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

LOSARTAN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J AMES N. P...

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LOSARTAN 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., 1960Losartan: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84485-2 1. Losartan-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 losartan. 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 LOSARTAN ................................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Losartan ........................................................................................ 5 E-Journals: PubMed Central ....................................................................................................... 30 The National Library of Medicine: PubMed ................................................................................ 30 CHAPTER 2. NUTRITION AND LOSARTAN ...................................................................................... 79 Overview...................................................................................................................................... 79 Finding Nutrition Studies on Losartan ....................................................................................... 79 Federal Resources on Nutrition ................................................................................................... 82 Additional Web Resources ........................................................................................................... 82 CHAPTER 3. CLINICAL TRIALS AND LOSARTAN ............................................................................. 85 Overview...................................................................................................................................... 85 Recent Trials on Losartan ............................................................................................................ 85 Keeping Current on Clinical Trials ............................................................................................. 86 CHAPTER 4. PATENTS ON LOSARTAN ............................................................................................. 89 Overview...................................................................................................................................... 89 Patents on Losartan ..................................................................................................................... 89 Patent Applications on Losartan.................................................................................................. 97 Keeping Current ........................................................................................................................ 101 CHAPTER 5. PERIODICALS AND NEWS ON LOSARTAN ................................................................. 103 Overview.................................................................................................................................... 103 News Services and Press Releases.............................................................................................. 103 Academic Periodicals covering Losartan.................................................................................... 107 CHAPTER 6. RESEARCHING MEDICATIONS .................................................................................. 109 Overview.................................................................................................................................... 109 U.S. Pharmacopeia..................................................................................................................... 109 Commercial Databases ............................................................................................................... 110 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 113 Overview.................................................................................................................................... 113 NIH Guidelines.......................................................................................................................... 113 NIH Databases........................................................................................................................... 115 Other Commercial Databases..................................................................................................... 117 APPENDIX B. PATIENT RESOURCES ............................................................................................... 119 Overview.................................................................................................................................... 119 Patient Guideline Sources.......................................................................................................... 119 Finding Associations.................................................................................................................. 122 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 125 Overview.................................................................................................................................... 125 Preparation................................................................................................................................. 125 Finding a Local Medical Library................................................................................................ 125 Medical Libraries in the U.S. and Canada ................................................................................. 125 ONLINE GLOSSARIES................................................................................................................ 131 Online Dictionary Directories ................................................................................................... 131 LOSARTAN DICTIONARY ........................................................................................................ 133 INDEX .............................................................................................................................................. 191

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

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

Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy Source: New England Journal of Medicine. 345(12): 861-869. September 20, 2001. Summary: Diabetic nephropathy (diabetes associated kidney disease) is the leading cause of end stage renal disease (ESRD). Interruption of the renin angiotensin system slows the progression of renal (kidney) disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. This article reports on a study that assessed the role of the angiotensin II receptor antagonist losartan in patients with type 2 diabetes and nephropathy. A total of 1,513 patients were enrolled in this randomized, double blind study comparing losartan (50 to 100 milligrams once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium channel antagonists, diuretics, alpha blockers, beta

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blockers, and centrally acting agents) for a mean of 3.4 years. The primary outcome was the composite of a doubling of the baseline serum creatinine concentration, end stage renal disease, or death. Secondary end points included a composite of morbidity (related illness or complications) and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease. A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group. Losartan reduced the incidence of a doubling of the serum creatinine concentration and end stage renal disease, but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was signficantly lower with losartan. The level of proteinuria (protein in the urine) declined by 35 percent with losartan. The authors conclude that losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated. 3 figure. 3 tables. 34 references. •

Low-Sodium Diet Potentiates the Effects of Losartan in Type 2 Diabetes Source: Diabetes Care. 25(4): 663-671. April 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Patients with diabetes have a high prevalence of hypertension (high blood pressure), increased total body exchangeable sodium levels, and an impaired ability to excrete a sodium load. This article reports on a study that assessed the effect of dietary sodium (salt) restriction on the efficacy of losartan in subjects with hypertension (high blood pressure), type 2 diabetes, and albumin (protein) excretion rates of 10 to 200 micrograms per minute. In the study, 20 subjects were randomized to losartan 50 milligrams per day (n = 10) or placebo (n = 10). Drug therapy was given in two 4 week phases separated by a washout period. In the last 2 weeks of each phase, patients were assigned to low or regular sodium diets, in random order. The results showed that a low-sodium diet dominates the antihypertensive and antiproteinuric effects of losartan in type 2 diabetes. The blood pressure reduction resulting from the addition of a low sodium diet to losartan was of similar magnitude to that predicted from the addition of a second antihypertensive agent. Thus, the low sodium diet optimizes the renoprotective (protective of the kidney) effects of the ANG-receptor blocker, losartan. In certain circumstances, the addition of a low-sodium diet should be considered as an appropriate alternative to additional pharmacological antihypertensive agents, including combination therapy with a diuretic. 5 figures. 4 tables. 41 references.

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Losartan Reduces the Costs Associated With Diabetic End-Stage Renal Disease Source: Diabetes Care. 26(3): 683-687. March 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study undertaken to evaluate the within-trial effect of losartan and conventional antihypertensive therapy (CT) compared with placebo and CT on the economic cost associated with end stage renal disease (ESRD). The study was a multinational double-blind randomized placebo-controlled clinical trial designed to evaluate the renal protective effects of losartan on a background of CT in patients with type 2 diabetes and nephropathy (kidney disease). The primary composite end point was doubling of serum creatinine, ESRD, or death. The results showed that losartan and

Studies

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CT compared with placebo and CT reduced the number of days with ESRD by 33.6 days per patient over 3.5 years. This reduction in ESRD days resulted in a decrease in cost associated with ESRD of $5,144 per patient. After accounting for the cost of losartan, the reduction in ESRD days resulted in a net savings of $3,522 per patient over 3.5 years. The authors conclude that treatment with losartan in patients with type 2 diabetes and nephropathy not only reduced the incidence of ESRD, but also resulted in substantial cost savings. 1 figure. 4 tables. 13 references.

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

Project Title: ANEMIA NEPHROPATHY

AND

CLINICAL

OUTCOMES

IN

DIABETIC

Principal Investigator & Institution: Mohanram, Anupama; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-DEC-2002; Project End 30-NOV-2004 Summary: (provided by applicant): Diabetic nephropathy (DN) is the leading cause of ESRD in the U.S. and cardiovascular (CV) morbidity and mortality are excessive in this population. Preliminary data from the Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial indicate that anemia is a modifiable risk factor for ESRD and CV morbidity and mortality in type 2 DN. I hypothesize that hemoglobin (Hb) is an independent predictor of both renal and CV disease in this population. The specific aims of this project are to determine if anemia is an independent predictor of 1) ESRD; 2) cardiovascular morbidity (non-fatal CV events defined as hospitalization for heart failure, myocardial infarction, and unstable angina, and mortality (sudden cardiac death, death due to progressive heart failure, myocardial infarction, and other cardiac causes) and 3) hospitalization for revascularization (coronary, peripheral, cerebral, or renal), amputation, and stroke. I will use the RENAAL trial database involving 1,513 Type 2 diabetic patients with nephropathy followed on average for 3.4 years. Cox proportional hazards regression models using baseline and follow-up (Hb) will be employed as the independent variable, and renal 2

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

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disease, cardiovascular disease, and vascular disease outcomes as dependent variables. Power analysis based on observed event rates in the RENAAL trial indicate 95% power to detect a 30% reduction in risk of the primary composite endpoint of doubling serum creatinine, ESRD or death for patients in the highest compared to the lowest quartile of baseline Hb. I expect these results will establish anemia as an independent risk factor for ESRD and cardiovascular morbidity and mortality in type 2 diabetics with progressing renal disease. These data could change practice and lead to new clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANG RELAXATION

II:

PERMISSIVE

ROLE

TO

MAINTAIN

VASCULAR

Principal Investigator & Institution: Lombard, Julian H.; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2008 Summary: Elevated dietary salt intake in normotensive animals leads to impaired relaxation of resistance arteries in response to a variety of vasodilator stimuli. This appears to be mediated by suppression of the renin-angiotensin system (RAS), since it can be prevented by i.v. infusion of a low dose of angiotensin II (ANGII). This project will study the response of the middle cerebral artery (MCA) to vasodilator stimuli in four novel inbred genetic rat strains: 1) Dahl salt sensitive (Dahl S; SS/Mcw) rats, a genetic model of salt sensitive hypertension that exhibits impaired relaxation to vasodilator stimuli and an impaired ability to regulate plasma ANGII levels in response to changes in dietary salt intake; 2) normotensive Brown Norway (BN/Mcw) rats; 3) SS.BN13 consomic rats, with chromosome 13 of BN rat on the Dahl S background; and 4), renin congenic rats, with the Dahl R renin gene on the Dahl S genetic background. These rat strains will be used to test two fundamental hypotheses related to the role of ANGII in maintaining normal vascular relaxation mechanisms. The first hypothesis is that ANGII, acting through its specific receptor subtypes, plays a role in the maintenance of vascular relaxation mechanisms in middle cerebral arteries under normal physiological conditions. The second hypothesis is that the impaired relaxation of the middle cerebral artery to vasodilator stimuli that occurs in Dahl S rats on a low salt diet is due to defective regulation of plasma ANGII levels in these animals. In Aim 1, we will compare the response of isolated middle cerebral arteries to a variety of vasodilator stimuli acting via different signal transduction mechanisms in inbred normotensive BN/Mcw rats, SS/Mcw rats, and SS.BN13 consomic rats on a low salt diet, in order to demonstrate that SS/Mcw rats on low salt diet exhibit impaired relaxation mechanisms that are not shared by BN/Mcw rats, SS.BN13 rats, or other normotensive rat strains e.g., Sprague-Dawley rats, that have been extensively characterized in studies by our laboratory and others. Aim 2 will utilize pharmacological tools, endothelial removal, and measurement of key biochemical mediators of vascular relaxation in order to determine the mechanisms that mediate vascular relaxation in response to vasodilator stimuli in isolated middle cerebral arteries of SS.BN13 consomic rats on a low salt diet, and to identify vascular relaxation mechanisms that are impaired in vessels of SS/Mcw rats on low salt diet. Aim 3 will utilize i.v. infusions of the ANGII receptor antagonists losartan (ATI) and PD123319 (AT2) to determine the role of specific ANGII receptor subtypes in maintaining vascular relaxation mechanisms in the middle cerebral artery under normal physiological conditions in SS.BN13 rats and in renin congenic rats, and to assess the role of specific ANGII receptor subtypes in mediating any protective effect of low dose ANGII infusion to restore normal responses of the middle cerebral artery to vasodilator stimuli in

