexosyltransferases, pentosyltransferases, sialyltransferases, and those transferring other glycosyl groups. EC 2.4. [NIH] Goats: Any of numerous agile, hollow-horned ruminants of the genus Capra, closely related to the sheep. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadotropic: Stimulating the gonads; applied to hormones of the anterior pituitary which influence the gonads. [EU] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Gp120: 120-kD HIV envelope glycoprotein which is involved in the binding of the virus to its membrane receptor, the CD4 molecule, found on the surface of certain cells in the body. [NIH]

Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are

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different for each type of cancer. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Gram-Negative Bacteria: Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. [NIH] Gram-positive: Retaining the stain or resisting decolorization by alcohol in Gram's method of staining, a primary characteristic of bacteria whose cell wall is composed of a thick layer of peptidologlycan with attached teichoic acids. [EU] Gram-Positive Bacteria: Bacteria which retain the crystal violet stain when treated by Gram's method. [NIH] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granulocyte-Macrophage Colony-Stimulating Factor: An acidic glycoprotein of MW 23 kDa with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages. [NIH] Granulomas: Small lumps in tissues caused by inflammation. [NIH] Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [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] Haematemesis: The vomiting of blood. [EU] Haematoma: A localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel. [EU] Haemorrhage: The escape of blood from the vessels; bleeding. Small haemorrhages are classified according to size as petechiae (very small), purpura (up to 1 cm), and ecchymoses (larger). The massive accumulation of blood within a tissue is called a haematoma. [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] Halitosis: An offensive, foul breath odor resulting from a variety of causes such as poor oral hygiene, dental or oral infections, or the ingestion of certain foods. [NIH] Haloperidol: Butyrophenone derivative. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody

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response. [NIH] Hay Fever: A seasonal variety of allergic rhinitis, marked by acute conjunctivitis with lacrimation and itching, regarded as an allergic condition triggered by specific allergens. [NIH]

Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Headache Disorders: Common conditions characterized by persistent or recurrent headaches. Headache syndrome classification systems may be based on etiology (e.g., vascular headache, post-traumatic headaches, etc.), temporal pattern (e.g., cluster headache, paroxysmal hemicrania, etc.), and precipitating factors (e.g., cough headache). [NIH] Health Care Costs: The actual costs of providing services related to the delivery of health care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hematopoietic growth factors: A group of proteins that cause blood cells to grow and mature. [NIH] Hematopoietic tissue: Tissue in which new blood cells are formed. [NIH] Heme: The color-furnishing portion of hemoglobin. It is found free in tissues and as the prosthetic group in many hemeproteins. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemofiltration: Extracorporeal ultrafiltration technique without hemodialysis for treatment of fluid overload and electrolyte disturbances affecting renal, cardiac, or pulmonary function. [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] Hemoglobin A: Normal adult human hemoglobin. The globin moiety consists of two alpha

Dictionary 301

and two beta chains. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Hepatic: Refers to the liver. [NIH] Hepatic Encephalopathy: A condition that may cause loss of consciousness and coma. It is usually the result of advanced liver disease. Also called hepatic coma. [NIH] Hepatocellular: Pertaining to or affecting liver cells. [EU] Hepatocellular carcinoma: A type of adenocarcinoma, the most common type of liver tumor. [NIH] Hepatocyte: A liver cell. [NIH] Hepatorenal Syndrome: Renal failure in those with liver disease, usually liver cirrhosis or obstructive jaundice. Historically called Heyd disease, urohepatic syndrome, or bile nephrosis. [NIH] Hepatotoxic: Toxic to liver cells. [EU] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Herbicide: A chemical that kills plants. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes Zoster: Acute vesicular inflammation. [NIH] 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]

Heterotrophic: Pertaining to organisms that are consumers and dependent on other organisms for their source of energy (food). [NIH] Hexosyltransferases: Enzymes that catalyze the transfer of hexose groups. EC 2.4.1.-. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded

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Metabolites

structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] HIV: Human immunodeficiency virus. Species of lentivirus, subgenus primate lentiviruses, formerly designated T-cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). It is acknowledged to be the agent responsible for the acute infectious manifestations, neurologic disorders, and immunologic abnormalities linked to the acquired immunodeficiency syndrome. [NIH] HIV Protease: Enzyme of the human immunodeficiency virus that is required for posttranslational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. EC 3.4.23.- [NIH] HIV Protease Inhibitors: Inhibitors of HIV protease, an enzyme required for production of proteins needed for viral assembly. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydatidiform Mole: A trophoblastic disease characterized by hydrops of the mesenchymal portion of the villus. Its karyotype is paternal and usually homozygotic. The tumor is indistinguishable from chorioadenoma destruens or invasive mole ( = hydatidiform mole, invasive) except by karyotype. There is no apparent relation by karyotype to choriocarcinoma. Hydatidiform refers to the presence of the hydropic state of some or all of the villi (Greek hydatis, a drop of water). [NIH] Hydralazine: A direct-acting vasodilator that is used as an antihypertensive agent. [NIH] Hydration: Combining with water. [NIH] Hydrocephalus: Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial hypertension; headache; lethargy; urinary incontinence; and ataxia (and in infants macrocephaly). This condition may be caused by obstruction of cerebrospinal fluid pathways due to neurologic abnormalities, intracranial hemorrhages; central nervous system infections; brain neoplasms; craniocerebral trauma; and other conditions. Impaired resorption of cerebrospinal fluid from the arachnoid villi results in a communicating form of hydrocephalus. Hydrocephalus ex-vacuo refers to ventricular dilation that occurs as a result of brain substance loss from cerebral infarction and other conditions. [NIH]

Dictionary 303

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] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrogenation: Specific method of reduction in which hydrogen is added to a substance by the direct use of gaseous hydrogen. [NIH] Hydrolases: Any member of the class of enzymes that catalyze the cleavage of the substrate and the addition of water to the resulting molecules, e.g., esterases, glycosidases (glycoside hydrolases), lipases, nucleotidases, peptidases (peptide hydrolases), and phosphatases (phosphoric monoester hydrolases). EC 3. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxyeicosatetraenoic Acids: Eicosatetraenoic acids substituted in any position by one or more hydroxy groups. They are important intermediates in a series of biosynthetic processes leading from arachidonic acid to a number of biologically active compounds such as prostaglandins, thromboxanes, and leukotrienes. [NIH] Hydroxylamines: Organic compounds that contain the (-NH2OH) radical. [NIH] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hydroxysteroid Dehydrogenases: Enzymes of the oxidoreductase class that catalyze the dehydrogenation of hydroxysteroids. (From Enzyme Nomenclature, 1992) EC 1.1.-. [NIH] Hyperaemia: An excess of blood in a part; engorgement. [EU] Hyperbilirubinemia: Pathologic process consisting of an abnormal increase in the amount of bilirubin in the circulating blood, which may result in jaundice. [NIH] Hypercalcemia: Abnormally high level of calcium in the blood. [NIH] Hypercapnia: A clinical manifestation of abnormal increase in the amount of carbon dioxide in arterial blood. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hyperreflexia: Exaggeration of reflexes. [EU] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH]

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Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypotensive: Characterized by or causing diminished tension or pressure, as abnormally low blood pressure. [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] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Idoxifene: A drug that blocks the effects of estrogen. [NIH] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune function: Production and action of cells that fight disease or infection. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [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] Immunodeficiency syndrome: The inability of the body to produce an immune response. [NIH]

Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [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]

Dictionary 305

Immunophilin: A drug for the treatment of Parkinson's disease. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Incubation: The development of an infectious disease from the entrance of the pathogen to the appearance of clinical symptoms. [EU] Indigestion: Poor digestion. Symptoms include heartburn, nausea, bloating, and gas. Also called dyspepsia. [NIH] Indinavir: A potent and specific HIV protease inhibitor that appears to have good oral bioavailability. [NIH] Indole-3-carbinol: A substance that is being studied as a cancer prevention drug. It is found in cruciferous vegetables. [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] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]

Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called

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Metabolites

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] Inoculum: The spores or tissues of a pathogen that serve to initiate disease in a plant. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insect Control: The reduction or regulation of the population of noxious, destructive, or dangerous insects through chemical, biological, or other means. [NIH] Insecticides: Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. [NIH] 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] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interindividual: Occurring between two or more individuals. [EU] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH]

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Interleukin-8: A cytokine that activates neutrophils and attracts neutrophils and Tlymphocytes. It is released by several cell types including monocytes, macrophages, Tlymphocytes, fibroblasts, endothelial cells, and keratinocytes by an inflammatory stimulus. IL-8 is a member of the beta-thromboglobulin superfamily and structurally related to platelet factor 4. [NIH] 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] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] 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

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Metabolites

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] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Isoniazid: Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. [NIH] Isosorbide: 1,4:3,6-Dianhydro D-glucitol. Chemically inert osmotic diuretic used mainly to treat hydrocephalus; also used in glaucoma. [NIH] Isosorbide Dinitrate: A vasodilator used in the treatment of angina. Its actions are similar to nitroglycerin but with a slower onset of action. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Itraconazole: An antifungal agent that has been used in the treatment of histoplasmosis, blastomycosis, cryptococcal meningitis, and aspergillosis. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH]

Kainate: Glutamate receptor. [NIH] Kainic Acid: (2S-(2 alpha,3 beta,4 beta))-2-Carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid. Ascaricide obtained from the red alga Digenea simplex. It is a potent excitatory amino acid agonist at some types of excitatory amino acid receptors and has been used to discriminate among receptor types. Like many excitatory amino acid agonists it can cause neurotoxicity and has been used experimentally for that purpose. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Keratin: A class of fibrous proteins or scleroproteins important both as structural proteins and as keys to the study of protein conformation. The family represents the principal constituent of epidermis, hair, nails, horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms an alpha-helix, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. [NIH] Keratinocytes: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. [NIH] Keto: It consists of 8 carbon atoms and within the endotoxins, it connects poysaccharide and lipid A. [NIH]

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Ketoconazole: Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. [NIH] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketonuria: Having ketone bodies in the urine; a warning sign of diabetic ketoacidosis (DKA). [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney stone: A stone that develops from crystals that form in urine and build up on the inner surfaces of the kidney, in the renal pelvis, or in the ureters. [NIH] 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] Lactose Intolerance: The disease state resulting from the absence of lactase enzyme in the musocal cells of the gastrointestinal tract, and therefore an inability to break down the disaccharide lactose in milk for absorption from the gastrointestinal tract. It is manifested by indigestion of a mild nature to severe diarrhea. It may be due to inborn defect genetically conditioned or may be acquired. [NIH] Lag: The time elapsing between application of a stimulus and the resulting reaction. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Larynx: An irregularly shaped, musculocartilaginous tubular structure, lined with mucous membrane, located at the top of the trachea and below the root of the tongue and the hyoid bone. It is the essential sphincter guarding the entrance into the trachea and functioning secondarily as the organ of voice. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lectins: Protein or glycoprotein substances, usually of plant origin, that bind to sugar moieties in cell walls or membranes and thereby change the physiology of the membrane to cause agglutination, mitosis, or other biochemical changes in the cell. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH]

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Metabolites

Lentivirus: A genus of the family Retroviridae consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [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] Levorphanol: A narcotic analgesic that may be habit-forming. It is nearly as effective orally as by injection. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Lichens: Any of a group of plants formed by a mutual combination of an alga and a fungus. [NIH]

Lidocaine: A local anesthetic and cardiac depressant used as an antiarrhythmia agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. [NIH] Life cycle: The successive stages through which an organism passes from fertilized ovum or spore to the fertilized ovum or spore of the next generation. [NIH] Life Expectancy: A figure representing the number of years, based on known statistics, to which any person of a given age may reasonably expect to live. [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] Limb perfusion: A technique that may be used to deliver anticancer drugs directly to an arm or leg. The flow of blood to and from the limb is temporarily stopped with a tourniquet, and anticancer drugs are put directly into the blood of the limb. This allows the person to receive a high dose of drugs in the area where the cancer occurred. [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] Linoleic Acids: Eighteen-carbon essential fatty acids that contain two double bonds. [NIH] Lipid: Fat. [NIH]

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Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipophilic: Having an affinity for fat; pertaining to or characterized by lipophilia. [EU] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Liquor: 1. A liquid, especially an aqueous solution containing a medicinal substance. 2. A general term used in anatomical nomenclature for certain fluids of the body. [EU] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver Circulation: The circulation of blood through the vessels of the liver. [NIH] Liver Cirrhosis: Liver disease in which the normal microcirculation, the gross vascular anatomy, and the hepatic architecture have been variably destroyed and altered with fibrous septa surrounding regenerated or regenerating parenchymal nodules. [NIH] Liver Neoplasms: Tumors or cancer of the liver. [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] Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [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] Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. [NIH] Lubricants: Oily or slippery substances. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lyases: A class of enzymes that catalyze the cleavage of C-C, C-O, and C-N, and other bonds by other means than by hydrolysis or oxidation. (Enzyme Nomenclature, 1992) EC 4. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph).

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Metabolites

[NIH]

Lymphadenopathy: Disease or swelling of the lymph nodes. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] 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] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Lysophospholipids: Derivatives of phosphatidic acids that lack one of its fatty acyl chains due to its hydrolytic removal. [NIH] Lysosomal Storage Diseases: Inborn errors of metabolism characterized by defects in specific lysosomal hydrolases and resulting in intracellular accumulation of unmetabolized substrates. [NIH] Lytic: 1. Pertaining to lysis or to a lysin. 2. Producing lysis. [EU] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH]

Dictionary 313

Malathion: A wide spectrum aliphatic organophosphate insecticide widely used for both domestic and commercial agricultural purposes. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Man-made: Ionizing radiation emitted by artificial or concentrated natural, radioactive material or resulting from the operation of high voltage apparatus, such as X-ray apparatus or particle accelerators, of nuclear reactors, or from nuclear explosions. [NIH] Mannans: Polysaccharides consisting of mannose units. [NIH] Maple Syrup Urine Disease: A genetic disorder involving deficiency of an enzyme necessary in the metabolism of branched-chain amino acids, and named for the characteristic odor of the urine. [NIH] Mass Screening: Organized periodic procedures performed on large groups of people for the purpose of detecting disease. [NIH] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Matrilysin: The smallest member of the matrix metalloproteinases. It plays a role in tumor progression. EC 3.4.24.23. [NIH] Matrix metalloproteinase: A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis. [NIH] Maturation-Promoting Factor: Protein kinase that drives both the mitotic and meiotic cycles in all eukaryotic organisms. In meiosis it induces immature oocytes to undergo meiotic maturation. In mitosis it has a role in the G2/M phase transition. Once activated by cyclins, MPF directly phosphorylates some of the proteins involved in nuclear envelope breakdown, chromosome condensation, spindle assembly, and the degradation of cyclins. The catalytic subunit of MPF is protein P34CDC2. [NIH] Meconium: The thick green-to-black mucilaginous material found in the intestines of a fullterm fetus. It consists of secretions of the intestinal glands, bile pigments, fatty acids, amniotic fluid, and intrauterine debris. It constitutes the first stools passed by a newborn. [NIH]

Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediastinum: The area between the lungs. The organs in this area include the heart and its large blood vessels, the trachea, the esophagus, the bronchi, and lymph nodes. [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]

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Metabolites

MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melphalan: An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - melphalan, the racemic mixture - merphalan, and the dextro isomer medphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Meningitis: Inflammation of the meninges. When it affects the dura mater, the disease is termed pachymeningitis; when the arachnoid and pia mater are involved, it is called leptomeningitis, or meningitis proper. [EU] 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] Menthol: An alcohol produced from mint oils or prepared synthetically. [NIH] Mercaptopurine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH] Mesenchymal: Refers to cells that develop into connective tissue, blood vessels, and lymphatic tissue. [NIH]

Dictionary 315

Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesenteric Arteries: Arteries which arise from the abdominal aorta and distribute to most of the intestines. [NIH] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Metabolic acidosis: (met-ah-BOL-ik as-id-O-sis): A condition in which the blood is too acidic. It may be caused by severe illness or sepsis (bacteria in the bloodstream). [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] 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] Methanol: A colorless, flammable liquid used in the manufacture of formaldehyde and acetic acid, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Metronidazole: Antiprotozoal used in amebiasis, trichomoniasis, giardiasis, and as treponemacide in livestock. It has also been proposed as a radiation sensitizer for hypoxic cells. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985, p133), this substance may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which

316

Metabolites

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] Micronutrients: Essential dietary elements or organic compounds that are required in only small quantities for normal physiologic processes to occur. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Micro-organism: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microsomal: Of or pertaining to microsomes : vesicular fragments of endoplasmic reticulum formed after disruption and centrifugation of cells. [EU] Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Moclobemide: A reversible inhibitor of monoamine oxidase type A (RIMA) that has antidepressive properties. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molar pregnancy: A rare cancer in women of child-bearing age in which cancer cells grow in the tissues that are formed in the uterus after conception. Also called gestational trophoblastic disease, gestational trophoblastic neoplasia, gestational trophoblastic tumor, or choriocarcinoma. [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

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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] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocyte: A type of white blood cell. [NIH] Mononuclear: A cell with one nucleus. [NIH] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Motility: The ability to move spontaneously. [EU] Motivations: The most compelling inner determinants of human behavior; also called drives, urges, impulses, needs, wants, tensions, and willful cravings. [NIH] Motor nerve: An efferent nerve conveying an impulse that excites muscular contraction. [NIH]

Mucilaginous: Pertaining to or secreting mucus. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multiple Myeloma: A malignant tumor of plasma cells usually arising in the bone marrow; characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria, and anemia. [NIH]

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Metabolites

Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle relaxant: An agent that specifically aids in reducing muscle tension, as those acting at the polysynaptic neurons of motor nerves (e.g. meprobamate) or at the myoneural junction (curare and related compounds). [EU] Muscle tension: A force in a material tending to produce extension; the state of being stretched. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagen: Any agent, such as X-rays, gamma rays, mustard gas, TCDD, that can cause abnormal mutation in living cells; having the power to cause mutations. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagenic: Inducing genetic mutation. [EU] Mutagenicity: Ability to damage DNA, the genetic material; the power to cause mutations. [NIH]

Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplastic syndrome: Disease in which the bone marrow does not function normally. Also called preleukemia or smoldering leukemia. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme

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washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myristate: Pharmacological activator of protein kinase C. [NIH] Nafenopin: A peroxisome proliferator that is used experimentally to promote liver tumors. It has been used as an antihyperlipoproteinemic agent. [NIH] Naphthols: Naphthalene derivatives carrying one or more hydroxyl (-OH) groups at any ring position. They are often used in dyes and pigments, as antioxidants for rubber, fats, and oils, as insecticides, in pharmaceuticals, and in numerous other applications. [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] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] 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] Nelfinavir: A potent HIV protease inhibitor. It is used in combination with other antiviral drugs in the treatment of HIV in both adults and children. [NIH] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory

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Metabolites

component. [NIH] Nephrotic: Pertaining to, resembling, or caused by nephrosis. [EU] Nephrotic Syndrome: Clinical association of heavy proteinuria, hypoalbuminemia, and generalized edema. [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] 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] Neuralgia: Intense or aching pain that occurs along the course or distribution of a peripheral or cranial nerve. [NIH] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures. [NIH] Neurofibroma: A fibrous tumor, usually benign, arising from the nerve sheath or the endoneurium. [NIH] Neuroleptic: A term coined to refer to the effects on cognition and behaviour of antipsychotic drugs, which produce a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients cause a reduction in confusion and agitation and normalization of psychomotor activity. [EU] Neurologic: Having to do with nerves or the nervous system. [NIH] Neuroma: A tumor that arises in nerve cells. [NIH] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurophysiology: The scientific discipline concerned with the physiology of the 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]

Neurotoxins: Toxic substances from microorganisms, plants or animals that interfere with

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the functions of the nervous system. Most venoms contain neurotoxic substances. Myotoxins are included in this concept. [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, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutron Capture Therapy: A technique for the treatment of neoplasms in which an isotope is introduced into target cells followed by irradiation with thermal neutrons. [NIH] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] 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] Nimodipine: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. 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] Nitroglycerin: A highly volatile organic nitrate that acts as a dilator of arterial and venous smooth muscle and is used in the treatment of angina. It provides relief through improvement of the balance between myocardial oxygen supply and demand. Although total coronary blood flow is not increased, there is redistribution of blood flow in the heart when partial occlusion of coronary circulation is effected. [NIH] Nitrosamines: A class of compounds that contain a -NH2 and a -NO radical. Many members of this group have carcinogenic and mutagenic properties. [NIH] Non-small cell lung cancer: A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a

322

Metabolites

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] Nuclear Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [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] Nursing Care: Care given to patients by nursing service personnel. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Nutritional Support: The administration of nutrients for assimilation and utilization by a patient by means other than normal eating. It does not include fluid therapy which normalizes body fluids to restore water-electrolyte balance. [NIH] Nutritive Value: An indication of the contribution of a food to the nutrient content of the diet. This value depends on the quantity of a food which is digested and absorbed and the amounts of the essential nutrients (protein, fat, carbohydrate, minerals, vitamins) which it contains. This value can be affected by soil and growing conditions, handling and storage, and processing. [NIH] Observational study: An epidemiologic study that does not involve any intervention, experimental or otherwise. Such a study may be one in which nature is allowed to take its course, with changes in one characteristic being studied in relation to changes in other characteristics. Analytical epidemiologic methods, such as case-control and cohort study designs, are properly called observational epidemiology because the investigator is observing without intervention other than to record, classify, count, and statistically analyze results. [NIH] Obsessive-Compulsive Disorder: An anxiety disorder characterized by recurrent, persistent obsessions or compulsions. Obsessions are the intrusive ideas, thoughts, or images that are experienced as senseless or repugnant. Compulsions are repetitive and seemingly purposeful behavior which the individual generally recognizes as senseless and from which the individual does not derive pleasure although it may provide a release from tension. [NIH] Occupational Exposure: The exposure to potentially harmful chemical, physical, or biological agents that occurs as a result of one's occupation. [NIH]

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Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oedema: The presence of abnormally large amounts of fluid in the intercellular tissue spaces of the body; usually applied to demonstrable accumulation of excessive fluid in the subcutaneous tissues. Edema may be localized, due to venous or lymphatic obstruction or to increased vascular permeability, or it may be systemic due to heart failure or renal disease. Collections of edema fluid are designated according to the site, e.g. ascites (peritoneal cavity), hydrothorax (pleural cavity), and hydropericardium (pericardial sac). Massive generalized edema is called anasarca. [EU] Oestrogen: A generic term for oestrus-producing steroid compounds; the female sex hormones. In humans, oestrogen is formed in the ovary, possibly the adrenal cortex, the testis, and the foetoplacental unit; it has various functions in both sexes. It is responsible for the development of the female secondary sex characteristics, and during the menstrual cycle it acts on the female genitalia to produce an environment suitable for the fertilization, implantation, and nutrition of the early embryo. Oestrogen is used in oral contraceptives and as a palliative in cancer of the breast after menopause and cancer of the prostate; other uses include the relief of the discomforts of menopause, inhibition of lactation, and treatment of osteoporosis, threatened abortion, and various functional ovarian disorders. [EU]

Ofloxacin: An orally administered broad-spectrum quinolone antibacterial drug active against most gram-negative and gram-positive bacteria. [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] Oltipraz: A drug used in cancer prevention. [NIH] On-line: A sexually-reproducing population derived from a common parentage. [NIH] Oocytes: Female germ cells in stages between the prophase of the first maturation division and the completion of the second maturation division. [NIH] Oophorectomy: Surgery to remove one or both ovaries. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Ophthalmic: Pertaining to the eye. [EU] 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] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [NIH] Orbital: Pertaining to the orbit (= the bony cavity that contains the eyeball). [EU]

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Metabolites

Orchiectomy: The surgical removal of one or both testicles. [NIH] Organ Culture: The growth in aseptic culture of plant organs such as roots or shoots, beginning with organ primordia or segments and maintaining the characteristics of the organ. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Ornithine: An amino acid produced in the urea cycle by the splitting off of urea from arginine. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteoclasts: A large multinuclear cell associated with the absorption and removal of bone. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overactive bladder: A condition in which the patient experiences two or all three of the following conditions: [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]

Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the

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electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxides: Binary compounds of oxygen containing the anion O(2-). The anion combines with metals to form alkaline oxides and non-metals to form acidic oxides. [NIH] Oximetry: The determination of oxygen-hemoglobin saturation of blood either by withdrawing a sample and passing it through a classical photoelectric oximeter or by electrodes attached to some translucent part of the body like finger, earlobe, or skin fold. It includes non-invasive oxygen monitoring by pulse oximetry. [NIH] Oxycodone: Semisynthetic derivative of codeine that acts as a narcotic analgesic more potent and addicting than codeine. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] Oxygenation: The process of supplying, treating, or mixing with oxygen. No:1245 oxygenation the process of supplying, treating, or mixing with oxygen. [EU] P-450: Enzyme that donates electrons to P-450 enzymes which metabolize drugs in the liver. [NIH]

P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [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] Pancreatic: Having to do with the pancreas. [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

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Metabolites

may be inherited as an autosomal dominant trait. [NIH] Paracentesis: A procedure in which fluid is withdrawn from a body cavity via a trocar and cannula, needle, or other hollow instrument. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parasympathetic Nervous System: The craniosacral division of the autonomic nervous system. The cell bodies of the parasympathetic preganglionic fibers are in brain stem nuclei and in the sacral spinal cord. They synapse in cranial autonomic ganglia or in terminal ganglia near target organs. The parasympathetic nervous system generally acts to conserve resources and restore homeostasis, often with effects reciprocal to the sympathetic nervous system. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Parenteral Nutrition: The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). [NIH] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Patella: The flat, triangular bone situated at the anterior part of the knee. [NIH] Pathogen: Any disease-producing microorganism. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Care Management: Generating, planning, organizing, and administering medical and nursing care and services for patients. [NIH]

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Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Penicillium: A mitosporic Trichocomaceae fungal genus that develops fruiting organs resembling a broom. When identified, teleomorphs include Eupenicillium and Talaromyces. Several species (but especially Penicillium chrysogenum) are sources of the antibiotic penicillin. [NIH] Penis: The external reproductive organ of males. It is composed of a mass of erectile tissue enclosed in three cylindrical fibrous compartments. Two of the three compartments, the corpus cavernosa, are placed side-by-side along the upper part of the organ. The third compartment below, the corpus spongiosum, houses the urethra. [NIH] Pentachlorophenol: An insecticide and herbicide that has also been used as a wood preservative. Pentachlorphenol is a widespread environmental pollutant. Both chronic and acute pentachlorophenol poisoning are medical concerns. The range of its biological actions is still being actively explored, but it is clearly a potent enzyme inhibitor and has been used as such as an experimental tool. [NIH] Pentosyltransferases: Enzymes of the transferase class that catalyze the transfer of a pentose group from one compound to another. (Dorland, 28th ed) EC 2.4.2. [NIH] Peptic: Pertaining to pepsin or to digestion; related to the action of gastric juices. [EU] Peptic Ulcer: An ulceration of the mucous membrane of the esophagus, stomach or duodenum, caused by the action of the acid gastric juice. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide Synthases: Enzymes that catalyze the joining of an acid and an amino acid by the formation of a carbon-nitrogen bond. EC 6.3.2. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Perillyl alcohol: A drug used in cancer prevention that belongs to the family of plant drugs called monoterpenes. [NIH] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Periodontal disease: Disease involving the supporting structures of the teeth (as the gums and periodontal membranes). [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral vision: Side vision; ability to see objects and movement outside of the direct line

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of vision. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Cavity: The space enclosed by the peritoneum. It is divided into two portions, the greater sac and the lesser sac or omental bursa, which lies behind the stomach. The two sacs are connected by the foramen of Winslow, or epiploic foramen. [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Peritoneum: Endothelial lining of the abdominal cavity, the parietal peritoneum covering the inside of the abdominal wall and the visceral peritoneum covering the bowel, the mesentery, and certain of the organs. The portion that covers the bowel becomes the serosal layer of the bowel wall. [NIH] Peritonitis: Inflammation of the peritoneum; a condition marked by exudations in the peritoneum of serum, fibrin, cells, and pus. It is attended by abdominal pain and tenderness, constipation, vomiting, and moderate fever. [EU] Perivascular: Situated around a vessel. [EU] Peroral: Performed through or administered through the mouth. [EU] Peroxisome Proliferators: A class of nongenotoxic carcinogens that induce the production of hepatic peroxisomes and induce hepatic neoplasms after long-term administration. [NIH] Pesticides: Chemicals used to destroy pests of any sort. The concept includes fungicides (industrial fungicides), insecticides, rodenticides, etc. [NIH] Petechiae: Pinpoint, unraised, round red spots under the skin caused by bleeding. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Pharmaceutic Aids: Substances which are of little or no therapeutic value, but are necessary in the manufacture, compounding, storage, etc., of pharmaceutical preparations or drug dosage forms. They include solvents, diluting agents, and suspending agents, and emulsifying agents. Also, antioxidants; preservatives, pharmaceutical; dyes (coloring agents); flavoring agents; vehicles; excipients; ointment bases. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] 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]

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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] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an antiarrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phosphatidic Acids: Fatty acid derivatives of glycerophosphates. They are composed of glycerol bound in ester linkage with 1 mole of phosphoric acid at the terminal 3-hydroxyl group and with 2 moles of fatty acids at the other two hydroxyl groups. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipases A: Phosphatide acylhydrolases. Catalyze the hydrolysis of one of the acyl groups of phosphoglycerides or glycerophosphatidates. Phospholipase A1 hydrolyzes the acyl group attached to the 1-position (EC 3.1.1.32) and phospholipase A2 hydrolyzes the acyl group attached to the 2-position (EC 3.1.1.4). [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] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylating: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photoreceptor: Receptor capable of being activated by light stimuli, as a rod or cone cell of the eye. [NIH] Physicochemical: Pertaining to physics and chemistry. [EU] Physiologic: Having to do with the functions of the body. When used in the phrase

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Metabolites

"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] 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] Pineal gland: A tiny organ located in the cerebrum that produces melatonin. Also called pineal body or pineal organ. [NIH] Piper methysticum: For small images in peripheral vision, the product of intensity and the square root of the area stimulated is a constant for threshold effect. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plague: An acute infectious disease caused by Yersinia pestis that affects humans, wild rodents, and their ectoparasites. This condition persists due to its firm entrenchment in sylvatic rodent-flea ecosystems throughout the world. Bubonic plague is the most common form. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet 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] Platelet Factor 4: A high-molecular-weight proteoglycan-platelet factor complex which is released from blood platelets by thrombin. It acts as a mediator in the heparin-neutralizing capacity of the blood and plays a role in platelet aggregation. At high ionic strength (I=0.75), the complex dissociates into the active component (molecular weight 29,000) and the proteoglycan carrier (chondroitin 4-sulfate, molecular weight 350,000). The molecule exists

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in the form of a dimer consisting of 8 moles of platelet factor 4 and 2 moles of proteoglycan. [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]

Pleural: A circumscribed area of hyaline whorled fibrous tissue which appears on the surface of the parietal pleura, on the fibrous part of the diaphragm or on the pleura in the interlobar fissures. [NIH] Pleural cavity: A space enclosed by the pleura (thin tissue covering the lungs and lining the interior wall of the chest cavity). It is bound by thin membranes. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Pollen: The male fertilizing element of flowering plants analogous to sperm in animals. It is released from the anthers as yellow dust, to be carried by insect or other vectors, including wind, to the ovary (stigma) of other flowers to produce the embryo enclosed by the seed. The pollens of many plants are allergenic. [NIH] Polychlorinated Biphenyls: Industrial products consisting of a mixture of chlorinated biphenyl congeners and isomers. These compounds are highly lipophilic and tend to accumulate in fat stores of animals. Many of these compounds are considered toxic and potential environmental pollutants. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polymyxin: Basic polypeptide antibiotic group obtained from Bacillus polymyxa. They affect the cell membrane by detergent action and may cause neuromuscular and kidney damage. At least eleven different members of the polymyxin group have been identified, each designated by a letter. [NIH] Polyp: A growth that protrudes from a mucous membrane. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polyproteins: Proteins which are synthesized as a single polymer and then cleaved into

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Metabolites

several distinct proteins. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Portal Hypertension: High blood pressure in the portal vein. This vein carries blood into the liver. Portal hypertension is caused by a blood clot. This is a common complication of cirrhosis. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Precipitation: The act or process of precipitating. [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] Predictive factor: A situation or condition that may increase a person's risk of developing a certain disease or disorder. [NIH] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] Pregnancy Outcome: Results of conception and ensuing pregnancy, including live birth, stillbirth, spontaneous abortion, induced abortion. The outcome may follow natural or artificial insemination or any of the various reproduction techniques, such as embryo transfer or fertilization in vitro. [NIH] Preleukemia: Conditions in which the abnormalities in the peripheral blood or bone marrow represent the early manifestations of acute leukemia, but in which the changes are

Dictionary 333

not of sufficient magnitude or specificity to permit a diagnosis of acute leukemia by the usual clinical criteria. [NIH] Premalignant: A term used to describe a condition that may (or is likely to) become cancer. Also called precancerous. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Premenstrual Syndrome: A syndrome occurring most often during the last week of the menstrual cycle and ending soon after the onset of menses. Some of the symptoms are emotional instability, insomnia, headache, nausea, vomiting, abdominal distension, and painful breasts. [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Presumptive: A treatment based on an assumed diagnosis, prior to receiving confirmatory laboratory test results. [NIH] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Prickle: Several layers of the epidermis where the individual cells are connected by cell bridges. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection, as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Primary tumor: The original tumor. [NIH] Prinomastat: An anticancer drug that belongs to the family of drugs called angiogenesis inhibitors. Prinomastat is a matrix metalloproteinase inhibitor. Also called AG3340. [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] Probenecid: The prototypical uricosuric agent. It inhibits the renal excretion of organic anions and reduces tubular reabsorption of urate. Probenecid has also been used to treat patients with renal impairment, and, because it reduces the renal tubular excretion of other drugs, has been used as an adjunct to antibacterial therapy. [NIH] Procaine: A local anesthetic of the ester type that has a slow onset and a short duration of action. It is mainly used for infiltration anesthesia, peripheral nerve block, and spinal block. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1016). [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Proenzyme: 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] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH]

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Metabolites

Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promyelocytic leukemia: A type of acute myeloid leukemia, a quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. [NIH]

Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Propofol: A widely used anesthetic. [NIH] Propolis: Resinous substance obtained from beehives; contains many different substances which may have antimicrobial or antimycotic activity topically; its extracts are called propolis resin or balsam. Synonyms: bee bread; hive dross; bee glue. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Engineering: Procedures by which nonrandom single-site changes are introduced into structural genes (site-specific mutagenesis) in order to produce mutant genes which can be coupled to promoters that direct the synthesis of a specifically altered protein, which is then analyzed for structural and functional properties and then compared with the predicted and sought-after properties. The design of the protein may be assisted by computer graphic technology and other advanced molecular modeling techniques. [NIH] Protein Kinase C: An enzyme that phosphorylates proteins on serine or threonine residues

Dictionary 335

in the presence of physiological concentrations of calcium and membrane phospholipids. The additional presence of diacylglycerols markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by phorbol esters and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. EC 2.7.1.-. [NIH] Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein. EC 2.7.1.37. [NIH] Protein p53: Nuclear phosphoprotein encoded by the p53 gene whose normal function is to control cell proliferation. A mutant or absent p53 protein has been found in leukemia, osteosarcoma, lung cancer, and colorectal cancer. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Protein Subunits: Single chains of amino acids that are the units of a multimeric protein. They can be identical or non-identical subunits. [NIH] Protein-Energy Malnutrition: The lack of sufficient energy or protein to meet the body's metabolic demands, as a result of either an inadequate dietary intake of protein, intake of poor quality dietary protein, increased demands due to disease, or increased nutrient losses. [NIH]

Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Protein-Tyrosine Kinase: An enzyme that catalyzes the phosphorylation of tyrosine residues in proteins with ATP or other nucleotides as phosphate donors. EC 2.7.1.112. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Prothrombin: A plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions. Deficiency of prothrombin leads to hypoprothrombinemia. [NIH]

Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to

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Metabolites

macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] 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] Psychotomimetic: Psychosis miming. [NIH] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] 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]

Pupil: The aperture in the iris through which light passes. [NIH] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU]

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Putrefaction: The process of decomposition of animal and vegetable matter by living organisms. [NIH] Putrescine: A toxic diamine formed by putrefaction from the decarboxylation of arginine and ornithine. [NIH] Pyogenic: Producing pus; pyopoietic (= liquid inflammation product made up of cells and a thin fluid called liquor puris). [EU] Pyramidal Tracts: Fibers that arise from cells within the cerebral cortex, pass through the medullary pyramid, and descend in the spinal cord. Many authorities say the pyramidal tracts include both the corticospinal and corticobulbar tracts. [NIH] Pyrazinamide: A pyrazine that is used therapeutically as an antitubercular agent. [NIH] Pyrethrins: The active insecticidal constituent of pyrethrum flowers. Pyrethrin I is the pyretholone ester of chrysanthemummonocarboxylic acid and pyrethrin II is the pyretholone ester of chrysanthemumdicarboxylic acid monomethyl ester. [NIH] Pyrethrum: Species cinerafolium vis. and coccineum willd. of the genus Chrysanthemum (Compositae). The flowers contain pyrethrins, cinerolones, and chrysanthemines which are powerful contact insecticides. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quercetin: Aglucon of quercetrin, rutin, and other glycosides. It is widely distributed in the plant kingdom, especially in rinds and barks, clover blossoms, and ragweed pollen. [NIH] Quinones: Hydrocarbon rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups. [NIH] Quinoxaline: AMPA/Kainate antagonist. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] 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] Radiochemical: The proportion of the total activity of the radionuclide in the sample considered, which is due to the nuclide in the stated chemical form. [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure

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Metabolites

the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [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] Reabsorption: 1. The act or process of absorbing again, as the selective absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules, and their return to the circulating blood. 2. Resorption. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] 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 blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reference Standards: A basis of value established for the measure of quantity, weight, extent or quality, e.g. weight standards, standard solutions, methods, techniques, and procedures used in diagnosis and therapy. [NIH] Reflective: Capable of throwing back light, images, sound waves : reflecting. [EU]

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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] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regional chemotherapy: Treatment with anticancer drugs that is directed to a specific area. [NIH]

Regression Analysis: Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see linear models) the relationship is constrained to be a straight line and least-squares analysis is used to determine the best fit. In logistic regression (see logistic models) the dependent variable is qualitative rather than continuously variable and likelihood functions are used to find the best relationship. In multiple regression the dependent variable is considered to depend on more than a single independent variable. [NIH]

Relapse: The return of signs and symptoms of cancer after a period of improvement. [NIH] Relaxant: 1. Lessening or reducing tension. 2. An agent that lessens tension. [EU] 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 Circulation: The circulation of the blood through the vessels of the kidney. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal Replacement Therapy: Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. [NIH] Renal tubular: A defect in the kidneys that hinders their normal excretion of acids. Failure to excrete acids can lead to weak bones, kidney stones, and poor growth in children. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH]

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Metabolites

Reproduction Techniques: Methods pertaining to the generation of new individuals. [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] Restless legs: Legs characterized by or showing inability to remain at rest. [EU] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal pigment epithelium: The pigment cell layer that nourishes the retinal cells; located just outside the retina and attached to the choroid. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhabdomyolysis: Necrosis or disintegration of skeletal muscle often followed by myoglobinuria. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH]

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Rickets: A condition caused by deficiency of vitamin D, especially in infancy and childhood, with disturbance of normal ossification. The disease is marked by bending and distortion of the bones under muscular action, by the formation of nodular enlargements on the ends and sides of the bones, by delayed closure of the fontanelles, pain in the muscles, and sweating of the head. Vitamin D and sunlight together with an adequate diet are curative, provided that the parathyroid glands are functioning properly. [EU] Rickettsiae: One of a group of obligate intracellular parasitic microorganisms, once regarded as intermediate in their properties between bacteria and viruses but now classified as bacteria in the order Rickettsiales, which includes 17 genera and 3 families: Rickettsiace. [NIH]

Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] RNA: Ribonucleic acid. One of the two types of nucleic acids found in cells. The other is DNA (deoxyribonucleic acid). RNA plays a role in sending information from DNA to the protein-forming system of the cell. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rotenone: A botanical insecticide that is an inhibitor of mitochondrial electron transport. [NIH]

Rubber: A high-molecular-weight polymeric elastomer derived from the milk juice (latex) of Hevea brasiliensis and other trees. It is a substance that can be stretched at room temperature to atleast twice its original length and after releasing the stress, retractrapidly, and recover its original dimensions fully. Synthetic rubber is made from many different chemicals, including styrene, acrylonitrile, ethylene, propylene, and isoprene. [NIH] Rutin: 3-((6-O-(6-Deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranosyl)oxy)-2-(3,4dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one. Found in many plants, including buckwheat, tobacco, forsythia, hydrangea, pansies, etc. It has been used therapeutically to decrease capillary fragility. [NIH] Salicylic: A tuberculosis drug. [NIH] Saline: A solution of salt and water. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Saphenous: Applied to certain structures in the leg, e. g. nerve vein. [NIH] Saphenous Vein: The vein which drains the foot and leg. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Sarcoplasmic Reticulum: A network of tubules and sacs in the cytoplasm of skeletal muscles that assist with muscle contraction and relaxation by releasing and storing calcium ions. [NIH]

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Metabolites

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] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [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] Scleroderma: A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic). [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sedatives, Barbiturate: Those derivatives of barbituric or thiobarbituric acid that are used as hypnotics or sedatives. The structural class of all such derivatives, regardless of use, is barbiturates. [NIH] Sediment: A precipitate, especially one that is formed spontaneously. [EU] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are

Dictionary 343

SERMs. [NIH] Selegiline: A selective, irreversible inhibitor of Type B monoamine oxidase. It is used in newly diagnosed patients with Parkinson's disease. It may slow progression of the clinical disease and delay the requirement for levodopa therapy. It also may be given with levodopa upon onset of disability. (From AMA Drug Evaluations Annual, 1994, p385) The compound without isomeric designation is Deprenyl. [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Sella Turcica: A bony prominence situated on the upper surface of the body of the sphenoid bone. It houses the pituitary gland. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Senescence: The bodily and mental state associated with advancing age. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] 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] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Hormone-Binding Globulin: A glycoprotein migrating as a beta-globulin. Its molecular weight, 52,000 or 95,000-115,000, indicates that it exists as a dimer. The protein binds

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testosterone, dihydrotestosterone, and estradiol in the plasma. Sex hormone-binding protein has the same amino acid sequence as androgen-binding protein. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [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]

Sialyltransferases: A group of enzymes with the general formula CMP-Nacetylneuraminate:acceptor N-acetylneuraminyl transferase. They catalyze the transfer of Nacetylneuraminic acid from CMP-N-acetylneuraminic acid to an acceptor, which is usually the terminal sugar residue of an oligosaccharide, a glycoprotein, or a glycolipid. EC 2.4.99.-. [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 a physician, or subjective when perceived by the patient. [NIH] Simvastatin: A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic LDL receptors, it increases breakdown of LDL-cholesterol (lipoproteins, LDL cholesterol). [NIH] Sirolimus: A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small cell lung cancer: A type of lung cancer in which the cells appear small and round when viewed under the microscope. Also called oat cell lung cancer. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smoking Cessation: Discontinuation of the habit of smoking, the inhaling and exhaling of tobacco smoke. [NIH]

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Smoldering leukemia: Disease in which the bone marrow does not function normally. Also called preleukemia or myelodysplastic syndrome. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Spasmolytic: Checking spasms; antispasmodic. [EU] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] 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]

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Metabolites

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] Spectrometer: An apparatus for determining spectra; measures quantities such as wavelengths and relative amplitudes of components. [NIH] Spectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum. [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] Spermatogenesis: Process of formation and development of spermatozoa, including spermatocytogenesis and spermiogenesis. [NIH] Spermatozoa: Mature male germ cells that develop in the seminiferous tubules of the testes. Each consists of a head, a body, and a tail that provides propulsion. The head consists mainly of chromatin. [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] Spinous: Like a spine or thorn in shape; having spines. [NIH] Splanchnic Circulation: The circulation of blood through the vessels supplying the abdominal viscera. [NIH] Spontaneous Abortion: The non-induced birth of an embryo or of fetus prior to the stage of viability at about 20 weeks of gestation. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Spores: The reproductive elements of lower organisms, such as protozoa, fungi, and cryptogamic plants. [NIH] Squamous: Scaly, or platelike. [EU] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Squamous cell carcinoma: Cancer that begins in squamous cells, which are thin, flat cells resembling fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma. [NIH] Stabilization: The creation of a stable state. [EU] 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]

Status Epilepticus: Repeated and prolonged epileptic seizures without recovery of consciousness between attacks. [NIH] Steady state: Dynamic equilibrium. [EU]

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Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Sterile: Unable to produce children. [NIH] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stillbirth: The birth of a dead fetus or baby. [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] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [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]

Streptomycin: O-2-Deoxy-2-(methylamino)-alpha-L-glucopyranosyl-(1-2)-O-5- deoxy-3-Cformyl-alpha-L-lyxofuranosyl-(1-4)-N,N'-bis(aminoiminomethyl)-D-streptamine. Antibiotic substance produced by the soil actinomycete Streptomyces griseus. It acts by inhibiting the initiation and elongation processes during protein synthesis. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] 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

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responsiveness. [EU] Styrene: A colorless, toxic liquid with a strong aromatic odor. It is used to make rubbers, polymers and copolymers, and polystyrene plastics. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subarachnoid: Situated or occurring between the arachnoid and the pia mater. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Submaxillary: Four to six lymph glands, located between the lower jaw and the submandibular salivary gland. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. [NIH] Suction: The removal of secretions, gas or fluid from hollow or tubular organs or cavities by means of a tube and a device that acts on negative pressure. [NIH] Sulfadiazine: A short-acting sulfonamide used in combination with pyrimethamine to treat toxoplasmosis in patients with acquired immunodeficiency syndrome and in newborns with congenital infections. [NIH] Sulfotransferases: Enzymes which transfer sulfate groups to various acceptor molecules. They are involved in posttranslational sulfation of proteins and sulfate conjugation of exogenous chemicals and bile acids. EC 2.8.2. [NIH] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Sulfur Compounds: Inorganic or organic compounds that contain sulfur as an integral part of the molecule. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Surface Plasmon Resonance: A biosensing technique in which biomolecules capable of binding to specific analytes or ligands are first immobilized on one side of a metallic film. Light is then focused on the opposite side of the film to excite the surface plasmons, that is, the oscillations of free electrons propagating along the film's surface. The refractive index of light reflecting off this surface is measured. When the immobilized biomolecules are bound by their ligands, an alteration in surface plasmons on the opposite side of the film is created which is directly proportional to the change in bound, or adsorbed, mass. Binding is

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measured by changes in the refractive index. The technique is used to study biomolecular interactions, such as antigen-antibody binding. [NIH] Surgical castration: Surgical removal of the testicles (orchiectomy) or ovaries (oophorectomy) to stop the production of sex hormones. Decreasing the levels of hormones may stop the growth of certain cancers. [NIH] Survival Rate: The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. [NIH] Sweat: The fluid excreted by the sweat glands. It consists of water containing sodium chloride, phosphate, urea, ammonia, and other waste products. [NIH] Sweat Glands: Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. [NIH] Symbiosis: The living together of organisms of different species. [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] 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 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] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [EU] Synovial Fluid: The clear, viscous fluid secreted by the synovial membrane. It contains mucin, albumin, fat, and mineral salts and serves to lubricate joints. [NIH] Synovial Membrane: The inner membrane of a joint capsule surrounding a freely movable joint. It is loosely attached to the external fibrous capsule and secretes synovial fluid. [NIH]

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Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systemic therapy: Treatment that uses substances that travel through the bloodstream, reaching and affecting cells all over the body. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Temperament: Predisposition to react to one's environment in a certain way; usually refers to mood changes. [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] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Tenuazonic Acid: 3-Acetyl-5-sec-butyl-4-hydroxy-3-pyrrolin-2-one. A metabolite found in a strain of the fungus Alternaria tenuis Auct. which functions as an antibiotic with antiviral and antineoplastic properties, and may also act as a mycotoxin. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Teratoma: A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas occur most often in the ovaries in women, the testicles in men, and the tailbone in children. Not all teratomas are malignant. [NIH] Testicles: The two egg-shaped glands found inside the scrotum. They produce sperm and male hormones. Also called testes. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] 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]

Thalidomide: A pharmaceutical agent originally introduced as a non-barbiturate hypnotic,

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but withdrawn from the market because of its known tetratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor alpha from monocytes, and modulates other cytokine action. [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 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] Thermal: Pertaining to or characterized by heat. [EU] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Thioguanine: An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia. [NIH] Thiostrepton: Polypeptide-containing antibiotic isolated from a species of Streptomyces in New Mexican soil. It appears to be highly active against gram-positive bacteria. In veterinary medicine, thiostrepton has been used in mastitis caused by gram-negative organisms and in dermatologic disorders. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]

Thymidylate Synthase: An enzyme of the transferase class that catalyzes the reaction 5,10methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 2.1.1.45. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH]

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Metabolites

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] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Culture: Maintaining or growing of tissue, organ primordia, or the whole or part of an organ in vitro so as to preserve its architecture and/or function (Dorland, 28th ed). Tissue culture includes both organ culture and cell culture. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tome: A zone produced by a number of irregular spaces contained in the outermost layer of denture of the root of a tooth. [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] Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Tooth Preparation: Procedures carried out with regard to the teeth or tooth structures preparatory to specified dental therapeutic and surgical measures. [NIH] Topical: On the surface of the body. [NIH] Topoisomerase inhibitors: A family of anticancer drugs. The topoisomerase enzymes are responsible for the arrangement and rearrangement of DNA in the cell and for cell growth and replication. Inhibiting these enzymes may kill cancer cells or stop their growth. [NIH] Toremifene: A first generation selective estrogen receptor modulator (SERM). Like tamoxifen, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Tourniquet: A device, band or elastic tube applied temporarily to press upon an artery to stop bleeding; a device to compress a blood vessel in order to stop bleeding. [NIH] Toxemia: A generalized intoxication produced by toxins and other substances elaborated by an infectious agent. [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 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

Dictionary 353

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] Trachoma: A chronic infection of the conjunctiva and cornea caused by Chlamydia trachomatis. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transdermal: Entering through the dermis, or skin, as in administration of a drug applied to the skin in ointment or patch form. [EU] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Transgenes: Genes that are introduced into an organism using gene transfer techniques. [NIH]

Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trichloroethylene: A highly volatile inhalation anesthetic used mainly in short surgical procedures where light anesthesia with good analgesia is required. It is also used as an industrial solvent. Prolonged exposure to high concentrations of the vapor can lead to cardiotoxicity and neurological impairment. [NIH] Trichomoniasis: An infection with the protozoan parasite Trichomonas vaginalis. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU]

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Metabolites

Trimebutine: Proposed spasmolytic with possible local anesthetic action used in gastrointestinal disorders. [NIH] Trivalent: Having a valence of three. [EU] Troglitazone: A drug used in diabetes treatment that is being studied for its effect on reducing the risk of cancer cell growth in fat tissue. [NIH] 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] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberculostatic: Inhibiting the growth of Mycobacterium tuberculosis. [EU] 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] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs from it. It has a molecular weight of less than 70,000 kDa. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumorigenic: Chemical, viral, radioactive or other agent that causes cancer; carcinogenic. [NIH]

Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tylosin: Macrolide antibiotic obtained from cultures of Streptomyces fradiae. The drug is effective against many microorganisms in animals but not in humans. [NIH] Typhimurium: Microbial assay which measures his-his+ reversion by chemicals which cause base substitutions or frameshift mutations in the genome of this organism. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Ultrafiltration: The separation of particles from a suspension by passage through a filter with very fine pores. In ultrafiltration the separation is accomplished by convective transport; in dialysis separation relies instead upon differential diffusion. Ultrafiltration occurs naturally and is a laboratory procedure. Artificial ultrafiltration of the blood is referred to as hemofiltration or hemodiafiltration (if combined with hemodialysis). [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH]

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Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Uricosuric: 1. Pertaining to, characterized by, or promoting uricosuria (= the excretion of uric acid in the urine). 2. An agent that promotes uricosuria. [EU] Uridine Diphosphate: A uracil nucleotide containing a pyrophosphate group esterified to C5 of the sugar moiety. [NIH] Uridine Diphosphate Glucuronic Acid: A nucleoside diphosphate sugar which serves as a source of glucuronic acid for polysaccharide biosynthesis. It may also be epimerized to UDP iduronic acid, which donates iduronic acid to polysaccharides. In animals, UDP glucuronic acid is used for formation of many glucosiduronides with various aglycones. [NIH] Urinalysis: Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]

Urinate: To release urine from the bladder to the outside. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccines: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa, or rickettsiae), antigenic proteins derived from them, or synthetic constructs, administered for the prevention, amelioration, or treatment of infectious and other diseases. [NIH]

Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [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]

356

Metabolites

Valves: Flap-like structures that control the direction of blood flow through the heart. [NIH] Varicose: The common ulcer in the lower third of the leg or near the ankle. [NIH] Varicose vein: An abnormal swelling and tortuosity especially of the superficial veins of the legs. [EU] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vascular Headaches: A group of disorders characterized by recurrent headaches associated with abnormal dilation and constriction of cerebral blood vessels. Representative disorders from this category include migraine, cluster headache, and paroxysmal hemicrania. [NIH] Vascular Resistance: An expression of the resistance offered by the systemic arterioles, and to a lesser extent by the capillaries, to the flow of blood. [NIH] Vasoactive: Exerting an effect upon the calibre of blood vessels. [EU] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [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] Venoms: Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins, and other substances. These substances are produced in specialized glands and secreted through specialized delivery systems (nematocysts, spines, fangs, etc.) for disabling prey or predator. [NIH] Venous: Of or pertaining to the veins. [EU] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Ventricular Pressure: The pressure within a cardiac ventricle. Ventricular pressure waveforms can be measured in the beating heart by catheterization or estimated using imaging techniques (e.g., Doppler echocardiography). The information is useful in evaluating the function of the myocardium, cardiac valves, and pericardium, particularly with simultaneous measurement of other (e.g., aortic or atrial) pressures. [NIH] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH]