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SS/Mcw rats on a low salt diet. The demonstration that ANGII may have a permissive role in maintaining vascular relaxation mechanisms in normotensive animals is a completely new aspect of ANGII's complex physiological role that has only recently been described and is largely unexplored. In this respect, the studies proposed in this project address a conceptually innovative aspect of the physiological role of ANGII in regulating vascular function. When completed, these studies will not only enhance our understanding of the role of ANGII and its receptors in regulating vascular reactivity under normal physiological conditions, but will also provide insight into the mechanisms of the impaired reactivity of resistance vessels to vasodilator stimuli in SS/Mcw rats, a genetic model of salt sensitive hypertension that has many similarities to the salt sensitive forms of hypertension that develop in humans, particularly in AfricanAmericans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANGIOTENSIN II AND DIABETIC RETINOPATHY Principal Investigator & Institution: Scicli, Alfonso G.; Senior Staff Research Investigator; Molecular Biology; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 30-NOV-2006 Summary: (provided by applicant): Clinical trials suggest that Angiotensin Converting Enzyme inhibitors (ACEi) slow the progression of diabetic retinopathy. However, there is little experimental evidence that Angiotensin II (Ang II) is a critical pathogenetic factor in the development of diabetic retinopathy. ACEi's act systemically decreasing blood pressure (BP) and may also act by decreasing local Ang II effects or by non-Angdependent mechanisms. Vascular Endothelial Growth Factor (VEGF) is responsible for retinal neovascularization and stimulates expression of Intercellular Adhesion Molecule-1 (ICAM-1), causing leukostasis, capillary plugging and vasopermeability. Reactive oxygen species (ROS) may mediate in part Ang II effects. We have found that Ang II is angiogenic, and that this effect is supressed by SU5416, a highly selective inhibitorof VEGF receptor (VEGF R) responses, suggesting that Ang II can act via VEGF R. In addition, intravitreal Ang II induces retinal leukostasis in vivo. We hypothesize that: a) inhibitionof Ang II ameliorates diabetic retinopathy by mechanisms independent of BP reduction and b) Ang II acts via ROS and VEGF R to increase the expression of retinal leukocyte adhesion molecules, leukostasis, capillary plugging and vasopermeability. Our specific aims are: Aim 1: To compare the effects of chronic treatment with a Ca- Channel blocker, (nifedipine), an ACEi (ramipril), and a AT1 receptor antagonist (Iosartan), on diabetic retinopathy in streptozotocin-induced diabetes (SZD), a rat model of type 1 diabetes (12 months treatment), and in a novel model of retinal neovascularization, the Koletsky rat, a hypertensive model of type 2 diabetes, (10 months treatment). All treatments may lower BP but nifedipine does not inhibit the renin angiotensin system (RAS). We expect that retinopathy is decreased by ramipril and perhaps Iosartan but not nifedipine. Aim 2: To determine whether retinal leukostasis, capillary plugging, vasopermeability and adhesion molecules: a) decrease after treatment with either an ACEi or an Ang II ATl inhibitor in SZD rats (1-2 weeks), and in normal rats 48 hrs after ivt VEGF, and b) increase after ivt Ang II, and whether anti-oxidants or SU5416 inhibit these responses. In Aim 3 we will study in retinal endothelial cells in vitro if Ang II increases adhesion molecules and leukocyte adhesion via ROS and VEGF R and the role of NF-kB. These studies will help understand the role of the RAS in diabetic retinopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Losartan

Project Title: ANGIOTENSIN II BLOCKADE Principal Investigator & Institution: Ibrahim, Hassan N.; Medicine; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 05-SEP-2002; Project End 30-JUN-2007 Summary: (provided by applicant): Renal transplant loss due to chronic allograft nephropathy (CAN) is widely acknowledged as a major problem that has increased in relative importance as the incidence of early graft loss from acute rejection has declined. Studies from various centers, including the University of Minnesota, suggest that, after excluding patients dying with a functioning graft, as many as 80% of patients who will return to dialysis do so because of CAN. At the present time there are no therapeutic options once the clinical manifestations of CAN have developed. Testing measures to prevent CAN have not been addressed. The overall purpose of this project is to investigate the role of the renin-angiotensin-aldosterone system (RAAS) in the development of CAN. This system plays an important role in the progression of many experimental and clinical renal diseases. Furthermore, blockade of this system with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers has yielded beneficial results in retarding injury and progression in numerous intrinsic renal diseases. This study specifically investigates the long term benefit of the angiotensin II receptor blocker, Iosartan, in the prevention of cortical interstitial volume expansion (an accurate predictor of long term graft function) and graft loss from biopsy proven CAN in a 5 year, randomized, double masked, placebo controlled study of kidney transplant recipients. This clinical trial will directly test the hypothesis that blockade of the renin angiotensin aldosterone system will provide a substantial benefit through blood pressure lowering independent mechanisms, namely, interruption of tibrogenic pathways, anti-proteinuric actions, amelioration of hyperfiltration and possibly some immunomodulatory effects. The proposed studies will also characterize the interstitial ultrastructural compositional changes that occur in the renal allografts with CAN, the effects of treatment on these changes and provide a complete description of the incidence and predictors for the development of transplant glomerulopathy. These studies will also determine the impact of angiotensin II receptor blockade on the rate of decline of glomerular filtration rate, as well as the impact of glomerular size on the rate of graft loss from CAN, the incidence and the progression of post transplant proteinuria, the nature of the permselectivity defects responsible for the proteinuria and will also explore the association of proteinuna with graft loss from CAN. This trial will also help construct a profile for the RAAS in the transplant recipients and explore the relationship between two genes polymorphisms, ACE and TGF-b and CAN. These studies should help to describe the natural history, nature and pathogenesis of CAN, elucidate early markers and predictors of this important disorder and, perhaps, define a safe and useful preventative strategy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANGIOTENSIN II, OXIDATIVE STRESS, AND ATHEROSCLEROSIS Principal Investigator & Institution: Cohen, Richard A.; Associate Professor; Boston Medical Center Gambro Bldg, 2Nd Fl, 660 Harrison Ave, Ste a Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 01-SEP-1997; Project End 31-AUG-2005 Summary: (Adapted from the Investigator's Abstract): Oxidative stress is thought to participate in vascular dysfunction and remodeling that accompanies angiotensin II (AII)-induced hypertension, but the source and cellular sources of oxidant species and their precise role is poorly understood. Recent studies in the laboratories of the two PI's

Studies

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have elucidated a novel role for the aortic adventitia as the site of elaboration of both superoxide anion (O2-) and nitric oxide (NO) radicals, indicating that the adventitia is a major site of oxidative stress. New studies indicate that the increased elaboration of O2by AII is indicated by prominent nitrotyrosine staining of the adventitia, likely as a result of production of the reaction product of O2- and NO, peroxynitrite (OONO-). There are many sources of O2- in the vascular wall, but recent studies indicate that multiple subunits of the neutrophil NAD(P)H oxidase are present in the adventitia where O2- is greatest. Preliminary studies in which AII was infused into mice that are deficient in one NADPH oxidase subunit, gp91phox, show a blunted aortic O2-, hypertrophic, and proliferative response to AII compared with wild type mice, despite a similar hypertensive response. Proposed studies in rats and mice will elucidate the hypothesis that oxidative stress mediated by adventitial NAD(P)H oxidase-derived O2participates in the myogenic, hypertrophic, and proliferative vascular response in AIIinduced hypertension. The proposed studies will also take advantage of preliminary work on Apo E deficient mice (EKO) to determine the significance of AII-induced oxidative stress in atherosclerosis. Preliminary studies in these mice indicate that captopril and losartan reduce atherosclerosis (suggesting a role for AII), and that hypothetically under the influence of AII, there is increased production of O2- and OONO-, as indicated in preliminary studies by nitrotyrosine. Studies in Apo E deficient mice that overexpress human Cu/Zu SOD and double knockouts deficient in Apo E and gp91 phox or the AII type receptor, will help to elucidate the hypothesis that AIIinduced oxidative stress contributes significantly to vascular dysfunction and remodeling in atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AT2 MEDIATED ANGIOTENSIN II SIGNALING Principal Investigator & Institution: Mauch, Teri J.; Associate Professor; Pediatrics; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 30-APR-2005 Summary: (provided by applicant): Fetuses deprived of the vasoactive peptide and potent growth factor Angiotensin II (Ang II) are born with renal dysplasia, and they require dialysis and transplantation for long term survival. Ang II binds at least two receptors, AT1, and AT2. AT1 mediates cell growth and division, vasoconstriction, and salt retention. Decreased AT1 activation likely mediates some of the fetotoxicity in Ang U -deprived babies. AT2, however, is the predominant Ang II receptor in the fetal kidney, and its expression declines at birth. In mediating cell death, vasodilation, and salt excretion, AT2 seems to oppose AT1 action, but its downstream signaling pathways have yet to be identified, and its role in fetal nephrogenesis has not been delineated. In preliminary studies using cultured rat metanephroi, isolated from confounding variables, we found that a) Ang II stimulated ureteric bud (UB) branching, b) AT1 blockade decreased UB branching, whereas c) AT2 antagonism increased UB branching. Normal nephrogenesis involves tightly controlled reciprocal interactions between the metanephric mesenchyme and the invading UB. Excessive UB branching results in abnormal and ectopic induction of mesenchyme, whereas insufficient UB branching causes renal hypoplasia. We hypothesize that AT2 activation inhibits UB branching, and we seek to identify changes in downstream gene expression associated with this process.Specific Aim 1: To further test the hypothesis that AT2 inhibits UB branching in cultured fetal rat kidneys. a. Using confocal microscopy and lectin staining we will examine UB branching under conditions that specifically activate or antagonize AT2.b. We will optimize culture conditions that maximally activate or suppress AT2 signaling

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for subsequent subtraction cloning studies.Specific Aim 2: To identify which genes are differentially expressed following AT2 activation or suppression.a. Subtraction cloning will be performed between kidneys at 2 time points following AT2 activation or antagonismb. Hybridization analysis will be used to confirm differentially expressed clones.c. Differentially expressed cDNAs will be sequenced to identify candidate genes. NCBI BLAST searches and bioinformatics will be used to sort differentially expressed genes into structural and functional categories.d. Quantitative RT-PCR will confirm the magnitude of change of selected clones.e. The spatial expression of differentially expressed clones will be assessed using in situ hybridization.The ability of candidate genes identified by this screen to influence ureteric bud branching will be tested in future studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRAINSTEM NEURONS IN NEUROGENIC HYPERTENSION Principal Investigator & Institution: Sved, Judith C.; Neurology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 01-FEB-2004; Project End 31-JAN-2006 Summary: (provided by applicant): The overall objective of this proposal is to evaluate a central neural mechanism involved in the long term regulation of cardiovascular function that may ultimately be involved in the pathogenesis of certain forms of hypertension. Selective disruption of central nervous system function can produce acute as well as chronic elevations in arterial blood pressure (AP) and influence cardiovascular reflexes. The rostra ventral lateral medulla (RVLM) is important for the maintenance of baseline AP and its reflexive regulation and is comprised of two neurochemically distinct neuronal cell populations, the C1 cell population that contains the enzyme phenylethanolamine-N-transferase (PNMT) and those cells that do not contain PNMT. Recently a technique has been developed to selectively destroy the C1 cell population in rats that has allowed the evaluation of the role of these neurons in cardiovascular regulation. The proposed studies will examine the effect of C1 RVLM lesions in two strains of genetically hypertensive rats (spontaneously hypertensive rats, SHR and Dahl salt-sensitive rats, DS) using radio telemetry to monitor AP and heart rate in freely moving rats prior to and during an extended time course following destruction of C1 neurons. Responses to stressful stimuli and anti-hypertensive drugs will also be tested. These experiments will test the hypothesis that C1-RVLM neurons are important for the maintenance of hypertension in these two models, extending acute studies in anesthetized rats suggesting that the RVLM is important in these forms of hypertension and further our understanding of how the central nervous system is involved in the pathogenesis of hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARDIAC SYMPATHETIC AFFERENT RELEX IN HEART FAILURE Principal Investigator & Institution: Wang, Wei; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2002 Summary: Heart failure (HF) is characterized by an elevation in sympathetic tone. The mechanisms responsible for the sympatho-excitation of HF are not completely understood. Recent studies from this laboratory have shown that the cardiac "sympathetic afferent" reflex is enhanced in dogs with pacing-induced HF. The mechanisms by which this enhancement occurs are unclear. There is an enhancement in

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afferent fiber sensitivity to bradykinin and capsaicin. Preliminary evidence from this laboratory suggests that an enhanced central gain of this reflex is, in addition, responsible for the augmentation of this reflex. Furthermore, we have shown that central angiotensin II (Ang II) is at least one mediator for this enhancement. A second mechanism which may explain the increased gain of he cardiac sympathetic afferent reflex in HF is a decrease in nitric oxide (NO) production in several central sites which regulate sympathetic outflow. We hypothesize that both an increase in central Ang II and a decrease in central NO contributes to the increase in the sensitivity of the cardiac sympathetic afferent reflex and to the tonic sympatho-excitatory state in dogs with HF. Therefore, the specific aims of this project are to: 1) determine if the central gain of the cardiac sympathetic afferent reflex in dogs with HF is related to increased levels of central Ang II or to changes in Ang II type1 receptor density or both, 2) determine if acute and chronic central administration of the Ang II receptor antagonist, losartan and L-158,809 and/or NO donors prevent or reduce the enhancement of the cardiac sympathetic afferent reflex in dogs with HF, 3) determine if bradykinin prostaglandins and NO are mediators of the enhanced sensitivity of cardiac sympathetic sensory endings in dogs with HF, and 4) determine if chronic thoracic sympathetic deafferentation alters the time course and/or magnitude of the sympatho-excitatory response during the development of pacing-induced HF. These studies integrate into the overall scope of this Program Project in that the regulation of sympathetic outflow in HF is likely to be mediated by a variety of peripheral inputs with important modulation from central substances. The cardiac sympathetic understanding of neuro-humoral regulation in this disease state should include this potentially potent reflex. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPARATIVE EFFECTS OF RAMIPRIL & LOSARTAN ON FIBRINOLYSIS Principal Investigator & Institution: Vaughan, Douglas E.; Chief, Division of Cardiovascular Medici; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONCOMITANT CYP3A4 & CYP2C9 INHIBITION ON LOSARTAN PHARMACOKINETICS Principal Investigator & Institution: Parnell, Kimberly J.; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORTICAL OSTEOPONTIN EXPRESSION IN HYDRONEPHROSIS Principal Investigator & Institution: Scaduto, Russell C.; Medicine; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2002; Project Start 01-FEB-1999; Project End 31-DEC-2003 Summary: (Adapted from Investigator's Abstract): This application studies the mechanisms accounting for inflammation and fibrosis in the model of tubulointerstitial

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disease following obstruction of the urinary tract. The principal investigator hypothesizes that within hours of ureteral obstruction there is increased expression of the renin angiotensin system within the renal cortical proximal tubules. The increased epithelial production of angiotensin II stimulates the angiotensin II type I receptor and this increases the proximal tubule production of osteopontin. This is a potent chemoattractant for macrophages and this leads to the infiltration of macrophages and such macrophage-dependent mechanisms of inflammation and injury as is dependent on TGFbeta1. There are three specific aims: The first specific aim will investigate the critical role of increased osteopontin expression after urinary tract obstruction via its capacity to attract macrophages to increase cortical TGFbeta1 expression. This specific aim will utilize an osteopontin knockout mouse in which the effects of obstruction in this knockout model will be examined from the standpoint of evolution of interstitial disease assessed histologically, and by immunohistochemistry and by in situ hybridization. These studies would be complemented by in vitro studies in which primary cultures of proximal tubular suspensions from osteopontin knockout and wildtype mice will be studied for their ability to induce attraction of macrophages. The second specific aim is to determine proximal tubular angiotensinogen, angiotensinconverting enzyme, and angiotensin II type 1 receptor mRNA and protein, and ACE activity during the initial as well as during the sequential time points for up to 168 hours post-ligation. The third specific aim will mechanistically determine the roles for ACE and angiotensin II type 1 receptor activation in the expression and macrophage attraction, effects of osteopontin using an in vivo rat model of experimental hydronephrosis, and an osteopontin knockout mouse model. In these studies the renin angiotensin system will be manipulated with the use of an ACE inhibitor, enalapril, and an AT-1 blocker, losartan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETERMINANTS OF MAXIMAL O2 TRANSPORT Principal Investigator & Institution: Wagner, Peter D.; Professor of Medicine & Bioengineering; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002 Summary: Chronic diseases (COPD, heart failure, renal failure) are marked by reduced exercise capacity. There is increasing evidence that skeletal muscle structure and function may be intrinsically abnormal in such conditions. The present proposal continues work from the current cycle to better understand the mechanisms of exercise limitation in both health and disease, in particular the role of skeletal muscle. Physiological approaches already developed under the PPG involving muscle O2 transport analysis (large versus small muscle mass exercise, femoral blood flow, blood gas sampling, magnetic resonance spectroscopy to measure intracellular P02, morphology to assess diffusion distances and capillary surface area) will be combined with molecular-level studies focused on genes associated with muscle angiogenic responses to exercise, since the amount of capillary surface appears critical to O2 transport limitation. This integrated approach will be applied in both animal and human studies, the latter in both health and chronic disease (heart failure, chronic obstructive pulmonary disease). Animal work will use mechanistic interventions not possible in man to complement human experiments, and in both, the molecular approaches will be applied in intact physiological systems. Major goals include: 1) separating O2 transportbased exercise limitation from that due to intrinsic muscle abnormalities in chronic diseases; 2) determining if VEGF is essential to angiogenesis using Cre/loxP targeted