Dictionary 357

Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Villi: The tiny, fingerlike projections on the surface of the small intestine. Villi help absorb nutrients. [NIH] Villus: Cell found in the lining of the small intestine. [NIH] Vimentin: An intermediate filament protein found in most differentiating cells, in cells grown in tissue culture, and in certain fully differentiated cells. Its insolubility suggests that it serves a structural function in the cytoplasm. MW 52,000. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Vinyl Chloride: A gas that has been used as an aerosol propellant and is the starting material for polyvinyl resins. Toxicity studies have shown various adverse effects, particularly the occurrence of liver neoplasms. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Viral Load: The quantity of measurable virus in the blood. Change in viral load, measured in plasma, is used as a surrogate marker in HIV disease progression. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virulent: A virus or bacteriophage capable only of lytic growth, as opposed to temperate phages establishing the lysogenic response. [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] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitamin D: The vitamin that mediates intestinal calcium absorption, bone calcium metabolism, and probably muscle activity. It usually acts as a hormone precursor, requiring 2 stages of metabolism before reaching actual hormonal form. It is isolated from fish liver oils and used in the treatment and prevention of rickets. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye

358

Metabolites

(corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitreous Humor: The transparent, colorless mass of gel that lies behind the lens and in front of the retina and fills the center of the eyeball. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Void: To urinate, empty the bladder. [NIH] War: Hostile conflict between organized groups of people. [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] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xanthophyll: A carotenoid alcohol widespread in nature. It is present in egg yolk, algae, and petals of yellow flowers, among other sources. [NIH] Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc. [NIH]

Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH] 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]

359

INDEX 1 1-Methyl-4-phenyl-1,2,3,6tetrahydropyridine, 43, 253 A Abacavir, 109, 253 Abdominal, 202, 253, 308, 315, 325, 328, 333, 346, 354 Abdominal Pain, 202, 253, 308, 328, 354 Aberrant, 64, 253 Abortion, 253, 274, 323, 332 Acceptor, 253, 294, 298, 311, 324, 344, 348, 353 Acetaminophen, 49, 53, 253 Acetylcholine, 18, 46, 205, 253, 274, 321 Acetylcysteine, 186, 187, 253 Acidemia, 36, 253 Acidity, 253 Acidosis, 42, 223, 253 Acoustic, 190, 253 Acquired Immunodeficiency Syndrome, 191, 253, 302, 348 Acrylamide, 58, 254 Acrylonitrile, 254, 341 Actin, 7, 254, 318, 319 Action Potentials, 212, 254 Acute leukemia, 254, 332, 351 Acute lymphoblastic leukemia, 88, 132, 254 Acute lymphocytic leukemia, 254 Acute myelogenous leukemia, 9, 254 Acute myeloid leukemia, 254, 334 Acute nonlymphocytic leukemia, 254 Acute renal, 254, 301 Acyl, 4, 26, 80, 128, 209, 254, 312, 329 Acylation, 4, 254 Adaptability, 254, 272 Adaptation, 6, 254, 317 Adduct, 8, 20, 22, 28, 44, 47, 54, 59, 254 Adduction, 54, 254 Adenine, 22, 254, 336 Adenocarcinoma, 61, 141, 254, 268, 301, 321 Adenosine, 69, 254, 255, 263, 268, 329, 351 Adenosine Deaminase, 69, 255 Adenovirus, 53, 255 Adjustment, 254, 255 Adjuvant, 197, 255, 295 Adjuvant Therapy, 197, 255

Adolescence, 13, 255 Adrenal Cortex, 255, 256, 280, 290, 323, 333 Adrenal Medulla, 255, 271, 289, 290, 321 Adrenergic, 7, 255, 261, 285, 290, 349 Adsorption, 112, 255 Adsorptive, 255 Adverse Effect, 189, 255, 275, 329, 344, 357 Aerobic, 77, 181, 255, 291, 316, 325 Aerobic Metabolism, 255, 325 Aerobic Respiration, 255, 325 Aerosol, 255, 357 Affinity, 6, 18, 46, 68, 79, 171, 255, 256, 263, 275, 283, 311, 345 Affinity Chromatography, 6, 18, 68, 256 Agar, 256, 330 Agonist, 17, 30, 33, 35, 55, 187, 256, 265, 268, 285, 308, 321, 350, 352 Airway, 173, 256, 268, 344 Airway Resistance, 173, 256 Alanine, 56, 256 Albumin, 36, 78, 89, 256, 330, 349 Aldehyde Dehydrogenase, 45, 256 Aldehydes, 20, 256 Aldosterone, 216, 256 Alertness, 256, 268 Algorithms, 256, 266 Alimentary, 256, 326 Alkaline, 253, 256, 257, 269, 325, 350 Alkaloid, 256, 268, 269, 275, 276, 317, 321, 351 Alkylate, 17, 257 Alkylating Agents, 20, 257, 282, 354 Alkylation, 11, 20, 257 Allergic Rhinitis, 196, 257, 300 Allylamine, 257 Alpha Particles, 257, 337 Alternative medicine, 226, 257 Amebiasis, 257, 315 Ameliorated, 43, 257 Amine, 5, 6, 22, 70, 82, 257, 301 Amino Acid Sequence, 198, 257, 258, 259, 295, 344 Ammonia, 255, 257, 349, 354 Amnesia, 213, 257 Amnestic, 257, 293 Amniotic Fluid, 258, 313 Amphetamine, 17, 125, 258, 283

360

Metabolites

Amplification, 7, 85, 168, 258 Amylase, 195, 258 Anaerobic, 68, 70, 71, 77, 79, 181, 258 Anaesthesia, 99, 126, 258, 305 Anal, 258, 284 Analgesic, 35, 187, 188, 253, 258, 268, 276, 284, 303, 310, 317, 323, 325 Analog, 74, 186, 190, 253, 258, 265, 283, 293 Analogous, 18, 258, 331, 353 Analytes, 13, 45, 201, 206, 207, 222, 258, 348 Anaphylatoxins, 258, 277 Anaplasia, 258 Anatomical, 258, 263, 278, 284, 305, 311, 316, 342 Androgen-Binding Protein, 258, 344 Androgenic, 103, 258 Androgens, 30, 200, 255, 258 Anemia, 52, 202, 258, 293, 312, 317 Anesthesia, 95, 213, 256, 258, 259, 280, 333, 353 Anesthetics, 259, 264, 290 Aneurysm, 259, 356 Angina, 196, 259, 308, 321 Angiogenesis, 48, 106, 190, 259, 313, 333 Angiogenesis inhibitor, 190, 259, 333 Angiotensinogen, 63, 259, 339 Animal model, 19, 36, 41, 47, 259 Anions, 256, 259, 307, 333, 343 Ankle, 259, 356 Anorexia, 259, 261 Antagonism, 259, 268, 275, 351 Anthelmintic, 72, 259 Anthracycline, 69, 84, 259, 282 Antiandrogens, 200, 259 Antiangiogenesis, 144, 259 Antibacterial, 259, 308, 323, 333, 346 Antibiotic, 11, 69, 79, 82, 151, 259, 267, 282, 286, 290, 327, 331, 346, 347, 350, 351, 354 Antibodies, 25, 34, 54, 168, 171, 208, 259, 299, 302, 304, 312, 317, 330, 338 Anticholinergic, 192, 260 Anticoagulant, 78, 260, 334 Anticonvulsant, 117, 173, 260, 270, 329, 355 Antidiabetic, 11, 260 Antiepileptic, 117, 213, 260 Antifungal, 69, 131, 152, 260, 308, 309, 344 Antigen, 255, 259, 260, 277, 302, 303, 304, 305, 313, 316, 337, 349 Antigen-Antibody Complex, 260, 277

Antihypertensive, 260, 302 Anti-infective, 260, 293, 303 Anti-Infective Agents, 216, 260, 293 Anti-inflammatory, 48, 114, 253, 260, 272, 283, 284, 297, 332 Anti-Inflammatory Agents, 260, 272 Antimetabolite, 260, 293, 315, 351 Antimetastatic, 214, 260 Antimicrobial, 9, 77, 85, 136, 137, 260, 334 Antimycotic, 260, 334 Antineoplastic, 257, 260, 281, 286, 293, 295, 296, 314, 315, 325, 331, 344, 350, 351, 357 Antineoplastic Agents, 257, 260, 357 Antioxidant, 61, 143, 206, 260, 262, 268, 294, 324, 325 Antiphlogistic, 188, 260 Antipruritic, 260, 275 Antipsychotic, 260, 275, 320 Antipyretic, 253, 261, 284 Antiseptic, 261, 271 Antispasmodic, 192, 261, 323, 345 Antitumour, 182, 261 Antitussive, 261, 283, 323 Antiviral, 9, 70, 191, 253, 261, 295, 306, 319, 350 Anus, 258, 261, 267, 276 Anxiety, 196, 202, 203, 261, 273, 293, 322, 325 Aorta, 77, 261, 315, 356 Aplastic anemia, 9, 261 Apnea, 203, 261 Apoptosis, 5, 10, 21, 37, 43, 48, 52, 61, 63, 68, 112, 125, 126, 127, 136, 198, 261, 262, 271, 281 Appetite Stimulants, 220, 261 Aqueous, 134, 261, 274, 281, 303, 309, 311 Aqueous humor, 134, 261, 274 Arachidonate 12-Lipoxygenase, 261, 311 Arachidonate 15-Lipoxygenase, 261, 311 Arachidonate Lipoxygenases, 261, 311 Arginine, 73, 101, 216, 258, 262, 302, 321, 324, 337 Arrhythmia, 262, 356 Arsenic trioxide, 118, 262 Arterial, 40, 54, 183, 198, 216, 257, 262, 303, 304, 321, 335, 350 Arteries, 29, 261, 262, 266, 267, 273, 279, 315, 318, 351 Arterioles, 42, 54, 134, 262, 267, 269, 318, 356 Arteriolosclerosis, 262

361

Arteriosclerosis, 188, 262, 318 Arteriovenous, 223, 262 Artery, 129, 198, 259, 262, 263, 279, 287, 318, 336, 339, 352 Articular, 210, 262, 324 Ascites, 215, 262, 323 Ascitic Fluid, 216, 262 Ascorbic Acid, 135, 145, 262, 303 Aseptic, 262, 324 Aspartate, 16, 173, 211, 262, 283 Aspartic, 191, 262, 288, 302 Aspartic Acid, 262 Aspergillosis, 262, 308 Astringent, 263, 271 Astrocytes, 54, 263, 315, 317 Atmospheric Pressure, 111, 115, 125, 263 Atopic, 196, 263 ATP, 37, 263, 285, 294, 296, 329, 335, 353 Atrial, 216, 263, 356 Atrium, 263, 356 Atrophy, 200, 263, 320 Attenuated, 263, 284, 355 Attenuation, 196, 263 Atypical, 60, 90, 263, 275 Autoimmune disease, 263, 318 Autoimmunity, 202, 263 Autonomic, 205, 253, 261, 263, 280, 322, 326, 327, 345, 349 Autonomic Nervous System, 205, 263, 326, 327, 345, 349 Axillary, 263, 267 Axillary Artery, 263, 267 B Bacterial Infections, 31, 264, 272 Bacterial Physiology, 254, 264 Bactericidal, 264, 290 Bacteriophage, 264, 330, 353, 357 Bacteriostatic, 264, 290 Bacterium, 264, 278, 301 Bacteriuria, 264, 355 Barbiturate, 264, 350 Basal cell carcinoma, 213, 264 Basal cells, 264 Basal Ganglia, 261, 264, 267 Base Sequence, 264, 280, 294, 295 Basement Membrane, 264, 270, 292 Basidiomycete, 79, 84, 181, 264 Basophils, 264, 299, 310 Benign, 190, 208, 262, 264, 300, 319, 320, 338 Benign tumor, 190, 264 Benzamides, 137, 264

Benzene, 9, 53, 58, 75, 91, 107, 127, 131, 264, 265, 308 Benzo(a)pyrene, 76, 165, 264 Benzodiazepines, 109, 213, 265 Beta Rays, 265, 287 Beta-Glucosidase, 265, 297 Betahistine, 135, 265 Beta-Thromboglobulin, 265, 307 Bewilderment, 265, 278 Bile, 39, 70, 265, 294, 297, 301, 308, 311, 313, 347, 348 Bile Acids, 265, 347, 348 Bile Acids and Salts, 265 Bile duct, 265 Bile Pigments, 265, 308, 313 Biliary, 92, 143, 152, 265 Bilirubin, 105, 256, 265, 297, 303 Bioassay, 34, 265 Bioavailability, 42, 187, 189, 265, 305 Biochemical reactions, 172, 265 Biodegradation, 70, 72, 78, 265 Biological therapy, 265, 299 Biological Transport, 266, 284 Biomarkers, 12, 13, 22, 49, 57, 89, 91, 103, 118, 123, 131, 142, 266 Biomass, 193, 266 Biomolecular, 5, 266, 349 Biopolymers, 170, 266 Biotechnology, 56, 67, 88, 152, 209, 214, 218, 226, 237, 266 Biotic, 175, 266 Biotransformation, 49, 51, 53, 69, 70, 76, 93, 109, 180, 266 Bladder, 128, 192, 196, 266, 277, 281, 305, 318, 334, 355, 358 Blastomycosis, 266, 308 Bloating, 266, 305, 308 Blood Coagulation, 266, 269, 351 Blood Glucose, 176, 207, 266, 300, 306 Blood Platelets, 266, 330, 343 Blood pressure, 32, 188, 205, 260, 266, 270, 304, 317, 321, 332, 344, 345 Blood urea, 223, 267 Blood-Brain Barrier, 7, 267, 310 Body Fluids, 50, 72, 185, 222, 266, 267, 286, 293, 322, 339, 345, 354 Bone Marrow Cells, 267, 299 Bone Resorption, 59, 267 Bone scan, 267, 342 Boron, 94, 267, 280 Bowel, 202, 258, 267, 305, 307, 328, 347, 354

362

Metabolites

Bowel Movement, 267, 347 Brachial, 32, 267 Brachial Artery, 32, 267 Brachytherapy, 267, 307, 308, 337, 358 Bradykinin, 267, 321, 330 Brain Diseases, 15, 267 Brain Stem, 267, 272, 326 Broad-spectrum, 34, 45, 267, 323 Bronchi, 268, 290, 291, 313, 351, 353 Bronchial, 196, 265, 268, 301, 351 Bronchial Hyperreactivity, 196, 268 Bronchitis, 187, 268 Bronchus, 101, 268 Buccal, 40, 268, 311 Bupivacaine, 268, 310 Buprenorphine, 33, 268 Bupropion, 91, 268 Butylated Hydroxytoluene, 10, 268 Butyric Acid, 158, 174, 175, 268 C Caco-2 Cells, 95, 268 Cadaverine, 193, 268 Caffeine, 50, 135, 268, 336 Calcification, 199, 262, 268 Calcineurin, 168, 268 Calcitonin, 83, 95, 269 Calcitonin Gene-Related Peptide, 95, 269 Calcium channel blocker, 269, 356 Calmodulin, 7, 39, 268, 269 Caloric intake, 12, 269 Calpain, 39, 269 Camptothecin, 147, 269, 307 Cannula, 269, 326 Capecitabine, 117, 230, 269 Capillary, 6, 46, 49, 55, 93, 98, 110, 126, 184, 190, 267, 269, 271, 341, 356 Capillary Fragility, 269, 271, 341 Capsaicin, 150, 187, 269 Capsules, 175, 199, 270, 286, 295 Carbamazepine, 49, 270 Carbohydrate, 33, 35, 66, 73, 270, 297, 298, 322 Carbon Dioxide, 270, 280, 282, 303, 330, 340 Carboxy, 270, 308 Carboxylic Acids, 4, 270 Carcinoembryonic Antigen, 182, 270 Carcinogen, 6, 10, 16, 20, 21, 44, 47, 118, 254, 264, 270, 290, 314, 315 Carcinogenesis, 16, 22, 26, 37, 39, 41, 47, 60, 107, 112, 176, 270, 273

Carcinogenic, 17, 20, 39, 44, 47, 53, 102, 257, 264, 270, 273, 275, 306, 321, 334, 347, 354 Carcinogenicity, 47, 270 Carcinoma, 44, 60, 182, 213, 270, 281, 321, 346 Carcinoma in Situ, 60, 213, 270 Cardiac, 40, 135, 200, 257, 268, 269, 270, 279, 287, 290, 300, 310, 318, 319, 347, 356 Cardiac Output, 40, 270 Cardiotoxic, 40, 270 Cardiovascular, 7, 29, 32, 39, 40, 94, 95, 122, 188, 196, 200, 206, 217, 258, 270, 291, 343, 345 Cardiovascular disease, 39, 122, 200, 206, 270 Carnitine, 43, 270 Carotene, 58, 270, 340 Carotenoids, 31, 81, 270 Carrier Proteins, 271, 330, 338 Case report, 93, 271, 275 Case series, 271, 275 Case-Control Studies, 39, 271 Caspase, 39, 63, 136, 271 Castration, 271 Catabolism, 51, 70, 109, 271 Catalytic Domain, 14, 271 Cataracts, 64, 271 Catechin, 144, 271 Catechol, 8, 46, 271 Catecholamine, 46, 119, 148, 271, 285 Catheter, 198, 271 Catheterization, 271, 318, 356 Cathode, 265, 271, 287 Cations, 271, 307 Caudal, 271, 284, 304, 332 Causal, 63, 271 Cause of Death, 189, 198, 271 Celecoxib, 113, 271 Cell Adhesion, 153, 272 Cell Cycle, 56, 272, 275, 281, 291, 335, 356 Cell Death, 49, 51, 68, 173, 261, 262, 272, 291, 319 Cell Differentiation, 10, 65, 272 Cell Division, 263, 272, 280, 291, 299, 314, 316, 330, 334, 342 Cell membrane, 266, 271, 272, 283, 295, 329, 331, 332, 345 Cell proliferation, 42, 56, 63, 128, 145, 262, 272, 335 Cell Respiration, 255, 272, 316, 325, 340 Cell Survival, 272, 299

363

Cellular metabolism, 198, 272 Cellulose, 272, 294, 330 Central Nervous System Infections, 272, 300, 302 Centrifugation, 272, 316 Ceramide, 10, 51, 272 Cerebellum, 207, 267, 272 Cerebral, 16, 54, 97, 100, 120, 124, 146, 183, 185, 203, 264, 267, 272, 273, 279, 290, 291, 293, 302, 312, 336, 337, 345, 356 Cerebral Arteries, 55, 273 Cerebral Cortex, 267, 273, 291, 293, 337 Cerebrospinal, 3, 71, 79, 82, 94, 104, 109, 120, 123, 217, 273, 302 Cerebrospinal fluid, 3, 71, 79, 94, 104, 109, 120, 123, 273, 302 Cerebrovascular, 54, 206, 270, 273, 321 Cerebrum, 272, 273, 330 Cervical, 189, 273 Cervix, 253, 273 Chemical Warfare, 13, 273 Chemical Warfare Agents, 13, 273 Chemoprevention, 37, 52, 63, 176, 177, 204, 273 Chemopreventive, 16, 51, 61, 63, 65, 164, 176, 189, 204, 273 Chemotactic Factors, 273, 277 Chemotherapeutic agent, 52, 65, 273 Chemotherapeutics, 189, 273 Chemotherapy, 33, 46, 63, 92, 113, 157, 182, 189, 217, 255, 273 Chimaera, 182, 273 Chimera, 77, 273 Chloral Hydrate, 50, 273 Chloroform, 24, 273 Chlorogenic Acid, 129, 273 Chlorophyll, 273, 274, 280, 294 Chloroplasts, 274, 280 Chloroquine, 52, 78, 110, 274 Cholesterol, 20, 153, 188, 198, 265, 274, 279, 311, 314, 344, 347, 350, 352 Choline, 16, 46, 122, 138, 274 Cholinergic, 46, 205, 261, 274, 321 Chondrocytes, 136, 274, 293 Chondroitin sulfate, 210, 274 Choriocarcinoma, 33, 274, 296, 302, 316 Choroid, 274, 340 Chromatin, 261, 274, 321, 346 Chromium, 135, 145, 151, 274 Chromosomal, 152, 258, 274, 296, 301 Chromosome, 199, 274, 278, 299, 308, 310, 313, 342

Chronic, 10, 13, 16, 44, 46, 61, 85, 89, 92, 102, 119, 128, 155, 188, 196, 203, 211, 220, 221, 222, 257, 266, 268, 274, 276, 289, 305, 309, 327, 336, 342, 348, 350, 353, 354 Chronic Disease, 211, 274, 276 Chronic Fatigue Syndrome, 102, 274 Chronic renal, 188, 220, 221, 222, 274 Ciliary, 261, 274 Ciliary processes, 261, 274 Cirrhosis, 215, 274, 332 CIS, 21, 24, 71, 80, 110, 274, 340 Cisplatin, 182, 275 Clamp, 64, 275 Clear cell carcinoma, 275, 283, 284 Clinical Medicine, 275, 332 Clinical Protocols, 25, 275 Clinical study, 222, 275 Clinical trial, 4, 16, 19, 34, 43, 61, 124, 237, 275, 279, 281, 335, 338 Clone, 66, 275 Cloning, 8, 11, 266, 275 Clozapine, 101, 105, 157, 275 Coal Tar, 44, 275 Coca, 275 Cocaethylene, 131, 275 Cocaine, 25, 40, 97, 108, 122, 131, 203, 275 Codeine, 89, 276, 283, 303, 323, 325 Codon, 276, 296 Coenzyme, 43, 262, 276, 311, 344 Cofactor, 56, 276, 335, 351 Cognition, 47, 103, 276, 320 Cohort Studies, 39, 276 Colchicine, 134, 276 Colitis, 202, 276, 308 Collagen, 94, 196, 257, 264, 271, 276, 278, 292, 293, 295, 313, 330, 334 Collagen disease, 196, 276 Collagenases, 197, 276 Collapse, 276, 344 Colloidal, 256, 276, 287, 343 Colon, 37, 51, 60, 108, 164, 189, 213, 270, 276, 305, 308, 309, 354 Colorectal, 31, 39, 182, 184, 276, 335 Colorectal Cancer, 39, 184, 276, 335 Communis, 146, 276 Complement, 42, 62, 70, 258, 277, 296, 308, 330 Complementary and alternative medicine, 141, 161, 277 Complementary medicine, 141, 277 Compliance, 19, 34, 277

364

Metabolites

Compulsions, 277, 322 Computational Biology, 237, 277 Computed tomography, 277, 278, 342 Computerized axial tomography, 277, 342 Concentric, 262, 278, 322 Conception, 253, 274, 278, 292, 296, 316, 332 Cone, 278, 329 Confusion, 100, 278, 285, 320, 355 Conjugated, 49, 69, 99, 265, 278, 281 Conjugation, 10, 31, 266, 278, 297, 348 Conjunctiva, 278, 353 Conjunctivitis, 196, 278, 300 Connective Tissue, 136, 198, 210, 262, 267, 276, 278, 283, 295, 311, 314, 340, 341, 350 Connective Tissue Cells, 278 Connective Tissue Diseases, 136, 210, 278 Connexins, 64, 278, 295 Consciousness, 47, 258, 278, 282, 285, 301, 336, 346 Constipation, 261, 278, 308, 328, 344 Constriction, 278, 308, 356 Constriction, Pathologic, 278, 356 Consultation, 23, 25, 278 Contact dermatitis, 196, 279 Contamination, 13, 66, 114, 178, 279 Continuous infusion, 123, 279 Contractility, 40, 279 Contraindications, ii, 279 Control group, 3, 279 Conventional therapy, 279 Conventional treatment, 52, 279 Convulsions, 260, 264, 279 Coordination, 170, 272, 279, 318 Cornea, 67, 134, 261, 279, 298, 353 Corneum, 20, 279, 289 Coronary, 29, 129, 134, 198, 218, 270, 279, 315, 318, 321 Coronary Disease, 198, 279 Coronary heart disease, 270, 279 Coronary Thrombosis, 279, 315, 318 Coronary Vessels, 279 Corpus, 279, 327, 333, 358 Corpus Luteum, 279, 333 Cortex, 279, 280 Cortical, 71, 101, 280, 291, 342 Cortisol, 106, 256, 280 Cortisone, 280, 283, 332 Cranial, 272, 280, 300, 320, 326, 327 Cranial Nerves, 280 Craniocerebral Trauma, 185, 280, 300, 302 Creatine, 130, 150, 280

Creatinine, 280 Croton Oil, 280, 329 Cruciferous vegetables, 280, 305 Cultured cell line, 207, 280 Cultured cells, 116, 280 Curare, 280, 318 Curative, 280, 321, 341, 351 Curcumin, 144, 280 Cutaneous, 49, 196, 266, 279, 280, 311 Cyanobacteria, 153, 164, 280 Cyclic, 39, 73, 268, 269, 281, 299, 321, 351 Cyclins, 56, 281, 313 Cyclophosphamide, 281, 304 Cyclosporine, 62, 97, 117, 143, 157, 168, 281 Cyproterone, 281, 293 Cystamine, 281 Cysteamine, 82, 281 Cysteine, 10, 23, 54, 60, 132, 137, 186, 187, 193, 253, 269, 281, 285, 288, 348 Cysteinyl, 95, 101, 281 Cystine, 281, 285 Cystitis, 196, 281 Cytokine, 281, 307, 344, 351 Cytoplasm, 36, 72, 168, 261, 264, 272, 281, 282, 287, 289, 319, 321, 322, 341, 357 Cytosine, 182, 282, 337 Cytoskeletal Proteins, 269, 282 Cytostatic, 182, 282 Cytotoxic, 17, 53, 119, 120, 182, 189, 269, 282, 338 Cytotoxic chemotherapy, 189, 282 Cytotoxicity, 5, 11, 16, 45, 53, 71, 93, 122, 136, 150, 197, 208, 257, 275, 282 D Dacarbazine, 131, 282 Dairy Products, 199, 282 Data Collection, 26, 282 Daunorubicin, 282, 286 Decarboxylation, 268, 282, 301, 337 Degenerative, 282, 324, 340 Dehydroepiandrosterone, 26, 103, 107, 122, 157, 282 Deletion, 261, 282 Delivery of Health Care, 282, 300 Dementia, 3, 16, 39, 46, 197, 253, 260, 282 Denaturation, 24, 282 Dendrites, 282, 320 Density, 55, 190, 272, 282, 311, 323, 345 Deoxyribonucleic, 282, 340, 341 Depolarization, 54, 186, 282 Dermal, 221, 283

365

Dermatitis, 196, 283 Dermis, 283, 349, 353 DES, 164, 165, 193, 258, 283, 284 Detoxification, 11, 19, 23, 46, 49, 99, 283, 297 Deuterium, 24, 283, 303 Developed Countries, 283, 293 Dexamethasone, 75, 283 Dextroamphetamine, 258, 283, 315 Dextromethorphan, 62, 283 Diabetes Mellitus, 176, 210, 283, 297, 300 Diabetic Ketoacidosis, 283, 309 Diagnostic procedure, 167, 226, 283 Dialysate, 103, 220, 283 Dialyzer, 283, 300 Diarrhea, 202, 257, 283, 308, 309 Diastolic, 283, 304 Dichloroacetate, 50, 284 Diclofenac, 5, 90, 128, 284 Diclofenac Sodium, 284 Diencephalon, 284, 304, 350 Dietetics, 222, 284 Diethylstilbestrol, 74, 283, 284 Diffusion, 42, 100, 221, 266, 284, 354 Digestion, 51, 256, 265, 267, 284, 305, 307, 311, 327, 347, 355 Digestive tract, 221, 284, 344, 346 Dihydrotestosterone, 141, 284, 338, 344 Dihydroxy, 32, 47, 48, 256, 284, 291, 341 Dilatation, Pathologic, 284, 356 Dilate, 134, 284 Dilation, 29, 42, 267, 284, 302, 356 Dilator, 29, 54, 284, 321 Dilution, 23, 26, 114, 284 Dimerization, 11, 284 Dimethyl, 24, 48, 181, 193, 197, 203, 284 Dipeptidases, 10, 284 Dipeptides, 284 Diploid, 284, 330 Discrete, 284, 350 Discriminant Analysis, 12, 284 Discrimination, 17, 66, 284 Disease Transmission, 26, 285 Disease Transmission, Horizontal, 285 Disease Transmission, Vertical, 285 Disease Vectors, 285, 306 Disinfectant, 285, 290 Disorientation, 278, 285 Disposition, 63, 92, 93, 94, 123, 147, 150, 184, 187, 285 Dissociation, 65, 96, 255, 285, 307 Dissociative Disorders, 285

Distal, 285, 287 Disulphide, 148, 285 Diuresis, 268, 285, 351 Diuretic, 285, 308 DNA Topoisomerase, 285, 296 Dopamine, 43, 49, 181, 203, 205, 258, 261, 268, 275, 283, 285, 310, 317, 321, 329 Dosage Forms, 181, 203, 286, 328 Dose-dependent, 105, 286 Doxorubicin, 129, 286 Drive, ii, vi, 22, 23, 28, 59, 133, 220, 286, 310 Dross, 286, 334 Drug Interactions, 33, 41, 62, 208, 231, 286 Drug Monitoring, 90, 101, 110, 132, 168, 286 Drug Resistance, 16, 45, 189, 286 Drug Tolerance, 286, 352 Duct, 71, 200, 269, 271, 286, 341, 349 Duodenum, 265, 286, 327, 347 Dyes, 214, 264, 286, 294, 319, 321, 328 Dysplasia, 213, 286 Dystrophy, 196, 286 E Eating Disorders, 155, 203, 286 Echocardiography, 286, 356 Edema, 279, 286, 309, 318, 320, 323 Effector, 48, 57, 170, 171, 253, 277, 286 Efficacy, 12, 46, 52, 61, 62, 63, 182, 188, 189, 202, 286 Egg Yolk, 287, 358 Eicosanoids, 7, 38, 48, 55, 61, 287 Elasticity, 262, 287 Elastin, 276, 278, 287, 292 Electrode, 116, 271, 287 Electrolyte, 222, 256, 287, 293, 300, 322, 332, 345 Electrons, 24, 260, 265, 271, 287, 307, 312, 324, 325, 337, 338, 348 Electrophoresis, 46, 93, 98, 110, 126, 201, 254, 287 Electrophysiological, 37, 287 Electroplating, 271, 287 Elementary Particles, 287, 312, 321, 335 Emaciation, 253, 287 Embolus, 287, 305 Embryo, 86, 253, 272, 287, 305, 323, 331, 332, 346 Embryo Transfer, 287, 332 Emesis, 196, 287 Emollient, 287, 298, 323 Empirical, 41, 87, 287

366

Metabolites

Encapsulated, 26, 288 Encephalitis, 117, 288 Encephalitis, Viral, 288 Encephalomyelitis, 136, 288 Endemic, 288, 312, 346 Endometrial, 17, 31, 189, 288 Endometrium, 288 Endopeptidases, 288, 334 Endorphins, 288, 321 Endothelial cell, 39, 40, 42, 48, 54, 129, 145, 148, 190, 198, 267, 288, 293, 307, 351 Endothelium, 29, 32, 42, 79, 206, 288, 321 Endothelium, Lymphatic, 288 Endothelium, Vascular, 288 Endothelium-derived, 206, 288, 321 Endotoxic, 288, 311 Endotoxins, 186, 277, 289, 308 End-stage renal, 154, 222, 274, 289 Enhancers, 168, 289 Enkephalins, 289, 321 Enterocytes, 268, 289 Environmental Health, 44, 91, 96, 97, 100, 103, 111, 123, 130, 236, 238, 242, 289 Environmental Pollutants, 53, 289, 331 Enzymatic, 5, 7, 11, 23, 55, 59, 74, 208, 219, 257, 269, 270, 271, 277, 281, 289, 301, 314, 340 Enzyme Activation, 44, 289 Enzyme Inhibitors, 63, 289, 330 Eosinophil, 289, 299 Epidemic, 289, 346 Epidemiological, 6, 51, 132, 289 Epidermal, 7, 21, 289, 308, 314 Epidermal Growth Factor, 7, 289 Epidermis, 20, 44, 264, 279, 283, 289, 308, 333, 336 Epidural, 95, 289 Epinephrine, 255, 285, 290, 321, 354 Epithelial, 52, 56, 65, 76, 78, 81, 102, 109, 165, 254, 266, 270, 289, 290 Epithelial Cells, 52, 56, 65, 76, 78, 81, 102, 109, 165, 289, 290 Epithelium, 81, 95, 264, 274, 288, 289, 290, 307 Erectile, 290, 327 Erythema, 279, 290, 355 Erythrocytes, 129, 132, 258, 267, 269, 290, 338 Erythroleukemia, 81, 290 Erythromycin, 14, 290 Esophagus, 284, 290, 313, 327, 347 Estradiol, 28, 94, 95, 107, 188, 200, 290, 344

Estrogen Antagonists, 17, 290 Estrogen receptor, 17, 28, 65, 149, 151, 290 Estrogen receptor negative, 65, 290 Estrogen receptor positive, 17, 290 Estrone, 30, 83, 95, 290 Ethanol, 61, 104, 121, 218, 290, 292 Ether, 86, 136, 291 Ethnic Groups, 177, 291 Ethylene Glycol, 100, 136, 291 Etoposide, 8, 91, 291 Eukaryotic Cells, 282, 291, 324 Evoke, 291, 347 Excipients, 291, 293, 328 Excitation, 178, 179, 291, 321 Excitatory, 54, 291, 297, 308 Excitatory Amino Acid Agonists, 291, 308 Exercise Test, 291 Exercise Tolerance, 90, 291 Exhaustion, 259, 291, 312 Exogenous, 29, 35, 52, 59, 78, 195, 255, 266, 288, 291, 295, 297, 334, 348 Expectorant, 187, 291 Expiration, 291, 340 External-beam radiation, 292, 307, 337, 358 Extracellular, 20, 36, 97, 103, 169, 199, 216, 263, 278, 292, 293, 313, 315, 345, 350 Extracellular Matrix, 20, 199, 278, 292, 293, 313 Extracellular Matrix Proteins, 292, 313 Extracellular Space, 292, 315 Extraction, 22, 24, 74, 75, 98, 99, 106, 116, 131, 174, 209, 292 Extrapyramidal, 36, 261, 285, 292 Extravascular, 196, 292 Exudate, 291, 292, 323 Eye Infections, 255, 292 F Family Planning, 237, 292 Fascioliasis, 196, 292 Fatigue, 274, 292, 300 Feces, 153, 270, 278, 292, 347 Femoral, 123, 292 Femur, 292 Fermentation, 31, 75, 165, 177, 186, 193, 209, 220, 292, 294 Fertilization in Vitro, 292, 332 Fetus, 253, 292, 313, 330, 333, 346, 347, 355 Fibrinogen, 293, 330, 351 Fibroblast Growth Factor, 63, 293 Fibroblasts, 79, 100, 198, 278, 293, 306, 307 Filtration, 222, 293