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knockout strategy, as well as VEGF antagonists such as Suramin, Losartan and Captopril; 3) defining the mechanisms that normally increase VEGF message and protein capillarity in chronic diseases. Our ultimate objective is to identify abnormalities of muscle O2 transport in chronic disease at the level of gene regulation, in the hope of eventual gene-targeted therapy. We hypothesize that these will centrally involve the muscle angiogenic response to exercise. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EARLY NEPHROPATHY IN NIDDM Principal Investigator & Institution: Myers, Bryan D.; Professor; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: We propose to use novel methods to characterize the evolution of early diabetic glomerular injury (DGI) in 70 Pima Indians with NIDDM and microalbuminuria. They will be entered into a randomized, controlled trial of losartan vs placebo lasting 60-84 months. GFR, its hemodynamic determinants and albuminuria, will be monitored annually. More elaborate physiological studies, an analysis of glomeruli obtained by biopsy and mathematical modelling of filtration properties of glomeruli will be performed after 60 months. We wish to test the following four hypotheses. The first hypothesis is that evolution from micro- to macroalbuminuria is a consequence of impairment of a size-selective filtration barrier. We propose to compute the effective radii of functional pores from sieving coefficients of polydisperse ficoll, a rigid and spherical polymer of sucrose that replicates the molecular configuration of proteins. Confocal immunomicroscopy of podocytes will seek a structural basis for protein-permeable pores. The second hypothesis is that podocyte injury and deformation lowers glomerular hydraulic permeability (k) and is the principal determinant of a decline in GFR from elevated to normal levels as DGI becomes overt (macroalbuminuria). Morphometric analysis of glomeruli will examine podocyte density and foot process, slit diaphragm, GBM, and endothelial fenestral dimensions. A novel hydrodynamic model of viscous flow will be used to compute k from these quantities, and single nephron Kf from k and filtration surface area(s). The third hypothesis is that podocyte injury is a consequence of specific changes in epithelial cellcell and cell-substrate interactions. We will accordingly use confocal immunomicroscopy to examine for alterations in the distribution of adhesion and tight junction molecules in the podocyte cell membrane and slit diaphragm. The fourth hypothesis is that blockade of the renin-angiotensin system will confer renoprotection by conserving podocyte function and structure, as judged by less impairment of barrier function and computed k in losartan than placebo-treated individuals. Because GFR remains constant for up to 5 years after detection of microalbuminuria, it is our hope that structural determinants of computed k and SNKf will provide alternative outcome measures for demonstrating effective renoprotection by angiotensin blockade early in the course of DGI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECTS OF GINSENG AND GINKGO ON DRUG DISPOSITION IN MAN Principal Investigator & Institution: Hurwitz, Aryeh A.; Professor; Internal Medicine; University of Kansas Medical Center Msn 1039 Kansas City, Ks 66160 Timing: Fiscal Year 2002; Project Start 27-SEP-2001; Project End 30-JUN-2004

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Summary: Over 60 million Americans use herbal medicines, of whom one fourth also take prescription drugs. Physicians often are unaware of herbal use and of possible drug/herb interactions. Ginseng and ginkgo, enhancers of physical and mental performance, are two of the most widely taken herbals. We propose a double- blind, randomized, prospective study of effects of ginseng and ginkgo on 1) disposition of probe drugs, 2) cognitive function, and 3) glutathione-S-transferase (GST) and quinone reductase (NQO1), enzymes implicated in chemoprevention of cancer. Probe drugs will be administered to study effects of herbs on their disposition, not for therapeutic effect. Ideal probes must be safe, well tolerated, have minimal pharmacological effect, and share known metabolic pathways with other clinically used drugs. Medically stable drug-free non-smokers will be enrolled. During a 4-week single-blind run-in subjects will be given a 4-drug probe cocktail: caffeine to study cytochrome P4501A2 (CYP1A2), dextromethorphan for CYP2D6, buspirone (and endogenous cortisol) for CYP3A and fexofenadine for P-glycoprotein. Losartan will be given separately for CYP2C9. These enzymes metabolize over 95 percent of clinically used drugs. Enzyme activities will be determined by assaying appropriate blood and urine specimens for probe drugs and metabolites. Cognitive function will be tested and blood lymphocytes collected for measuring GST and NQO1 activities. Sixty subjects will then be randomly assigned to one of 4 double-blind treatment groups of 15 each: 1) ginseng extract (Ginsana), 2) ginkgo extract (EGb761), 3) both herbs, or 4) matching placebos. Tolerability of herbs will be determined. After 6 to 8 weeks of twice daily treatment with study agents, all effect parameters will be reevaluated: probe drug pharmacokinetics, cognitive function, and GST and NQO1 in blood lymphocytes. Interactions of chronic ginseng and ginkgo with drug-metabolizing pathways and with cognitive function will thus be determined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPLERENONE & LOSARTAN IN LOW RENIN HYPERTENSION Principal Investigator & Institution: Conlin, Paul R.; Assistant Professor of Medicine; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: The purpose of this study is to compare the effectiveness and safety of an investigational drug, Eplerenone, in subjects with low renin hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EVALUATE RENAL PROTECTIVE EFFECTS OF LOSARTAN IN NIDDM Principal Investigator & Institution: Appel, Gerald B.; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EVALUATION OF LOSARTAN IN PREVENTING AGE DEPENDENT ENDOTHELIAL DYSFUNCTION Principal Investigator & Institution: Rajagopalan, Sanjay; Assistant Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: This abstract is not available.

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

Project Title: IMPROVING OUTCOMES IN DIABETIC NEPHROPATHY Principal Investigator & Institution: Toto, Robert D.; Professor of Internal Medicine; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): The long-range objective of this project is to prevent progression of diabetic nephropathy, the leading cause of end-stage renal disease (ESRD). In most patients diabetic nephropathy progresses inexorably to ESRD despite inhibition of the renin-angiotensin-aldosterone system with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs). The specific aims of this proposal are to: 1) recruit a multi ethnic cohort of 72 young adults (ages 20-40) with type 1 (n=36) or type 2 (n=36) diabetes and overt nephropathy (defined as a urine albumin/creatinine ratio > 300 mg albumin/g creatinine) and randomize in a double blind fashion to a control group consisting of ACEI-based therapy alone (ramipril 40 mg once daily) or one of two experimental groups: a) ACEI + ARB (ramipril 40 mg once daily plus Iosartan100 mg once daily) or b) ACEI + mineralocorticoid receptor antagonist (MRA) (ramipril40 mg once daily plus spironolactone 25 mg once daily); 2) conduct a 12-month prospective study to determine if proteinuria is reduced to a greater extent when either the ARB or MRA is added to ACEi-based therapy. This study is powered to detect a 40% greater reduction in 24-hour urine albumin/creatinine ratio in either experimental group versus control (alpha= 0.05, beta=0.20, repeated measures analysis of variance). Secondary endpoints to be examined include:(a) serum potassium and creatinine to assess safety, (b) TGF-beta, as a surrogate marker for ongoing renal injury, (c) plasma renin activity, angiotensin II and aldosterone levels and (d) plasma lipids and lipoprotein composition; and 3) perform repeated ambulatory blood pressure monitoring (ABPM) to examine the renoprotective effect of the 3 different regimens at comparable 24-hour BP of < 125/75 mmHg. The deliverables include: 1) documentation of the safety of maximal dose combination therapy; 2) the feasibility of utilizing 24-hr ABPM to establish BP independent renoprotective effects of specific antihypertensive therapies; and 3) provide preliminary data for future largescale studies to test efficacy and safety of combining ACEi with MIRA therapy on renal outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INHIBITION OF CYTOCHROME P450 ON THERAPY EFFECTS OF ANGIOTENSIN RECEPT BLOCKER Principal Investigator & Institution: Siragy, Helmy M.; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LOSARTAN IN MILD TO MODERATE ESSENTIAL HYPERTENSION Principal Investigator & Institution: Ziegler, Michael G.; Professor of Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002 Summary: This abstract is not available.

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

Project Title: LOSARTAN INTERVENTION FOR ENDPOINT REDUCTION (LIFE) Principal Investigator & Institution: Randall, Otelio S.; Howard University 2400 6Th St Nw Washington, Dc 20059 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LOSARTAN ON INSULIN SENSITIVITY IN INSULIN RESISTANT HYPERTENSIVES Principal Investigator & Institution: Julius, Stevo; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LOSARTAN VS ATENOLOL IN HYPERTENSIVES WITH LEFT VENTRICULAR HYPERTROPHY Principal Investigator & Institution: Phillips, Bradley G.; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002 Summary: This study is evaluating the long-term effects of losartan compared to atenolol in hypertensive patients with documented left ventricular hypertrophy on the combination of cardiovascular mortality and morbidity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MAXIMIZE RAS BLOCKADE IN DIABETIC NEPHROPATHY Principal Investigator & Institution: Meyer, Timothy W.; Professor of Medicine; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Blockade of the renin-angiotensin system (RAS) by inhibition of angiotensin converting enzyme (ACE) reduces proteinuria and slows loss of renal function in patients with diabetic nephropathy. But the optimal manner in which ACE inhibitors should be used to limit renal injury has been remarkably little studied. In particular, further studies are needed to identify treatments which should be combined with ACE inhibition to maximize the benefit of RAS blockade. The proposed studies will assess the value of two such treatments. The first aim will be to determine whether angiotensin receptor blockade increases the antiproteinuric effect of ACE inhibition is patients with diabetic nephropathy. The putative beneficial effect of adding angiotensin receptor blockade to ACE inhibition has been widely advertised but not adequately tested. Studies conducted to date have shown only that adding an angiotensin receptor blocker (ARB) reduces proteinuria in patients maintained on relatively low doses of an ACE inhibitor. The proposed study will assess the effect of adding an ARB to higher doses of an ACE inhibitor. These studies will reveal whether ARB addition has any effect that cannot be obtained more simply and more cheaply by ACE inhibition alone. The second aim will be to determine whether diuretic use