367

Fissure, 277, 293 Flatus, 293, 295 Flavoring Agents, 293, 328 Fluid Therapy, 293, 322 Fluorescence, 59, 124, 134, 146, 153, 173, 178, 179, 194, 293 Fluorouracil, 106, 182, 230, 293 Flutamide, 104, 293 Fluvoxamine, 41, 105, 293 Folate, 31, 61, 293 Fold, 41, 54, 293, 315, 325 Folic Acid, 58, 61, 293 Food Additives, 175, 293 Food Coloring Agents, 293, 294 Food Preservatives, 293, 294 Foramen, 277, 294, 328 Forearm, 267, 294 Fossa, 272, 294 Fractionation, 34, 294 Frameshift, 70, 294, 354 Frameshift Mutation, 294, 354 Free Radicals, 260, 285, 294, 319 Friction, 210, 256, 294 Fungus, 71, 80, 92, 120, 142, 154, 294, 310, 350 G Galactitol, 15, 294 Galactokinase, 294 Galactosemia, 15, 294 Gallate, 147, 149, 294 Gallbladder, 253, 265, 294 Gamma Rays, 294, 318, 337, 338 Gamma-interferon, 75, 169, 295 Ganglia, 253, 295, 320, 326, 327, 349 Gap Junctions, 64, 278, 295, 349 Gasoline, 264, 295 Gastric, 96, 188, 270, 286, 289, 295, 301, 327 Gastrin, 295, 302 Gastrointestinal, 69, 115, 152, 202, 216, 221, 267, 270, 290, 295, 309, 312, 343, 345, 348, 354 Gastrointestinal tract, 270, 290, 295, 309, 343, 354 Gelatin, 295, 298, 351 Gelatinases, 198, 295 Gene Expression, 38, 40, 65, 72, 73, 175, 200, 295 Gene Silencing, 59, 295 Gene Targeting, 36, 295 Gene Therapy, 36, 208, 255, 295 Genetic Code, 213, 295, 322 Genetic Engineering, 11, 209, 266, 275, 296

Genetic Screening, 31, 296 Genetic Techniques, 14, 296 Genetics, 134, 255, 278, 296 Genistein, 27, 145, 150, 175, 296 Genomics, 38, 65, 296 Genotype, 8, 40, 296, 329 Germ Cells, 296, 314, 323, 324, 345, 346, 350 Gestation, 50, 296, 327, 330, 346 Gestational, 32, 296, 316 Gestational trophoblastic disease, 32, 296, 316 Gestational trophoblastic neoplasia, 296, 316 Gestational trophoblastic tumor, 296, 316 Giardiasis, 296, 315 Ginseng, 148, 159, 296 Gland, 78, 200, 255, 280, 296, 311, 313, 325, 326, 330, 334, 342, 347, 348, 349, 352 Glioma, 91, 112, 296 Glomerular, 222, 297, 339 Glomeruli, 73, 297 Glomerulus, 297 Glucocorticoid, 111, 283, 297, 332 Gluconeogenesis, 134, 297 Glucose Intolerance, 223, 283, 297 Glucose tolerance, 297 Glucose Tolerance Test, 297 Glucosylceramides, 21, 297 Glucuronic Acid, 297, 355 Glucuronides, 4, 146, 165, 297 Glucuronosyltransferase, 111, 297 Glutamate, 54, 91, 108, 205, 283, 297, 308 Glutamic Acid, 293, 297, 321, 334 Glutathione Peroxidase, 297, 343 Glycerol, 91, 209, 268, 298, 329 Glycerophospholipids, 298, 329 Glycine, 173, 211, 257, 265, 298, 321, 343 Glycoprotein, 76, 154, 270, 293, 298, 299, 309, 317, 343, 344, 351, 354 Glycosaminoglycan, 274, 298 Glycoside, 298, 303, 341 Glycosidic, 297, 298, 329 Glycosyltransferases, 35, 298 Goats, 282, 298 Gonad, 298 Gonadal, 35, 298, 347 Gonadotropic, 200, 298 Gonadotropin, 274, 298 Gout, 276, 298 Governing Board, 298, 332 Gp120, 76, 298

368

Metabolites

Grade, 123, 298 Gram-negative, 281, 289, 299, 323, 351 Gram-Negative Bacteria, 281, 289, 299 Gram-positive, 299, 323, 351 Gram-Positive Bacteria, 299, 323, 351 Granulocyte, 84, 299 Granulocyte-Macrophage ColonyStimulating Factor, 84, 299 Granulomas, 190, 299 Grasses, 293, 299 Growth factors, 31, 220, 221, 299, 316 Guanine, 20, 22, 83, 299, 336 Guanylate Cyclase, 86, 299, 321 H Haematemesis, 287, 299 Haematoma, 299 Haemorrhage, 120, 185, 253, 299 Half-Life, 51, 103, 299 Halitosis, 193, 299 Haloperidol, 106, 116, 299 Haploid, 299, 330 Haptens, 256, 299, 338 Hay Fever, 257, 300 Headache, 130, 196, 268, 300, 302, 333, 344, 356 Headache Disorders, 300 Health Care Costs, 45, 300 Health Expenditures, 300 Heart attack, 198, 270, 300 Heart failure, 123, 300, 323 Hematologic malignancies, 45, 300 Hematopoietic growth factors, 10, 300 Hematopoietic tissue, 10, 267, 300 Heme, 51, 109, 208, 265, 281, 300, 325 Hemodialysis, 132, 221, 222, 283, 300, 309, 354 Hemofiltration, 223, 300, 354 Hemoglobin, 6, 28, 109, 143, 183, 258, 290, 300, 301, 325 Hemoglobin A, 6, 28, 300 Hemoglobinopathies, 295, 301 Hemolytic, 52, 301 Hemorrhage, 97, 173, 199, 280, 300, 301, 319, 336, 347 Hemostasis, 301, 343 Hepatic, 5, 33, 45, 53, 62, 104, 109, 134, 144, 215, 256, 297, 301, 311, 317, 328, 344 Hepatic Encephalopathy, 109, 301 Hepatocellular, 182, 301 Hepatocellular carcinoma, 182, 301 Hepatocyte, 212, 301 Hepatorenal Syndrome, 173, 216, 301

Hepatotoxic, 51, 301 Hepatotoxicity, 49, 51, 53, 118, 301 Herbicide, 78, 86, 218, 301, 327 Hereditary, 278, 298, 301, 320 Heredity, 295, 296, 301 Herpes, 68, 301 Herpes Zoster, 301 Heterogeneity, 8, 256, 301 Heterotrophic, 294, 301 Hexosyltransferases, 298, 301 Histamine, 258, 261, 265, 301 Histidine, 54, 301 Histones, 269, 274, 301 HIV, 9, 16, 40, 62, 191, 226, 237, 238, 253, 298, 302, 305, 310, 319, 357 HIV Protease, 191, 302 HIV Protease Inhibitors, 191, 302 Homeostasis, 21, 55, 82, 216, 302, 326, 345 Homologous, 278, 295, 302, 342, 349 Hormonal, 222, 263, 302, 357 Hormone therapy, 255, 302 Hybrid, 14, 127, 275, 302 Hybridomas, 302, 306 Hydatidiform Mole, 32, 274, 302 Hydralazine, 206, 302 Hydration, 254, 302 Hydrocephalus, 302, 308 Hydrocodone, 124, 303 Hydrogen, 24, 193, 199, 253, 257, 270, 282, 283, 292, 298, 303, 311, 317, 321, 324, 335 Hydrogen Peroxide, 298, 303, 311 Hydrogenation, 265, 303 Hydrolases, 288, 303, 312 Hydrolysis, 170, 195, 209, 255, 262, 265, 266, 275, 298, 303, 311, 329, 331, 335 Hydrophobic, 20, 208, 298, 303 Hydroxyeicosatetraenoic Acids, 173, 262, 303 Hydroxylamines, 5, 303 Hydroxylation, 20, 31, 94, 303 Hydroxylysine, 276, 303 Hydroxyproline, 257, 276, 303 Hydroxysteroid Dehydrogenases, 107, 303 Hyperaemia, 278, 303 Hyperbilirubinemia, 303, 308 Hypercalcemia, 93, 303 Hypercapnia, 42, 303 Hyperplasia, 7, 303 Hyperreflexia, 196, 303, 350 Hypersensitivity, 196, 289, 303, 340

369

Hypertension, 7, 29, 32, 38, 169, 173, 176, 262, 270, 300, 302, 304, 332 Hypertrophy, 7, 200, 303, 304 Hyperuricemia, 169, 298, 304 Hypnotic, 213, 264, 273, 304, 350 Hypotensive, 135, 304 Hypothalamus, 200, 263, 267, 284, 304, 330 Hypoxia, 42, 198, 304 Hypoxic, 173, 211, 304, 315 I Idiopathic, 30, 304 Idoxifene, 16, 304 Ifosfamide, 45, 90, 304 Imidazole, 131, 301, 304 Immune function, 26, 193, 304 Immune response, 49, 74, 168, 255, 260, 263, 280, 299, 304, 305, 348, 357 Immune Sera, 304 Immune system, 213, 263, 265, 304, 305, 312, 318, 328, 358 Immunization, 168, 304, 333 Immunoassay, 33, 77, 97, 173, 304 Immunodeficiency, 70, 76, 191, 253, 302, 304 Immunodeficiency syndrome, 304 Immunogenic, 304, 311, 338 Immunoglobulin, 259, 304, 317 Immunologic, 273, 302, 304, 338 Immunology, 91, 101, 125, 136, 255, 304 Immunophilin, 168, 269, 305 Immunosuppressant, 62, 168, 257, 293, 305, 315, 344 Immunosuppressive, 168, 219, 269, 281, 297, 304, 305, 350 Impairment, 16, 29, 215, 223, 265, 292, 305, 314, 333, 353 Implant radiation, 305, 307, 308, 337, 358 Implantation, 278, 305, 323 In situ, 10, 42, 121, 182, 305 Incision, 305, 307 Incontinence, 192, 203, 302, 305 Incubation, 153, 305, 310 Indigestion, 305, 309 Indinavir, 62, 305 Indole-3-carbinol, 189, 305 Infarction, 206, 302, 305, 339 Inflammatory bowel disease, 202, 305 Infusion, 35, 79, 87, 305, 319 Ingestion, 34, 85, 121, 144, 175, 297, 299, 306, 315, 331, 350 Inhalation, 204, 255, 306, 331, 353 Initiation, 15, 20, 44, 48, 49, 184, 306, 347

Inoculum, 177, 306 Inorganic, 222, 275, 298, 306, 317, 348 Inotropic, 285, 306 Insect Control, 186, 306 Insecticides, 18, 97, 110, 114, 186, 306, 319, 328, 337, 358 Insight, 5, 13, 28, 39, 55, 201, 306 Insomnia, 273, 306, 333, 344 Insulator, 306, 318 Insulin, 25, 29, 63, 89, 92, 158, 283, 297, 306, 309 Insulin-dependent diabetes mellitus, 306 Interferon, 66, 137, 295, 306, 312 Interferon-alpha, 306 Interindividual, 49, 86, 113, 114, 306 Interleukin-1, 11, 84, 306 Interleukin-2, 306 Interleukin-6, 96, 306 Interleukin-8, 115, 307 Intermittent, 293, 307, 328 Internal radiation, 307, 308, 337, 358 Interstitial, 169, 267, 292, 307, 308, 339, 358 Intestine, 265, 267, 276, 307, 309 Intoxication, 307, 352, 358 Intrahepatic, 61, 307 Intramuscular, 307, 326 Intravenous, 79, 87, 128, 147, 306, 307, 326 Intrinsic, 63, 178, 179, 256, 264, 307 Invasive, 60, 98, 183, 206, 207, 302, 307, 312, 325 Invertebrates, 186, 285, 307 Involuntary, 307, 319, 339, 345 Ion Channels, 263, 307, 329, 349 Ionization, 65, 94, 99, 110, 111, 115, 116, 121, 125, 150, 307 Ionizing, 24, 257, 307, 313, 338 Ions, 24, 36, 65, 88, 170, 186, 253, 269, 285, 287, 289, 303, 307, 316, 332, 335, 341, 345 Irinotecan, 134, 143, 146, 151, 152, 153, 307 Iris, 279, 307, 336 Irradiation, 183, 307, 321, 358 Irritable Bowel Syndrome, 196, 203, 308 Ischemia, 83, 146, 263, 308, 318, 339 Isoflavones, 27, 142, 150, 153, 308 Isoniazid, 78, 308 Isosorbide, 206, 308 Isosorbide Dinitrate, 206, 308 Isozymes, 47, 53, 56, 62, 308 Itraconazole, 41, 101, 308 J Jaundice, 216, 301, 303, 308

370

Metabolites

K Kainate, 173, 284, 308, 337 Kainic Acid, 173, 308 Karyotype, 302, 308 Kb, 236, 308 Keratin, 308 Keratinocytes, 20, 69, 91, 99, 307, 308 Keto, 15, 81, 98, 156, 308 Ketoconazole, 33, 309 Ketone Bodies, 283, 309 Ketonuria, 211, 309 Kidney Disease, 93, 220, 236, 309 Kidney Failure, 289, 309 Kidney stone, 309, 339, 355 Kinetic, 24, 34, 79, 114, 307, 309 L Labile, 277, 309 Lactation, 165, 309, 323 Lactose Intolerance, 199, 309 Lag, 35, 309 Large Intestine, 276, 284, 307, 309, 338, 344 Larynx, 309, 353 Latent, 12, 176, 177, 309 Lectins, 171, 309 Lens, 64, 134, 194, 261, 271, 294, 309, 358 Lentivirus, 302, 310 Lethal, 83, 264, 310 Leucocyte, 40, 289, 310, 312 Leukemia, 118, 155, 286, 295, 300, 310, 333, 335 Leukocytes, 83, 85, 264, 267, 273, 306, 310, 321, 354 Levo, 310, 314 Levodopa, 310, 343 Levorphanol, 283, 310 Libido, 258, 310 Lichens, 164, 310 Lidocaine, 95, 310 Life cycle, 191, 294, 310 Life Expectancy, 184, 310 Ligament, 310, 334 Ligands, 35, 66, 310, 348 Limb perfusion, 46, 310 Linkage, 54, 84, 297, 310, 329 Linoleic Acids, 79, 310 Lipid A, 39, 311 Lipid Peroxidation, 52, 130, 311, 325 Lipophilic, 311, 331 Lipopolysaccharide, 141, 299, 311 Lipoxygenase, 7, 37, 48, 55, 75, 79, 81, 121, 125, 141, 148, 187, 262, 311 Liquor, 311, 337

Liver Circulation, 216, 311 Liver Cirrhosis, 301, 311 Liver Neoplasms, 311, 357 Liver scan, 311, 342 Liver Transplantation, 109, 216, 311 Lobe, 200, 311 Localized, 15, 55, 84, 288, 299, 305, 311, 317, 323, 330, 342, 354, 355 Locomotion, 311, 330 Lovastatin, 311, 344 Lubricants, 311, 328 Lumbar, 3, 311 Lupus, 156, 196, 311, 350 Lyases, 171, 311 Lymph, 61, 191, 263, 273, 288, 302, 311, 312, 313, 348 Lymph node, 61, 263, 273, 311, 312, 313 Lymphadenopathy, 191, 302, 312 Lymphatic, 288, 305, 311, 312, 314, 323, 345, 351 Lymphatic system, 311, 312, 345, 351 Lymphoblasts, 254, 312 Lymphocyte, 191, 253, 260, 312, 313 Lymphocyte Count, 253, 312 Lymphoid, 81, 259, 310, 312 Lymphoma, 118, 300, 312 Lysine, 54, 268, 302, 303, 312 Lysophospholipids, 48, 312 Lysosomal Storage Diseases, 65, 312 Lytic, 312, 343, 357 M Macrophage, 198, 299, 306, 312 Magnetic Resonance Imaging, 112, 312, 342 Magnetic Resonance Spectroscopy, 15, 16, 66, 121, 146, 150, 312 Malaria, 52, 59, 83, 312 Malaria, Falciparum, 312 Malaria, Vivax, 312 Malathion, 142, 313 Malignant, 32, 91, 182, 204, 213, 253, 254, 260, 262, 270, 274, 313, 317, 319, 338, 341, 350 Malignant tumor, 270, 274, 313, 317 Malnutrition, 220, 256, 263, 313 Mammary, 44, 47, 82, 165, 313, 350, 352 Mammogram, 268, 313, 315 Man-made, 271, 313 Mannans, 294, 313 Maple Syrup Urine Disease, 15, 313 Mass Screening, 9, 313 Mastitis, 313, 351

371

Matrilysin, 198, 313 Matrix metalloproteinase, 125, 143, 197, 313, 333 Maturation-Promoting Factor, 281, 313 Meconium, 106, 313 Medial, 262, 313, 323 Mediastinum, 274, 313 Mediate, 14, 39, 84, 104, 285, 313 Mediator, 56, 306, 313, 330, 343 Medicament, 184, 313 MEDLINE, 237, 314 Medullary, 283, 314, 337 Megaloblastic, 293, 314 Meiosis, 313, 314, 349 Melanin, 307, 314, 329, 354 Melanocytes, 314 Melanoma, 213, 314 Melphalan, 46, 314 Membrane Lipids, 314, 329 Memory, 169, 257, 259, 282, 314 Meninges, 272, 280, 314 Meningitis, 308, 314 Menopause, 30, 100, 156, 175, 314, 323, 332, 333 Menstruation, 314 Mental, iv, 4, 236, 238, 273, 276, 278, 282, 285, 292, 314, 333, 336, 342, 343, 355 Mental Disorders, 314, 333, 336 Mental Health, iv, 4, 236, 238, 314, 333, 336 Mental Processes, 285, 314, 336 Menthol, 174, 314 Mercaptopurine, 88, 110, 118, 132, 202, 230, 314 Mesenchymal, 289, 299, 302, 314 Mesenteric, 29, 315 Mesenteric Arteries, 29, 315 Mesentery, 315, 328 Metabolic acidosis, 222, 283, 315 Metabolic disorder, 26, 298, 315 Metastasis, 190, 204, 313, 315 Metastatic, 61, 198, 315, 342 Methamphetamine, 43, 98, 125, 315 Methanol, 100, 173, 315 Methionine, 61, 193, 284, 315, 348 Methotrexate, 159, 182, 230, 315 Metronidazole, 68, 77, 87, 315 MI, 28, 41, 71, 183, 202, 252, 315 Microbe, 178, 181, 315, 352 Microbiology, 136, 152, 177, 217, 218, 254, 263, 264, 315 Microcalcifications, 268, 315

Microdialysis, 7, 46, 91, 146, 218, 315 Microglia, 263, 315, 317 Micronutrients, 58, 316 Microorganism, 169, 276, 316, 326, 358 Micro-organism, 180 Micro-organism, 180 Micro-organism, 193 Micro-organism, 316 Microsomal, 19, 41, 53, 54, 316 Microtubules, 316, 325 Migration, 38, 40, 48, 316 Mitochondria, 63, 92, 316, 318, 324 Mitochondrial Swelling, 316, 319 Mitosis, 261, 309, 313, 316 Mitotic, 291, 313, 316, 357 Mobility, 46, 86, 316 Moclobemide, 115, 316 Modeling, 9, 18, 66, 103, 316, 334 Modification, 14, 27, 40, 47, 54, 57, 71, 257, 296, 316, 337 Modulator, 39, 173, 211, 316 Molar pregnancy, 33, 296, 316 Molecular, 9, 11, 14, 18, 21, 24, 26, 29, 34, 37, 40, 44, 51, 54, 56, 63, 64, 65, 81, 85, 102, 104, 107, 108, 127, 128, 134, 137, 142, 150, 153, 166, 182, 185, 214, 237, 239, 258, 266, 268, 269, 277, 293, 316, 330, 334, 338, 341, 343, 348, 353, 354 Molecular Structure, 34, 316, 353 Monitor, 21, 46, 53, 59, 90, 270, 280, 317, 322 Monoamine, 3, 80, 104, 116, 181, 203, 258, 283, 316, 317, 343 Monoamine Oxidase, 258, 283, 316, 317, 343 Monoclonal, 97, 168, 302, 308, 317, 337, 358 Monoclonal antibodies, 168, 317 Monocyte, 76, 317 Mononuclear, 317, 354 Morphine, 35, 89, 99, 113, 128, 196, 268, 276, 286, 317, 319, 323 Morphological, 287, 294, 314, 317 Motility, 317, 343 Motivations, 57, 317 Motor nerve, 317, 318 Mucilaginous, 313, 317 Mucins, 289, 317, 341 Mucolytic, 186, 187, 253, 317 Mucosa, 289, 311, 317 Mucus, 268, 291, 317, 354 Multidrug resistance, 149, 154, 317

372

Metabolites

Multiple Myeloma, 96, 128, 317 Multiple sclerosis, 137, 196, 318 Muscle Contraction, 258, 268, 318, 341 Muscle relaxant, 213, 318, 329 Muscle tension, 318 Muscular Dystrophies, 286, 318 Mutagen, 264, 318 Mutagenesis, 53, 55, 76, 318, 334 Mutagenic, 28, 76, 257, 318, 321 Mutagenicity, 28, 80, 318 Mydriatic, 284, 318 Myelin, 318 Myelodysplastic syndrome, 9, 318, 345 Myelogenous, 155, 318 Myocardial infarction, 206, 265, 279, 315, 318 Myocardial Ischemia, 218, 279, 318 Myocardial Reperfusion, 318, 339 Myocardial Reperfusion Injury, 318, 339 Myocardium, 83, 315, 318, 319, 356 Myofibrils, 269, 319 Myosin, 269, 318, 319 Myristate, 56, 319 N Nafenopin, 26, 319 Naphthols, 70, 319 Narcolepsy, 203, 283, 319 Narcosis, 319 Narcotic, 188, 303, 310, 317, 319, 325 Nausea, 261, 286, 305, 319, 325, 333, 355 NCI, 1, 21, 235, 275, 319 Necrosis, 61, 261, 305, 315, 318, 319, 339, 340 Nelfinavir, 70, 226, 319 Neoplasia, 212, 319 Neoplasm, 319, 341, 354 Neoplastic, 127, 190, 212, 258, 302, 312, 319 Nephrology, 220, 319 Nephropathy, 221, 309, 319 Nephrosis, 301, 319, 320 Nephrotic, 94, 320 Nephrotic Syndrome, 94, 320 Nerve, 171, 186, 254, 255, 258, 282, 313, 317, 318, 320, 333, 340, 341, 342, 347, 353 Nervous System, 7, 49, 188, 204, 205, 218, 253, 256, 258, 263, 264, 267, 268, 272, 275, 283, 295, 297, 310, 313, 315, 316, 317, 318, 320, 321, 326, 327, 343, 349, 351, 356 Networks, 212, 320 Neural, 54, 119, 197, 269, 316, 317, 320, 345

Neuralgia, 196, 320 Neuroblastoma, 44, 320 Neurodegenerative Diseases, 5, 43, 119, 185, 320 Neurofibroma, 190, 320 Neuroleptic, 260, 275, 320 Neurologic, 36, 302, 320 Neuroma, 190, 320 Neuromuscular, 253, 320, 331 Neuromuscular Junction, 253, 320 Neuronal, 5, 23, 59, 106, 173, 181, 203, 211, 212, 319, 320 Neurons, 36, 43, 54, 83, 205, 275, 282, 291, 295, 310, 318, 320, 321, 349 Neuropathy, 196, 203, 320 Neuropeptide, 6, 269, 320 Neurophysiology, 282, 320 Neurotoxic, 49, 51, 136, 253, 320, 321 Neurotoxicity, 13, 43, 45, 46, 48, 51, 119, 283, 308, 320 Neurotoxins, 48, 320 Neurotransmitter, 5, 6, 94, 106, 186, 205, 253, 255, 257, 262, 267, 269, 285, 297, 298, 301, 307, 321, 322, 348, 349 Neutron Capture Therapy, 94, 267, 321 Neutrons, 257, 307, 321, 337 Neutrophils, 69, 91, 261, 299, 307, 310, 321 Niacin, 321, 354 Nicotine, 18, 98, 120, 203, 205, 226, 321 Nimodipine, 185, 321 Nitric Oxide, 7, 39, 82, 89, 90, 92, 95, 101, 102, 122, 130, 141, 147, 205, 206, 216, 321 Nitrogen, 5, 13, 68, 83, 105, 118, 223, 256, 257, 258, 280, 281, 292, 314, 321, 327, 354 Nitroglycerin, 308, 321 Nitrosamines, 20, 321 Non-small cell lung cancer, 60, 321 Norepinephrine, 7, 136, 181, 203, 205, 255, 285, 321, 344 Nuclear Envelope, 7, 55, 313, 322 Nuclear Pore, 322 Nuclei, 257, 278, 287, 295, 296, 302, 312, 316, 321, 322, 326, 335 Nucleic acid, 6, 68, 172, 207, 208, 264, 282, 295, 321, 322, 336, 337, 340, 341 Nucleus, 55, 168, 261, 264, 265, 274, 280, 281, 283, 287, 291, 295, 314, 317, 321, 322, 334, 335, 345, 347 Nursing Care, 322, 326 Nutritional Status, 220, 221, 222, 322 Nutritional Support, 222, 322 Nutritive Value, 293, 322

373

O Observational study, 37, 322 Obsessive-Compulsive Disorder, 203, 293, 322 Occupational Exposure, 13, 322 Ocular, 196, 323 Oedema, 196, 323 Oestrogen, 175, 323 Ofloxacin, 79, 323 Ointments, 286, 323 Oltipraz, 53, 323 On-line, 23, 98, 99, 121, 251, 323 Oocytes, 144, 313, 323 Oophorectomy, 323, 349 Opacity, 271, 282, 323 Ophthalmic, 196, 323 Opiate, 317, 323 Opium, 286, 317, 323 Opportunistic Infections, 253, 323 Opsin, 323, 340 Optic Chiasm, 304, 323 Oral Hygiene, 299, 323 Orbital, 277, 323 Orchiectomy, 324, 349 Organ Culture, 81, 324, 352 Organelles, 58, 171, 272, 281, 282, 314, 324, 330 Ornithine, 324, 337 Osmotic, 256, 308, 316, 324, 343 Osteoarthritis, 156, 203, 324 Osteoclasts, 269, 324 Osteoporosis, 30, 59, 156, 323, 324 Osteosarcoma, 324, 335 Ovaries, 323, 324, 343, 349, 350 Ovary, 30, 189, 279, 290, 298, 323, 324, 331 Overactive bladder, 192, 324 Ovum, 279, 296, 310, 324, 333, 358 Oxidants, 105, 324 Oxidation-Reduction, 266, 324 Oxidative metabolism, 10, 45, 52, 54, 255, 325 Oxidative Stress, 13, 59, 126, 197, 198, 273, 325 Oxides, 191, 325 Oximetry, 183, 325 Oxycodone, 124, 325 Oxygen Consumption, 72, 291, 325, 340 Oxygenase, 109, 136, 325 Oxygenation, 5, 82, 183, 325 P P-450, 45, 120, 134, 173, 325 P53 gene, 47, 325, 335

Paclitaxel, 149, 325 Palliative, 128, 281, 323, 325, 351 Pancreas, 253, 266, 306, 325, 354 Pancreatic, 270, 325 Panic, 293, 325 Panic Disorder, 293, 325 Paracentesis, 216, 326 Parasite, 52, 212, 326, 353 Parasitic, 52, 148, 326, 341 Parasympathetic Nervous System, 192, 326 Parathyroid, 83, 93, 326, 341, 350 Parathyroid Glands, 326, 341 Parathyroid hormone, 83, 93, 326 Parenteral, 177, 223, 326 Parenteral Nutrition, 223, 326 Partial remission, 326, 339 Particle, 173, 182, 313, 326, 345, 353 Patch, 25, 326, 353 Patella, 164, 326 Pathogen, 305, 306, 326 Pathogenesis, 48, 49, 61, 67, 186, 215, 326 Pathologic, 253, 261, 267, 279, 303, 326, 336 Pathologic Processes, 261, 326 Pathophysiology, 36, 127, 326 Patient Care Management, 221, 326 Pelvic, 327, 334 Pelvis, 309, 311, 324, 327, 355 Penicillin, 85, 220, 259, 327 Penicillium, 78, 80, 84, 87, 165, 170, 327 Penis, 200, 327 Pentachlorophenol, 73, 327 Pentosyltransferases, 298, 327 Peptic, 265, 327 Peptic Ulcer, 265, 327 Peptide, 11, 14, 33, 63, 216, 257, 269, 276, 288, 293, 295, 303, 308, 327, 331, 334, 335 Peptide Synthases, 11, 327 Perception, 6, 278, 327, 342 Perfusion, 304, 327 Perillyl alcohol, 204, 327 Perinatal, 50, 327 Periodontal disease, 193, 327 Peripheral Nervous System, 289, 320, 321, 327, 348 Peripheral vision, 327, 330 Peritoneal, 83, 221, 262, 283, 323, 328 Peritoneal Cavity, 262, 323, 328 Peritoneal Dialysis, 83, 221, 283, 328 Peritoneum, 315, 328 Peritonitis, 216, 328 Perivascular, 269, 316, 328

374

Metabolites

Peroral, 187, 328 Peroxisome Proliferators, 26, 328 Pesticides, 13, 96, 97, 170, 186, 214, 218, 219, 265, 306, 328 Petechiae, 299, 328 Petroleum, 209, 268, 295, 328 Phagocyte, 59, 324, 328 Phagocytosis, 52, 83, 85, 316, 328 Pharmaceutic Aids, 293, 328 Pharmaceutical Preparations, 184, 272, 290, 295, 328 Pharmaceutical Solutions, 286, 328 Pharmacodynamic, 35, 328 Pharmacokinetic, 9, 35, 42, 62, 110, 151, 153, 163, 218, 328 Pharmacologic, 29, 258, 280, 299, 328, 352 Phenotype, 22, 36, 61, 87, 200, 329 Phenyl, 23, 53, 172, 196, 211, 329 Phenylalanine, 80, 329, 354 Phenytoin, 270, 329 Phorbol, 56, 329, 335 Phorbol Esters, 56, 329, 335 Phosphatidic Acids, 312, 329 Phospholipases, 38, 329 Phospholipases A, 39, 329 Phospholipids, 23, 48, 292, 314, 329, 335 Phosphorus, 83, 269, 326, 329 Phosphorylase, 269, 329 Phosphorylate, 7, 329 Phosphorylated, 75, 276, 329 Phosphorylating, 7, 329 Phosphorylation, 7, 39, 55, 56, 63, 329, 335 Photoreceptor, 36, 329, 340 Physicochemical, 78, 329 Physiologic, 29, 62, 256, 266, 299, 314, 316, 329, 338 Pigment, 265, 274, 314, 330, 340 Pilot study, 47, 330 Pineal gland, 274, 330 Piper methysticum, 147, 159, 330 Pituitary Gland, 200, 293, 330, 343 Placenta, 290, 330, 333 Plague, 208, 330 Plaque, 194, 198, 330 Plasma, 16, 19, 32, 42, 51, 58, 61, 62, 70, 78, 87, 90, 95, 97, 101, 102, 104, 105, 106, 109, 110, 111, 113, 115, 116, 117, 119, 124, 125, 127, 128, 131, 132, 134, 135, 137, 144, 145, 146, 147, 149, 153, 154, 170, 187, 192, 217, 222, 226, 256, 259, 265, 269, 272, 288, 293, 295, 297, 300, 301, 309, 317, 330, 335, 339, 343, 344, 357

Plasma cells, 259, 317, 330 Plasma protein, 256, 288, 330, 335, 343 Plastids, 324, 330 Platelet Aggregation, 148, 258, 321, 330, 351 Platelet Factor 4, 307, 330 Platelets, 261, 265, 269, 321, 330, 331, 351 Platinum, 164, 275, 331 Pleural, 323, 331 Pleural cavity, 323, 331 Pneumonia, 52, 279, 331 Podophyllotoxin, 291, 331 Poisoning, 19, 156, 307, 319, 327, 331 Pollen, 331, 337 Polychlorinated Biphenyls, 27, 100, 121, 143, 331 Polymers, 209, 266, 331, 335, 348 Polymorphic, 8, 274, 331 Polymorphism, 114, 331 Polymyxin, 95, 331 Polyp, 37, 331 Polypeptide, 172, 201, 207, 257, 276, 289, 293, 331, 333, 334, 351, 358 Polyposis, 276, 331 Polyproteins, 191, 302, 331 Polyunsaturated fat, 37, 332, 351 Portal Hypertension, 216, 332 Posterior, 258, 272, 274, 307, 325, 332 Postmenopausal, 30, 33, 103, 126, 324, 332 Postnatal, 332, 347 Postoperative, 129, 216, 332 Post-translational, 55, 258, 302, 332, 344 Potassium, 29, 36, 134, 223, 256, 332 Potassium Channels, 29, 134, 332 Potentiates, 205, 306, 332 Practice Guidelines, 238, 332 Precancerous, 212, 273, 332, 333 Precipitation, 115, 332 Precursor, 11, 28, 51, 172, 191, 210, 259, 262, 274, 281, 285, 286, 288, 289, 302, 310, 321, 329, 332, 333, 335, 354, 357 Predictive factor, 50, 332 Prednisolone, 332 Prednisone, 225, 332 Pregnancy Outcome, 50, 332 Preleukemia, 318, 332, 345 Premalignant, 33, 332, 333 Premenopausal, 86, 154, 333 Premenstrual Syndrome, 203, 333 Prenatal, 287, 296, 333 Presumptive, 68, 333 Presynaptic, 46, 321, 333, 349

375

Prevalence, 25, 32, 206, 220, 333 Prickle, 308, 333 Primary Prevention, 19, 40, 333 Primary tumor, 61, 204, 333 Prinomastat, 197, 333 Probe, 62, 315, 333 Probenecid, 152, 333 Procaine, 310, 333 Prodrug, 182, 333 Proenzyme, 289, 333 Progeny, 278, 333 Progesterone, 86, 102, 105, 129, 226, 333, 347 Progression, 48, 51, 56, 184, 188, 259, 313, 333, 343, 357 Progressive, 36, 37, 262, 272, 274, 282, 286, 318, 319, 320, 324, 334, 339, 354 Projection, 12, 322, 334 Proline, 276, 303, 334 Promoter, 8, 11, 36, 172, 195, 334 Promyelocytic leukemia, 108, 334 Prophase, 323, 334, 349 Prophylaxis, 210, 216, 334 Propofol, 126, 334 Propolis, 147, 334 Prostaglandins, 55, 127, 219, 262, 287, 303, 334 Prostate, 22, 63, 98, 121, 125, 128, 142, 176, 189, 200, 266, 323, 334, 354 Protease, 63, 70, 191, 302, 305, 319, 334 Protease Inhibitors, 191, 334 Protein Binding, 39, 334 Protein C, 5, 63, 168, 172, 186, 256, 257, 264, 276, 308, 334, 354 Protein Conformation, 257, 308, 334 Protein Engineering, 35, 334 Protein Kinase C, 42, 334 Protein Kinases, 39, 63, 335 Protein p53, 47, 335 Protein S, 20, 24, 60, 201, 266, 290, 295, 334, 335, 347 Protein Subunits, 24, 335 Protein-Energy Malnutrition, 220, 335 Protein-Tyrosine Kinase, 296, 335 Proteinuria, 211, 317, 320, 335 Proteolytic, 39, 277, 293, 335 Prothrombin, 335, 351 Protocol, 3, 335 Protons, 257, 303, 307, 312, 335, 337 Proto-Oncogene Proteins, 325, 335 Proto-Oncogene Proteins c-mos, 325, 335