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increases the antiproteinuric effect of ACE inhibition in patients with diabetic nephropathy. Previous studies have shown that addition of a diuretic lowers proteinuria in patients with non-diabetic renal disease who are maintained on ACE inhibitors. This finding suggests that ACE inhibition reduces proteinuria most effectively when ECF volume is low. The proposed studies will establish where addition of a diuretic to an ACE inhibitor has the same beneficial effect in patients with diabetic nephropathy. Ultimately, the ability of improved RAS blocking regimens to slow the progression of diabetic nephropathy can only be established by large, long term trials. But the number of such trials which can be performed is limited. Short term trials, such as those described in this proposal, are urgently required to help identify treatment regimens which merit further, longer term study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS FOR CARDIOVASCULAR CONTROL EARLY IN DIABETES Principal Investigator & Institution: Brands, Michael W.; Professor; Physiology and Endocrinology; Medical College of Georgia 1120 15Th St Augusta, Ga 30912 Timing: Fiscal Year 2003; Project Start 01-JAN-1997; Project End 31-MAR-2007 Summary: (provided by applicant): We have shown that hyperglycemia at the onset of Type I diabetes causes significant hypertension if it is induced in rats with chronic blockade of nitric oxide synthesis. The hypertension is prevented by blocking angiotensin II, or the sympathetic nervous system; but our data suggest the two systems are linked in this response and may involve superoxide and thromboxane. Blood pressure and nitric oxide also track closely with GFR. The studies in this proposal will test the central hypothesis that nitric oxide protects against hypertension at the onset of diabetes by counteracting pressor actions of the sympathetic and renin-angiotensin systems. The Specific Aims are: 1) to test the hypothesis that nitric oxide protects against AngII-induced hypertension at the onset of diabetes by: a) chronically clamping (fixing) renin-angiotensin system activity at normal levels;b) blocking AngII action in rats with chronic intravenous and intrarenal i) ramipril and ii) iosartan; c) blocking AngII action in mice with ACE gene knockout; d) determining if gradual onset of diabetes causes the same renin secretion and blood pressure responses; e) determining whether low sodium intake increases the dependence of blood pressure on nitric oxide. 2) to test the hypothesis that the SNS contributes to the hypertensive response primarily through renal mechanisms. We will: a) determine the roles of a versus b receptors in mediating the renal, renin, and blood pressure responses:b) remove the renal nerves to test the role of the kidney in mediating the sympathetic pressor effect; c) determine if a decrease in ANG II is required for adrenergic blockade to prevent the hypertension; d) determine if the SNS effect is due to increases in SNS activity, or whether it plays a permissive role, 3) to test the hypothesis that nitric oxide counteracts AngII-dependent superoxide and thromboxane production to control blood pressure at the onset of diabetes. We will determine this by: a) "blocking" superoxide with a superoxide dismutase mimetic in rats and gene overexpression in mice; b) quantifying the degree to which AngII determines whether superoxide significantly affects blood pressure: c) determining if thromboxane receptor blockade will decrease blood pressure if superoxide is not increased: d) determining whether knockout of superoxide dismutase 1 exacerbates the hypertensive response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MODIFIER CARDIOMYOPATHY

GENES

OF

FAMILIAL

HYPERTROPHIC

Principal Investigator & Institution: Marian, Ali J.; Associate Professor of Medicine; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The objective is to identify modifier genes that affect hypertrophy in human familial hypertrophic cardiomyopathy (FHCM) and determine whether pharmacological inhibition of their effects can induce regression of established hypertrophy in a transgenic rabbit model of human FHCM. FHCM, an autosomal dominant disorder occurring 1 in 500, is the most common cause of sudden cardiac death (SCD) in the young. In the elderly, occurring 9 in 500, it is a major cause of mortality and morbidity. Ten genes and >100 mutations were identified with the majority due to 3 genes. Reasons to search selectively for modifier genes of hypertrophy are: hypertrophy is the main determinant of mortality and morbidity in FHCM; it is required for the diagnosis; it is an independent risk factor for SCD and failure due to FHCM and other causes; can be quantified non-invasively and hypertrophy whether due to FHCM or other causes, is known to be modified genetically. Hypertrophy due to any cause is always associated with fibrosis, a putative substrate for SCD. Genotypephenotype correlation studies indicate marked variation in age of onset and severity of hypertrophy even within the same family with the same mutation. The variation is due in large part to modifier genes and is suggested by association studies (e.g. ACE gene) but a systematic genomic search is necessary. This requires a repository of families with FHCM, a mathematical model and ideally an established genetic animal model of FHCM to confirm the predicted biological effect of modifier genes. Recent application of the Monte Carlo Markov Chain Methods (MCMC) in multiple families with Alzheimer's was shown to be highly sensitive in detecting modifier genes. Thus, utilizing 50 previously well-characterized families with FHCM from a computerized database, the genome will be screened initially with 400 DNA markers and analyzed by the MCMC methods to identify regions with modifier genes (Aim 1) followed by additional closely spaced markers in these regions to identify candidate genes (Aim 2). Independently, 350 unrelated probands with FHCM will be analyzed to determine if an association exists between hypertrophy and SNPS identified in candidate modifier genes (Aim 3). An established rabbit model with a phenotype identical to human FHCM will be utilized to determine the biological effect of identified candidate modifier genes. The ACE gene, previously implicated as a modifier of hypertrophy, is the initial candidate. It's effect will be inhibited with Losartan, a renin- angiotensin system (RAS) blocker, in the rabbit model to determine if there is regression of hypertrophy. Similarly, as other modifiers are identified they will be tested in the rabbit model. Identification of modifiers is necessary to assess prognosis and develop more comprehensive treatment. Treatment found to induce regression of hypertrophy in the rabbit with FHCM will most likely also induce regression of hypertrophy in human FHCM and hypertrophy due to other cardiac causes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR FUNCTION(S)

BASIS

FOR

ANGIOTENSIN

II

RECEPTOR

Principal Investigator & Institution: Karnik, Sadashiva S.; Associate Staff; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2002; Project Start 20-AUG-1997; Project End 30-JUN-2006

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Summary: (provided by applicant): Our broad, long-term objective is to understand the structural basis of the functions of receptors for angiotensin II (Ang II). The type 1 (AT1) receptor mediates diverse intracellular responses to Ang II in the regulation of blood pressure, hydromineral balance, cardiac hypertrophy and cell proliferation. The AT1 receptor is a novel paradigm for study since it is a G protein-coupled receptor with the unique ability to directly activate, besides G proteins, tyrosine kinases. Our structurefunction analysis has identified critical interactions of the AT1 receptor with the agonist Ang II and the competitive antagonist losartan. These studies have yielded valuable mutants with loss of specific function and ligand-independent activation. Interpretation of structural consequences of these mutations by using a molecular model provides important insight into the mechanism of activation, desensitization, internalization and differential tyrosine kinase activation by the AT1 receptor. A novel class of dominantnegative (dn) AT1 receptor mutants have indicated that oligomerization of AT1 receptor may be essential for some functions. A combination of site-directed mutagenesis, sitedirected chemical modification, molecular pharmacology, cell signaling and molecular modeling studies will be used to investigate some novel aspects of AT1 receptor structure-function. The specific aims for this competing renewal are: (1) To validate the novel structural features predicted by the homology model of the AT1 receptor based on the crystal structure of rhodopsin; (2) To elucidate the structural basis of prolonged inhibition of the AT1 receptor by insurmountable antagonists which are therapeutically better than competitive antagonists; and (3) To dissect the molecular basis of dominantnegative AT1 receptor mutants. Specific Aims 1 and 2 will use the experimental strategy employed in our previous studies. In addition, we will use site-directed cystein modification studies to obtain structural information. The dnmutants will be tested for non-productive G-protein interaction and oligomerization using coimmunoprecipitation and fluorescence resonance energy transfer studies. The dnmutant effects on Ang Il-specific cellular function and proteome responses will be evaluated. Validation of the model is critical for identification of structural constraints regulating the functions of the AT1 receptor. A refined molecular model will allow future improvement of antagonists. A better understanding of the mechanism of insurmountable antagonism will provide insight into design of novel anti-hypertensive, cardio- and reno-protective drugs that harbor greater therapeutic benefits. The study of trans-dominant effects will lead to novel mechanisms of signal transduction through oligomerization. The dn-mutants may serve as important tools for discovering cross regulation of intracellular signal-transduction pathways that are relevant to pathophysiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTICENTER TRIAL OF FOCAL GLOMERULOSCLEROSIS Principal Investigator & Institution: Gipson, Debbie S.; Medicine; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Idiopathic focal segmental glomerulosclerosis (FSGS) is a progressive scarring disorder that causes proteinuria and kidney failure in the majority of affected individuals. There is considerable controversy regarding the best therapeutic intervention and the definition of pathological variants of FSGS that may impact therapeutic response rates. This proposal focuses on the design and conduct of a collaborative multicenter trial that will evaluate response rates of children and young adults with the nephrotic syndrome due to FSGS treated with cyclosporin A as compared to corticosteroids plus angiotensin receptor blocker therapy. It will utilize a

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newly determined FSGS classification scheme as defined by the NY Pathology Consensus Group that includes one of our collaborators. In addition, since incidence of idiopathic FSGS has been increasing over the past 2 decades, a case-control study that will evaluate risk factors for FSGS is proposed to run concurrently with the trial. Our proposed southeastern clinical coordinating center will provide strength to the planned nation-wide trial through our large patient population with FSGS, the strength of the UNC nephropathology service, and the investigators' long track record of clinical trial and epidemiologic research in glomerular diseases through the UNC-Chapel Hill based Glomerular Disease Collaborative Network. In conjunction with committed collaborating sites, our group has over 400 FSGS patients who would be eligible for the proposed trial, as well as established mechanisms for including prospectively identified patients. The proposed case-control study will evaluate risk factors for the development of FSGS such as body mass, birth weight, viral illnesses and smoking in all patients screened for entry into the trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NO AND THE MAGNOCELLULAR NEUROENDOCRINE SYSTEM Principal Investigator & Institution: Kadekaro-Kutyna, Massako; Professor; Surgery; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from the Investigator's Abstract) The investigators have shown previously that nitric oxide (NO), a lipophilic gas synthesized by NO synthase (NOS) from L-arginine, has important functions in neuroendocrine and behavioral osmoregulation, as well as blood pressure control. The experiments proposed in this application will clarify the site and mechanisms by which NO modulates the magnocellular neuroendocrine system. Since NO is synthesized in magnocellular neurons and cells in the supraoptic nuclei (SON) project almost exclusively to the posterior lobe of the pituitary gland to regulate neuroendocrine responses to fluid and electrolyte imbalances our studies will focus on the SON. The studies are designed to test two hypotheses: 1) NO synthesized locally in the SON during osmotic stimulation activates guanylyl cyclase to increase 3',5' cyclic guanosine monophosphate (cGMP) which results in 2) inhibition of angiotensin II and prostaglandin release in the SON to attenuate peripheral secretion of oxytocin. The specific aims are to determine: 1a) whether the activities of NOS (i.e. citrulline) and guanylyl cyclase (i.e. cGMP) increase in microdialysates of the SON during osmotic stimulation; 1b) whether inhibiting the production of NO with L-Name retrodialyzed in both SON prevents the increase of cGMP in microdialysates associated with increasing plasma levels of oxytocin during osmotic stimulation; 1c) whether retrodialyzing both SON with 1H-[1,2,4) oxodiazolo [4,3-a)quinoxalin-1-one (ODQ), a specific inhibitor of soluble guanylyl cyclase, decreases intranuclear production of cGMP and reproduces the effects of L-Name on plasma secretion of oxytocin during osmotic stimulation. 2a) whether ANG II and prostaglandin levels increase locally in the SON following retrodialysis with L-NAME during osmotic stimulation; 2b1) whether this neuroendocrine response to L-NAME can be prevented by losartan, an ANG II AT1 subtype receptor antagonist, or 2b2) indomethacin, an inhibitor of cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandins. This research is important because it will further our understanding of the neurobiology of body fluid regulation by NO. Since NO is required for plasticity of neural systems involved in learning and memory, as well as participates in neurotoxicity, clarifying the mechanisms of action of this novel neurotransmitter may

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lead to new drug therapies selective for treatment of pathological disorders affecting water balance with minimal effect on other physiological responses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PEPTIDOMIMETICS ANTIBACTERIALS

OF

D-ALA-D-ALA

AS

NOVEL

Principal Investigator & Institution: Dunlap, Norma K.; Chemistry; Middle Tennessee State University Murfreesboro, Tn 37132 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): Although there are currently numerous antibacterial drugs on the market, many bacteria are becoming resistant to existing drugs, and the emergence of these drug-resistant microorganisms is a significant threat to public health. Virtually all classes of antibacterials in use have been circumvented to some extent by various resistance mechanisms and as a result there is a continual need for new structural classes of antibacterials. Penicillins are bacterial cell wall synthesis inhibitors and act by inhibition of Penicillin Binding Proteins (PBP's), also know as D-Dpeptidases. The substrate for the D-D-peptidases is the cell wall peptidoglycan strand ending in D-alanine-D-alanine. However, penicillins and other drugs of that class were not designed to inhibit the D-D-peptidases. The objective of this application is to design and synthesize inhibitors of the D-D-peptidases as potential antibacterial drugs. Hydroxyethylene peptidomimetics of peptidic enzyme substrates such as the HIV protease substrate have been previously developed as drugs. A similar design concept should also apply to the D-D-peptidase substrate. The long-term objective of this project is to synthesize a series of peptidomimetics of the dipeptide D-alanine-D-alanine. These compounds will be tested for enzyme binding and for antibacterial activity. Various peptidomimetics have been designed and the syntheses of several have been initiated. Linear analogs of D-ala-D-ala containing a carboxylic acid will be synthesized, as will cyclopropyl analogs. Tetrazoles have been used successfully as bioisosteric replacements for the carboxylic acids in a number of drugs. An example is the angiotensin receptor antagonist Losartan. Along those lines, both linear and cyclopropyl analogs of D-ala-Dala containing a tetrazole as a replacement for the carboxylic acid will be synthesized and tested for enzyme binding and antibacterial activity. The proposed compounds constitute an entirely new structural class of potential antibacterials and as such should possess activity against resistant organisms. This would have a significant impact in the ability to treat bacterial infections. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POLYCYSTIC KIDNEY DISEASE CLINICAL TRIALS NETWORK Principal Investigator & Institution: Chapman, Arlene B.; Professor of Medicine; Medicine; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JAN-2009 Summary: (provided by applicant): We seek to be a participating clinical center (PCC) in the RFA entitled "Polycystic Kidney Disease Clinical Trials Network." Hypertension is common, occurs early, and is associated with a faster progression to renal failure in ADPKD. We have shown activation of the systemic renin-angiotensin-aldosterone system (RAAS) in hypertension associated with ADPKD prior to loss of renal function, and that intrarenal activation of RAAS is present. We have demonstrated that angiotensin converting enzyme inhibition alone (ACEI) has beneficial effects by reducing proteinuria and regression of left ventricular hypertrophy as well as

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improving effective renal plasma flow, and this may relate to filtration fraction. In contrast to other kidney diseases, ACEI has not been as successful in preventing loss of renal function. This may relate to study design issues, sample size, inclusion of low risk individuals not progressing, and less than maximal blockade of RAAS. Therefore, we propose to assess the effect of combination therapy, i.e. ACEI, angiotensin receptor blockade (ARB), and aldosterone antagonism (spironolactone) in the setting of rigorous blood pressure control (<125/75 mm Hg) on the rate of loss of renal function in ADPKD while controlling for other potential contributors to loss of renal function. ADPKD children with hypertension demonstrate a greater increase in renal volume than other ADPKD children in the setting of normal renal function. Using MRI, we have shown decreased renal blood flow in ADPKD as compared to age and gender-matched children suggesting that activation of RAAS occurs early in ADPKD children. We propose to study a special population of ADPKD subjects (children) throughout adolescence to determine the safety and efficacy of ACE/ARB combination therapy in the acute and chronic setting on renal blood flow, and the rate of renal cyst and total renal growth. Taken together, these studies will determine if maximal inhibition of RAAS prevents loss of renal function in ADPKD adults and if combination ACEI/ARB therapy maintains renal blood flow while slowing renal and cyst growth in ADPKD children. Ultimately these studies should demonstrate slowing or halting progression of ADPKD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POTENTIAL LOSARTAN PHENYTOIN DRUG INTERACTIONS IN VOLUNTEERS Principal Investigator & Institution: Allen, Tracy J.; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PPARGAMMA AND AII IN GLOMERULOSCLEROSIS Principal Investigator & Institution: Hsueh, Willa A.; Professor of Medicine and Chief; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-JUL-1982; Project End 31-MAR-2004 Summary: An imbalance whereby glomerular extracellular matrix (ECM) production is increased and degradation is decreased leads to a relative and absolute increase in ECM volume in the diabetic mesangium. This crucical alteration impairs glomerular filtering capacity and results in glomerulosclerosis and end-stage renal disease. Plasminogen activator inhibitor-1 (PAI-1) is produced by mesangial cells in response to growth factor stimulation, is increased in glomeruli of diabetic animals and humans and, importantly, is a major factor preventing the degradation of mesangial ECM by inhibiting the activation of plasmin and metalloproteinases (MMP). We identified the presence of novel steroid receptors, which function as heterodimers, peroxisomal proliferatoractivated receptors, PPARgamma, and retinoic acid receptor, RXRalpha, in cultured mesangial cells and in glomerular cores. PPARgamma activation substantially decreased PAI-1 expression, which likely resulted from inhibition of the nuclear effects of the mitogen activated protein kinase (MAPK) pathway. We hypothesize that PPARgamma activation will attenuate the development and progression of diabetic glomerulopathy. Specific aims include: 1) Demonstrate that administration of PPARgamma ligands or