Protozoa, 148, 178, 278, 316, 335, 336, 346, 355 Protozoan, 272, 296, 312, 336, 353 Psoriasis, 275, 336 Psychiatric, 62, 104, 196, 217, 314, 336 Psychiatry, 15, 101, 104, 122, 150, 205, 336, 347 Psychic, 310, 314, 336, 342 Psychoactive, 336, 358 Psychology, 43, 277, 285, 336 Psychomotor, 270, 320, 336 Psychotomimetic, 258, 283, 336 Public Health, 13, 31, 38, 39, 50, 188, 238, 264, 336 Public Policy, 237, 336 Publishing, 67, 336 Pulmonary, 40, 65, 256, 266, 268, 291, 300, 309, 336, 356 Pulmonary Artery, 266, 336, 356 Pulse, 15, 183, 317, 325, 336 Pupil, 279, 284, 318, 336 Purifying, 201, 336 Purines, 12, 59, 219, 264, 336, 343 Purpura, 299, 336 Purulent, 187, 336 Putrefaction, 337 Putrescine, 193, 337 Pyogenic, 190, 337 Pyramidal Tracts, 292, 337 Pyrazinamide, 78, 337 Pyrethrins, 337 Pyrethrum, 110, 337 Pyrimidines, 182, 219, 264, 337, 343 Q Quality of Life, 190, 337 Quaternary, 46, 334, 337 Quercetin, 111, 135, 139, 144, 152, 337 Quinones, 17, 21, 56, 337 Quinoxaline, 6, 337 R Race, 32, 181, 191, 203, 308, 314, 316, 337 Racemic, 181, 191, 203, 314, 337 Radiation therapy, 255, 292, 294, 307, 308, 337, 358 Radioactive, 58, 77, 267, 299, 303, 305, 307, 308, 311, 313, 317, 322, 337, 338, 342, 354, 358 Radiochemical, 11, 337 Radioimmunoassay, 24, 82, 265, 337 Radioimmunotherapy, 338 Radiolabeled, 308, 337, 338, 358

376

Metabolites

Radiotherapy, 204, 267, 308, 337, 338, 347, 358 Randomized, 122, 287, 338 Reabsorption, 222, 333, 338 Reactive Oxygen Species, 8, 10, 17, 21, 338 Receptors, Serotonin, 338, 343 Recombinant, 53, 98, 171, 182, 208, 338, 356 Recombination, 278, 295, 338 Rectum, 261, 267, 276, 284, 293, 295, 305, 309, 334, 338 Recurrence, 176, 189, 273, 338 Red blood cells, 290, 301, 325, 338, 341 Reductase, 19, 141, 148, 209, 311, 315, 338, 344 Refer, 1, 268, 277, 288, 294, 301, 311, 320, 321, 338, 352, 357 Reference Standards, 22, 338 Reflective, 12, 338 Reflex, 196, 339 Refraction, 339, 346 Refractory, 216, 339 Regeneration, 293, 339 Regimen, 16, 223, 275, 286, 339 Regional chemotherapy, 45, 339 Regression Analysis, 284, 339 Relapse, 32, 339 Relaxant, 329, 339 Reliability, 86, 339 Remission, 33, 338, 339 Renal Circulation, 216, 339 Renal failure, 89, 216, 220, 221, 222, 301, 339 Renal Replacement Therapy, 220, 339 Renal tubular, 333, 339 Renin, 216, 259, 339 Reperfusion, 59, 146, 318, 339 Reperfusion Injury, 60, 339 Reproduction Techniques, 332, 340 Respiration, 178, 261, 270, 280, 317, 340 Restless legs, 120, 340 Retina, 274, 309, 323, 340, 341, 358 Retinal, 36, 65, 278, 323, 340 Retinal pigment epithelium, 36, 340 Retinoid, 92, 340 Retinol, 65, 340 Retinopathy, 48, 340 Retroviral vector, 295, 340 Reversion, 340, 354 Rhabdomyolysis, 93, 340 Rheumatism, 340 Rheumatoid, 103, 196, 274, 276, 324, 340

Rheumatoid arthritis, 103, 196, 274, 276, 340 Rhodopsin, 323, 340 Ribonucleic acid, 83, 340, 341 Ribose, 254, 340 Rickets, 341, 357 Rickettsiae, 178, 341, 355 Risk factor, 13, 30, 31, 50, 53, 207, 341 RNA, 16, 59, 63, 66, 135, 170, 255, 257, 264, 266, 272, 276, 304, 306, 310, 322, 340, 341, 343 Rod, 264, 275, 329, 341 Rotenone, 44, 341 Rubber, 254, 319, 341 Rutin, 337, 341 S Salicylic, 175, 341 Saline, 81, 341 Saliva, 153, 341 Salivary, 341, 348 Salivary glands, 341 Saphenous, 95, 117, 341 Saphenous Vein, 95, 117, 341 Saponins, 148, 341, 347 Sarcoma, 46, 324, 341 Sarcoplasmic Reticulum, 135, 341 Scans, 16, 342 Scatter, 184, 342 Schizoid, 342, 358 Schizophrenia, 5, 119, 342, 358 Schizotypal Personality Disorder, 342, 358 Scleroderma, 156, 196, 262, 342 Sclerosis, 262, 276, 318, 342 Screening, 31, 55, 62, 103, 122, 125, 152, 176, 275, 296, 342, 355 Secondary tumor, 315, 342 Secretory, 20, 78, 342, 349 Sedative, 213, 264, 273, 276, 342 Sedatives, Barbiturate, 342 Sediment, 28, 342, 355 Segregation, 58, 264, 338, 342 Seizures, 172, 211, 270, 329, 342, 346 Selective estrogen receptor modulator, 342, 350, 352 Selegiline, 125, 219, 343 Selenium, 63, 84, 125, 343 Sella Turcica, 330, 343 Semen, 334, 343 Semisynthetic, 11, 269, 291, 325, 343 Senescence, 80, 198, 343 Senile, 324, 343 Sensor, 13, 171, 183, 343

377

Sepsis, 315, 343 Septic, 95, 262, 343 Sequencing, 13, 50, 201, 343 Serine, 55, 173, 288, 334, 335, 343 Serologic, 304, 343 Serotonin, 43, 181, 203, 205, 261, 275, 293, 317, 321, 338, 343, 344, 354 Serous, 262, 288, 343 Serum Albumin, 338, 343 Sex Characteristics, 255, 258, 323, 343, 350 Sex Hormone-Binding Globulin, 153, 343 Shock, 7, 344, 353 Sialyltransferases, 298, 344 Sibutramine, 180, 181, 202, 203, 344 Side effect, 51, 169, 176, 188, 205, 208, 229, 255, 261, 265, 281, 304, 344, 352 Signs and Symptoms, 339, 344 Simvastatin, 101, 344 Sirolimus, 104, 344 Skeletal, 30, 205, 258, 275, 280, 317, 318, 319, 340, 341, 344, 345 Skeleton, 30, 150, 254, 292, 344 Skull, 184, 280, 344, 350 Sleep apnea, 122, 126, 344 Small cell lung cancer, 344 Small intestine, 221, 286, 296, 302, 307, 344, 357 Smoking Cessation, 268, 344 Smoldering leukemia, 318, 345 Social Environment, 337, 345 Sodium, 94, 135, 173, 194, 223, 256, 284, 298, 338, 345, 349, 355 Sodium Channels, 345, 355 Soft tissue, 267, 344, 345 Solid tumor, 45, 190, 259, 286, 345 Solitary Nucleus, 263, 345 Solvent, 24, 264, 273, 290, 298, 315, 324, 328, 345, 353 Soma, 345 Somatic, 196, 255, 280, 314, 316, 327, 345 Sound wave, 338, 345 Soybean Oil, 332, 345 Spasm, 261, 345, 350 Spasmolytic, 345, 354 Spastic, 308, 345 Specialist, 164, 243, 284, 345 Specificity, 14, 18, 45, 59, 62, 171, 256, 262, 288, 333, 346 Spectrometer, 21, 23, 24, 58, 346 Spectrophotometry, 198, 346 Spectroscopic, 23, 34, 66, 85, 98, 119, 180, 312, 346

Spectrum, 8, 45, 49, 280, 309, 313, 316, 346 Sperm, 258, 274, 331, 346, 350 Spermatogenesis, 200, 346 Spermatozoa, 343, 346 Spinous, 289, 308, 346 Splanchnic Circulation, 216, 346 Spontaneous Abortion, 156, 332, 346 Sporadic, 184, 320, 346 Spores, 170, 178, 306, 346 Squamous, 321, 346 Squamous cell carcinoma, 321, 346 Stabilization, 45, 329, 346 Staging, 96, 342, 346 Status Epilepticus, 173, 346 Steady state, 179, 180, 346 Steel, 275, 347 Stem Cells, 10, 36, 347 Stereotactic, 91, 347 Sterile, 262, 326, 347 Stillbirth, 332, 347 Stimulant, 258, 268, 283, 301, 315, 347 Stimulus, 17, 29, 268, 279, 286, 287, 291, 307, 309, 339, 347, 351 Stomach, 253, 284, 290, 295, 297, 302, 319, 327, 328, 344, 347 Stool, 85, 199, 276, 305, 308, 309, 347 Strand, 63, 97, 347 Street Drugs, 18, 347 Streptomycin, 78, 347 Striatum, 71, 76, 113, 146, 347 Stroke, 38, 100, 185, 198, 236, 270, 347 Structure-Activity Relationship, 9, 17, 23, 347 Stupor, 319, 347 Styrene, 97, 121, 127, 341, 348 Subacute, 305, 348 Subarachnoid, 97, 120, 173, 185, 300, 348 Subclinical, 305, 342, 348 Subcutaneous, 286, 323, 326, 348 Submaxillary, 289, 348 Subspecies, 345, 348 Substance P, 6, 196, 220, 290, 315, 342, 347, 348 Substrate, 8, 14, 20, 29, 37, 177, 201, 206, 212, 271, 289, 303, 348 Substrate Specificity, 14, 348 Suction, 293, 348 Sulfadiazine, 77, 348 Sulfotransferases, 128, 348 Sulfur, 70, 85, 192, 193, 292, 315, 348 Sulfur Compounds, 192, 193, 348 Superoxide, 63, 348

378

Metabolites

Supplementation, 27, 135, 144, 145, 150, 154, 220, 348 Suppression, 9, 52, 85, 141, 196, 295, 348 Surface Plasmon Resonance, 126, 348 Surgical castration, 200, 349 Survival Rate, 190, 349 Sweat, 25, 180, 283, 349 Sweat Glands, 283, 349 Symbiosis, 181, 349 Sympathetic Nervous System, 216, 263, 326, 349 Sympathomimetic, 258, 283, 285, 290, 315, 322, 349 Symphysis, 334, 349 Symptomatic, 90, 268, 349 Synapse, 255, 320, 326, 333, 349, 353 Synaptic, 186, 321, 349 Synaptic Transmission, 321, 349 Synergistic, 27, 85, 349 Synovial, 210, 349 Synovial Fluid, 210, 349 Synovial Membrane, 349 Systemic lupus erythematosus, 103, 274, 276, 350 Systemic therapy, 274, 350 Systolic, 304, 350 T Tacrolimus, 168, 218, 350 Tamoxifen, 16, 30, 66, 89, 91, 93, 114, 124, 342, 350, 352 Temperament, 104, 350 Temporal, 35, 46, 86, 132, 300, 350 Tendon, 276, 350 Tenuazonic Acid, 86, 350 Teratogenic, 257, 350 Teratoma, 274, 350 Testicles, 324, 349, 350 Testicular, 33, 200, 350 Testis, 135, 200, 258, 274, 290, 323, 350 Testosterone, 86, 98, 141, 200, 338, 344, 350 Tetany, 326, 350 Thalamus, 267, 284, 350 Thalidomide, 96, 128, 190, 350 Theophylline, 50, 135, 160, 336, 351 Therapeutics, 5, 45, 48, 59, 89, 93, 94, 118, 152, 186, 201, 231, 317, 351 Thermal, 24, 196, 217, 285, 321, 351 Thigh, 292, 351 Thioguanine, 110, 351 Thiostrepton, 11, 351 Thorax, 311, 351 Threonine, 334, 335, 343, 351

Threshold, 304, 330, 351 Thrombin, 99, 293, 330, 334, 335, 351 Thrombomodulin, 334, 351 Thrombosis, 198, 265, 335, 347, 351 Thromboxanes, 262, 287, 303, 351 Thrombus, 198, 279, 305, 318, 330, 351 Thymidine, 182, 351 Thymidylate Synthase, 79, 351 Thymus, 304, 312, 351 Thyroid, 85, 269, 326, 352, 354 Thyroid Gland, 326, 352 Thyroxine, 85, 87, 256, 329, 352 Tissue Culture, 219, 352, 357 Tolerance, 63, 73, 220, 221, 254, 268, 297, 352 Tome, 157, 161, 352 Tone, 29, 38, 42, 75, 173, 323, 352 Tonus, 352 Tooth Preparation, 254, 352 Topical, 177, 230, 263, 275, 290, 303, 352 Topoisomerase inhibitors, 307, 352 Toremifene, 16, 91, 177, 352 Torsion, 305, 352 Tourniquet, 310, 352 Toxemia, 173, 352 Toxin, 71, 77, 84, 85, 86, 288, 352 Trace element, 267, 274, 353 Trachea, 81, 268, 291, 309, 313, 352, 353 Trachoma, 190, 353 Traction, 275, 353 Transcriptase, 253, 353 Transdermal, 186, 353 Transduction, 40, 41, 55, 200, 212, 269, 353 Transfection, 208, 266, 295, 353 Transfer Factor, 304, 353 Transferases, 34, 353 Transgenes, 209, 353 Translation, 257, 290, 353 Translational, 37, 172, 295, 353 Translocation, 7, 8, 55, 56, 168, 290, 353 Transmitter, 253, 263, 285, 307, 313, 322, 353 Transplantation, 69, 97, 104, 117, 274, 287, 304, 353 Trauma, 185, 319, 353 Trichloroethylene, 50, 217, 353 Trichomoniasis, 315, 353 Tricyclic, 23, 353 Trimebutine, 125, 354 Trivalent, 112, 354 Troglitazone, 176, 354 Tryptophan, 12, 46, 74, 276, 343, 354

379

Tubercle, 67, 78, 354 Tuberculosis, 308, 311, 341, 354 Tuberculostatic, 308, 354 Tumor marker, 32, 266, 354 Tumor Necrosis Factor, 84, 351, 354 Tumor suppressor gene, 325, 354 Tumorigenic, 11, 164, 354 Tumour, 129, 182, 207, 213, 261, 354 Tylosin, 14, 354 Typhimurium, 136, 172, 354 Tyrosine, 7, 12, 51, 285, 335, 354 U Ulcer, 354, 356 Ulcerative colitis, 196, 202, 305, 354 Ultrafiltration, 300, 354 Uracil, 337, 354, 355 Urea, 267, 324, 349, 354, 355 Uremia, 222, 223, 309, 339, 355 Ureters, 309, 355 Urethra, 327, 334, 355 Uric, 222, 298, 304, 336, 355 Uricosuric, 333, 355 Uridine Diphosphate, 111, 297, 355 Uridine Diphosphate Glucuronic Acid, 297, 355 Urinalysis, 25, 355 Urinary tract, 34, 126, 264, 355 Urinary tract infection, 34, 264, 355 Urinate, 355, 358 Urticaria, 196, 355 Uterus, 253, 273, 279, 288, 296, 314, 316, 324, 333, 355 V Vaccines, 355, 357 Vacuoles, 72, 324, 355 Vagina, 273, 283, 284, 314, 355 Valproic Acid, 49, 355 Valves, 356 Varicose, 107, 117, 356 Varicose vein, 107, 356 Vascular endothelial growth factor, 96, 100, 105, 106, 356 Vascular Headaches, 265, 356 Vascular Resistance, 40, 356 Vasoactive, 32, 42, 55, 356 Vasoconstriction, 55, 81, 290, 356 Vasodilation, 101, 216, 356 Vasodilator, 265, 267, 269, 285, 301, 302, 308, 318, 356 Vector, 195, 353, 356 Vegetative, 68, 266, 356 Vein, 129, 259, 262, 307, 322, 332, 341, 356

Venoms, 321, 356 Venous, 184, 262, 265, 321, 323, 335, 356 Ventricle, 304, 336, 350, 356 Ventricular, 40, 302, 319, 356 Ventricular Pressure, 40, 356 Venules, 267, 269, 288, 356 Verapamil, 123, 132, 154, 356 Vertebrae, 346, 356 Vesicular, 301, 316, 357 Vestibular, 135, 357 Vestibule, 357 Veterinary Medicine, 171, 237, 351, 357 Villi, 302, 357 Villus, 302, 357 Vimentin, 7, 357 Vinblastine, 182, 214, 357 Vinca Alkaloids, 357 Vincristine, 182, 357 Vinyl Chloride, 24, 357 Viral, 16, 208, 253, 288, 302, 353, 354, 357 Viral Load, 16, 357 Virulence, 34, 67, 71, 80, 263, 352, 357 Virulent, 68, 357 Virus, 16, 68, 70, 76, 182, 191, 253, 264, 272, 289, 296, 298, 302, 306, 330, 340, 353, 357 Viscera, 315, 345, 346, 357 Visceral, 263, 280, 328, 357 Visceral Afferents, 263, 357 Viscosity, 178, 187, 253, 357 Vitamin D, 74, 78, 87, 137, 220, 341, 357 Vitreous, 123, 309, 340, 357, 358 Vitreous Body, 340, 357, 358 Vitreous Humor, 123, 358 Vitro, 4, 6, 7, 8, 22, 33, 34, 35, 37, 41, 43, 46, 48, 49, 52, 53, 55, 56, 62, 69, 74, 76, 77, 85, 91, 92, 95, 101, 112, 114, 115, 118, 135, 136, 147, 148, 153, 172, 204, 268, 287, 295, 305, 350, 352, 358 Vivo, 4, 6, 9, 13, 15, 20, 23, 26, 32, 33, 41, 46, 48, 49, 51, 52, 53, 56, 61, 67, 72, 73, 74, 77, 83, 85, 112, 118, 148, 152, 172, 175, 183, 204, 207, 295, 305, 315, 324, 350, 351, 358 Void, 62, 358 W War, 273, 358 White blood cell, 254, 259, 299, 310, 312, 317, 330, 358 Windpipe, 268, 352, 358 Withdrawal, 196, 220, 358 Wound Healing, 293, 313, 358

380

Metabolites

X Xanthophyll, 142, 358 Xenobiotics, 51, 221, 358 Xenograft, 259, 358 X-ray, 18, 23, 85, 271, 277, 278, 293, 295, 307, 313, 318, 322, 337, 338, 342, 347, 358

X-ray therapy, 308, 358 Y Yeasts, 294, 329, 358 Z Zygote, 278, 358 Zymogen, 289, 333, 334, 358