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novel MAPK inhibitors will prevent glomerular structural changes in rats given streptozotocin (STZ). This aim will determine whether PPARgamma activation affects the glomerulus in vivo, which would support our preliminary data. 2) Define the role of PAI-1 in mediating glomerulosclerosis. This aim will examine changes in the PAI-1 system and MMP in cultured cells and in glomeruli of animal models treated with PPARgamma ligands. Importantly, PAI-1 knockout mice will be given STZ and the development of nephropathy will be compared with that of wild type controls. 3) Investigate the regulation and function of PPARgamma in cultured mesangial cells. This aim will assess whether growth factors or the diabetic milieu alters PPARgamma or RXRalpha expression and examines the effects of receptor activation on mesangial cell growth, apoptosis, ECM and integrin expression. The major contribution of this proposal will be to develop a readily applicable, potential therapeutic approach to inhibit or attenuate the development of diabetic nephropathy by using PPARgamma ligands and to elucidate the mechanism by which activation of these receptors impact on critical cellular signaling pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTION OF COLON CANCER BY AN AT2 RECEPTOR ANTAGONIST Principal Investigator & Institution: Tamura, Masaaki; Biochemistry; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2003 Summary: (provided by applicant): Epidemiological studies indicate that a majority of the cases of colorectal cancer are etiologically related to environmental factors. Carcinogenic xenobiotics are activated by phase I biotransformation enzymes. This biotransformation mainly occurs in the liver, but also in extrahepatic tissues. Cytochrome P4501A1, 1A2 and 2E1 (CYP1A1, lA2 and 2E1) are major catalysts in the bioactivation of a number of putative colorectal cancer procarcinogens such as polycyclic aromatic hydrocarbons, heterocyclic amines and N-nitrosoamines. Thus, control of biotransformation enzymes is a potential approach to prevent tumorigenesis in the colon. Recently, we were able to demonstrate that mice deficient in the angiotensin II (Ang II) subtype 2 (AT2) receptor gene are resistant to azoxymethane (AOM)-induced colon adenocarcinoma. AOM-stimulated CYP1A1, 1A2 and 2E1 protein induction in the liver of wild type mice is more significant than in AT2: receptordeficient (AT2-KO) mice. These preliminary studies suggest that Ang II-AT2 receptor signaling may function as a regulator of cytochrome P450 enzyme activities in the liver. Based upon our preliminary studies we hypothesize that 1) Ang II- AT2 receptormediated signaling is involved in the induction of carcinogen- metabolizing cytochrome P450s in the liver and/or colon epithelial cells, 2) attenuation of AT2 receptor function diminishes DNA adduct formation in the liver and colon epithelial cells, and thus 3) the Ang II-AT2 receptor-mediated signal is involved in the initiation of tumorigenesis in the colon. Accordingly, pharmacological attenuation of the AT2 receptor function prevents colon tumorigenesis. In this proposal we place our priority on the chemoprevention of AOM-induced colon cancer. Thus, we propose to determine the effect of blockade of the AT2 receptor function by the AT2 receptor- specific antagonist PD123319 in AOMinduced colon adenocarcinoma and to clarify the mechanism of low susceptibility to AOM in AT2-KO mice. These studies will clarify the role of the Ang II-AT2 receptor in colorectal tumorigenesis and will provide a totally new target for the chemoprevention of colon cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: REGULATION OF ANGIOTENSIN PEPTIDE RECEPTORS Principal Investigator & Institution: Diz, Debra I.; Professor; Wake Forest University 2240 Reynolda Rd Winston-Salem, Nc 27106 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: Ang-(1-7) activates the vasodilator systems which oppose the hypertensive At1-mediated actions of Ang II. We propose three aims to investigate the potential mechanisms for the actions of Ang-(1-7). Aim 1: A novel non-At1, non-AT2 receptor [AT(1-7)] is responsible for the hemodynamic and vascular actions of Ang-(1-7). 125I[Sar/1-Thr/8]Ang II binding, in the presence of blocking concentrations of AT1 and AT2 receptor antagonists, demonstrated a novel Ang-(1-7) receptive site sit mesenteric artery and aorta of SHR treated with a combination of lisinopril/losartan. The binding site displayed a pharmacological profile with agonists and antagonists that previously characterized in endothelial cells. We will now determine whether this receptor is unique to the vasculature or exhibits a more widespread distribution (kidney, heart and brain) using receptor binding techniques. Aim 2: Ang-(1-7) actions blocked by At1 or AT2 receptor antagonists are not attributable to classical AT1 or AT2 receptors. In addition to the actions of Ang-(1- 7) at the novel non-AT1 non-AT2 AT(1-7) receptor, several actions of Ang-(1-7) are similar to Ang II or are blocked by AT1 or AT2 receptor antagonists. Ang-(1-7) generally displays low affinity for typical AT1 or AT2 receptors and is not associated with vasoconstrictor, pressor or drinking responses. Thus, we propose that isoforms of AT1 or AT2 receptors are responsible for the actions of Ang-(17) that are blocked by AT1 or AT2 receptor antagonists. We will use receptor knockout mice to show that the Ang-(1-7) actions or binding sites inhibited by AT1 or AT2 receptor antagonists do not persist in these receptor knockout animals. We will also characterize the protein forms of At1 and AT2 receptors known to exist in various tissues for differences in pharmacology toward Ang-(1-7) and [D-Ala/7]-Ang-(1-7). Aim 3: Ang-(1-7) counteracts the actions of Ang II at the AT1 receptor by desensitization and/or down-regulation of the AT1 receptor via homologous (through prostaglandins or nitric oxide) mechanisms. Acute and chronic exposure to elevated Ang-(1-7) decreases AT1 receptors and AT1 receptor-mediated responses in brain, kidney and cells in cultured. Prostaglandins causes heterologous down-regulation of other receptors and decrease in AT1 receptor mRNA with nitric oxide are reported. Alternatively, Ang(1-7) acts as a weak agonist at the AT1 receptor, in a process similar to homologous receptor regulation. Preliminary studies in CHO-AT/1A cells indicated a direct effect of Ang-(1-7) on the AT/1A receptor, consistent with agonist-induced homologous downregulation. We will use in vivo and in vitro models to determine the effects of acute and long-term treatments with Ang-(1-7) on AT1 receptor affinity and density and AT1 receptor mRNA by RT-PCR in the presence or absence of cyclooxygenase or nitric oxide synthase blockade. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RENAL PROTECTIVE EFFECTS OF LOSARTAN IN PATIENTS WITH NIDDM AND NEPHROPATHY Principal Investigator & Institution: Mcgill, Janet; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This study is designed to demonstrate that losartan compared to placebo will reduce the number of NIDDM patients with nephropathy who experience doubling of serum creatinine, ESRD (dialysis, transplantation) or death. This study will also

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investigate the effect of losartan compared to placebo or cardiovascular morbidity and mortality, proteinuria and safety and tolerability. Tertiary parameters include quality of life and healthcare resource utilization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RENIN ANGIOTENSIN SYSTEM BLOCKAGE-DN (RASS) Principal Investigator & Institution: Mauer, S Michael.; Professor; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 16-MAR-1997; Project End 31-MAY-2008 Summary: (provided by applicant): Diabetes nephropathy (DN) is the most important cause of kidney failure. Patients (pts) with Type 1 diabetes mellitus (DM) who develop DN have a markedly increased death rate from kidney failure, coronary artery disease and stroke. Glycemia only partly explains why some pts develop these DM complications. Further, since tight blood sugar control is extremely difficult to maintain, other efforts need to be made to reduce risks of DM complications. Renin-angiotensin system (RAS) inhibitors slow the progress of established DN. The specific aim of this study is to determine whether treatment at the early stages of DM can slow or stop DN structural changes. The long-term objective is to prevent DN from developing. Two hundred eight five pts ages 16-59 with 2-29 yrs of Type 1 DM and no renal functional abnormalities have been randomized into a parallel, double-blind, placebo-controlled study involving 3 groups (95 pts/group). Each group receives an angiotensinconverting enzyme inhibitor (ACEI) (enalapril), or an angiotensin II receptor blocker (losartan), or placebo. All pts have their usual DM management. Baseline studies included measures of glomerular filtration rate (GFR), urinary albumin excretion rate (UAE), blood pressure (BP), and a percutaneous renal biopsy. Pts are followed by quarterly measures of BP, HbA1C, UAE, and drug compliance. There are annual measures of GFR and a repeat renal biopsy after 5 yrs in the study. The main endpoint is kidney structural changes over time, especially mesangial fractional volume [Vv(Mes/glom)]. Secondary endpoints will be other DN structural measures and measures of kidney function (UAE, GFR). These studies will determine whether RAS blockage in the early stages of DN can prevent the early kidney structural changes in this important disorder. Ancillary studies will evaluate the effects of treatment group on the development and progression of diabetic retinopathy and will develop predictors of study participants' compliance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RENIN ANGIOTENSIN SYSTEM STUDY (RASS) Principal Investigator & Institution: Mauer, Michael S.; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002 Summary: This is a randomized, controlled, double-blinded, three armed, 5 year trial of angiotensin converting enzyme inhibition (Enalapril), angiotensin II receptor blockade (Losartan), and placebo in prevention of the early renal structural changes of diabetes measured by morphometry in normoalbuminuric, normotensive, IDDM patients with normal glomerular filtration rate (GFR). The aim is to recruit 285 patients in three centers (U of Minnesota, McGill University and the University of Toronto) and to compare the three groups for the primary endpoint of the rate of mesangial expansion as measured in two renal biopsies performed five years apart. Interval measures will include urinary albumin excretion, GFR and glycemia.

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

Project Title: ROLE OF BRAIN RENIN-ANGIOTENSIN SYSTEM IN INSULININDUCED SYMPATHOEXCITATION Principal Investigator & Institution: Muntzel, Martin S.; Herbert H. Lehman College 250 Bedford Park Blvd. West Bronx, Ny 10468 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: Obesity, syndrome X, and type 2 diabetes are increasing in prevalence and represent major causes of premature morbidity and mortality in westernized socities. The insulin resistance characterizing these diverse pathologies frequently results in a compensatory and sustained hyperinsulinemia. Chronically high insulin, apart from stimulating glucose uptake, has also been shown to be a powerfully activate sympathetic nerve activity (SNA). Importantly, elevated SNA produces several pathophysiological effects, including hypertension, atherosclerosis, ventricular hypertrophy, insulin resistance, and end-organ damage. These actions may partly explain why insulin is powerful and independent predictor of atherosclerosis and cardiovascular events. It remains unclear, however, what mechanisms mediate the excitatory effect of insulin on SNA. We and others have examined the possibility that insulin activates brain renin-angiotensin to then cause increases in sympathetic outflow. This hypothesis is based on the following evidence: 1) systemically-infused insulin increases SNA, 2) insulin penetrates into the brain to bind with insulin-specific receptors, 3) direct administration of insulin into the brain increases lumbar SNA, 4) insulin activates several components of the renin-angiotensin system, 5) insulin-induced SNA elevations are abolished by systemic or by intracerebroventricular reninangiotensin blockade, 6) insulin-activated sympathetic increases are also abolished by lesions of the anteroventral third ventricle (AV3V) region, which is a primary site for the sympathoexcitatory actions of angiotensin II, and 7) renin-angiotensin pathways from AV3V nuclei to the paraventricular nucleus (PVN) exert powerful control over sympathetic output. Altogether, these findings indicate that insulin-induced sympathoexcitation is dependent upon components of the brain renin-angiotensin system. To extend these findings, the present studies will first, determine whether angiotensin II receptor antagonism in the organum vasculosum of the lamina terminalis (OVLT), the median preoptic nucleus (MnPO), and PVN abolish increases in SNA to acute insulin, and second, will determine whether chronic SNA increases, activated by long-term insulin infusion or by high dietary fructose, are abolished by inhibition of brain renin-angiotensin using intracerebroventricular losartan. Finally, we will determine whether physiologically generated modulations of renin-angiotensin function, produced by altering dietary sodium intake, will affect acute sympathoexcitatory responses to insulin. By demonstrating the precise role of brain renin-angiotensin in eliciting SNA increases to hyperinsulinemia, the present experiments will provide fundamental new information regarding central neural regulation of autonomic output. In addition, these findings will generate new hypotheses for intervention strategies to prevent the deleterious consequences of sympathoexcitation in disease states characterized by insulin resistance and hyperinsulinemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STUDY TO EVALUATE THE RENAL PROTECTIVE EFFECTS OF LOSARTAN Principal Investigator & Institution: Nachman, Patrick H.; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TACROLIMUS VS INTENSIVE PREDNISONE IN PEDIATRIC FSGS Principal Investigator & Institution: Kaskel, Frederick J.; Developmental Renal and Electrolyte Phys; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Focal Segmental Glomerulosclerosis (FSGS) is a major cause of chronic kidney disease in childhood. This glomerulopaty is more frequent in minority populations, and often recurs in the transplanted kidney. Despite advances particulary in molecular genetics, the cause and optimal treatment of this condition remains poorly defined. Uncontrolled studies in adults with FSGS support the use of prolonged prednisone therapy. Preliminary data in children suggests that the calcineurin inhibitor tacrolimus may be efficacious in patients who have been refractory to other therapies. The purpose of this multicenter study is to compare the relative efficacy of tacrolimus with that of intensive prednisone therapy in preventing the progression of primary FSGS. This represents the first controlled evaluation of these two promising therapies in children with FSGS. We are proposing a randomized, open-label clinical trial in patients with nephrotic range proteinuria who fail to respond to 4 weeks of oral prednisone and who are found to have FSGS on renal biopsy. Patients will be assigned to receive daily prednisone (60 mg/m2) for 3 months followed by either alternate day prednisone (40 mg/m2) for the ensuing 15 months or tacrolimus plus lowdose alternate day (10 mg/m2) for 18 months. In addition, patients will receive optimal doses of losartan and atorvostatin to control proteinuria, hypertension, and hypelipidemia. The primary outcome indicators will be: complete or partial remission of proteinuria, preservation of glomerular filtration rate, and prevention of renal scarring. Secondary outcome indicators will include correlation of response with a novel histopathologic classification, assessed by a centrol core pathology group. The study design will incorporate collection and storage of potentially important biological samples at the direction of the Data Coordinating Center and the Steering Committee of the NIDDK. The Eastern Regional Group for the Study of Focal Segmental Glomerulosclerosis in Children will be comprised of 41 sites under the direction of the Regional Coordinating Center at Montefiore Medical Center of the Albert Einstein College of Medicine. This project is expected to: 1) improve the outcome of children with FSGS, and, 2) create a nationwide network of clinical investigators that will facilitate future basic and clinical research in the field of pediatric nephrology, in general, and FSGS, in particular. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: UDP GLUCURONOSYLTRANSFERASES IN PHARMACOLOGY Principal Investigator & Institution: Tephly, Thomas R.; Professor; Pharmacology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-APR-1979; Project End 30-JUN-2003

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Losartan

Summary: Glucuronide formation is a major route of xenobiotic and endobiotic metabolism in humans. UDP-glucuron-osyltransferases (UGTs), protein products of a supergene family, mediate these reactions whereby hydrophobic compounds (aglycones) are conjugated to glucuronic acid, forming metabolites which are rapidly excreted by the kidney or liver. Four areas of research are planned. First, the significance of the polymorphic isoforms of UGT2B7 in the metabolism of certain substrates (losartan and zidovudine) will be explored using HK293 cell lines stable expressing these proteins. Using hepatic microsomes from individuals homozygous for these polymorphic isoforms, studies will address the question of whether inter-individual variation in AZT glucuronidation can be predicted base don the genotype of the individual. mRNA and glucuronidation activities for UGT2B7 and UGT1A6 have been found in human brain. Studies are proposed to use immunohistochemical localization to identify the cell types that express these proteins in the brain. Since immunohistochemical localization to identify the cell types that express these proteins in the brain. Since UGT2B7 catalyzes the formation of morphine-6-glucuronide (which is 50 times more potent that morphine as an analgesic) it is important to know where in the rain morphine-6-glucuronide can be formed because its local formation may account for part of the mechanism of action of morphine. Studies determining the substrate specificities of UGTs expressed in intestine, 1A8 and 1A5, are proposed. These isoforms are not expressed in liver and, therefore, may play an important role in xenobiotic and endobiotic metabolism in the intestine. UGT1A4 is an important enzyme because it catalyzes the glucuronidation of tertiary amines (e.g., anti-histamines) and progestins, whereas UGT1A3 catalyzes the glucuronidation of estrogens and NSAIDs. Studies are proposed that will investigate how the protein structure of UGT1A3 and UGT1A4 affects the function of the expressed enzymes. Chimeric proteins and amino acid substitutions will examine the aglycone binding sites for substrates which are unique to each protein and which are common for each UGT. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VASCULAR AND CARDIAC INJURY IN HYPERTENSIVE ANIMAL MODELS Principal Investigator & Institution: Brecher, Peter; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002 Summary: Cardiovascular responses to angiotensin II (ang II) and catecholamines will be studied in vivo using mouse models for experimental hypertension and atherosclerosis. The potential effects of conditions related to oxidative stress will be evaluated with the intent of determined the influence on damage to the heart or vasculature. Experiment also will be proposed in vitro using cultured aortic adventitial fibroblasts to determine if a molecular basis for the in vivo responses that occur can be explained at a cellular level. The in vitro studiers will focus on signaling pathways that mediate the vascular responses to ang II and catecholamines under conditions of reduced or exacerbated oxidative stress. The specific aims are: 1) To catecholamines under conditions of reduced or exacerbated oxidative stress. The specific aims are: 1) To extend our previous studies on the role of AT1 and alpha1-adrenergic receptor blockade by losartan and prazosin in slowing the development of atherosclerosis in the apoprotein E-deficient mouse. A hypothesis to be tested is that the alpha2-adrenergic response may be influential in reducing the vascular response to hypercholesterolemia that characterizes this mouse model. 2) To characterize the cardiovascular responses to chronic infusion of both ang II and catecholamines in mice, and to determine what effect

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oxidative stress has on these responses. Changes in cardiac tissue will be measured using biochemical and morphometric techniques and correlated with vasoactive responses. The interrelationships between ang II and catecholamines will be emphasized, using selective antagonists to the receptors for each endocrine system, or by using receptor-deficient mice that are current available. Possible interactions between responses induced by ang II and the alpha2-adrenergic receptor will be examined with regard to cardiac damage as well as the hemodynamic changes. 3) To evaluate the role of ang II, catecholamines, and nitric oxide (NO) on the activation of mitogen activated protein kinases (MAPK) and the expression of p231 in cultured adventitial fibroblasts. The adventitial fibroblast is proposed to be an important cell type in modulating vascular responses to vasoactive agents and its response to NO may influence vascular responses to other agonists. A specific hypothesis to be tested is if interrelationships between MAPK and p21 expression is influenced by ang II, catecholamines, NO, or oxidative stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: VASOACTIVE HORMONES: RECEPTORS AND SIGNALING MECHANISM Principal Investigator & Institution: Hopfer, Ulrich; Professor; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-JUL-1989; Project End 30-APR-2005 Summary: The renin-angiotensin system regulates blood pressure and fluid homeostasis through effects mediated by specific receptors that are widely distributed. Molecular biological and pharmacological observations have confirmed the existence of two major subtypes of angiotensin II receptors: AT1 receptors that are highly sensitive to biphenylimidazoles (e.g. losartan), and AT2 receptors that are sensitive to tetrahydroimidopyridines (e.g. PD 123319). Abundant physiological and pharmacological data have been accumulated to substantiate the observation that the AT1 receptor mediates a majority of the known effects of Ang II. By contrast, much less is known about AT1 mediated effects, however, it is generally accepted that there is a "yin yang" relationship. Functional data indicate that the AT2 receptor opposes the blood pressure elevation of the AT1 receptor and other cellular actions as well. Data is now accumulating that a major mechanism whereby the AT2 receptor regulates blood pressures is through its ability to facilitate Na excretion. The overall goal of the PPG is to elucidate cellular/molecular mechanisms important for the regulation of blood pressure through effects on ion transport. The central hypothesis is that the AT2 receptor in the proximal tubule is responsible for diminished salt and fluid reabsorption that is observe in high physiological concentrations of angiotensin II. To test this hypothesis, we have assembled three projects that are directed at gaining a better understanding of structural/functional aspects of angiotensin receptors and cellular signaling pathways with influences on cytoskeleton and ion transporters in kidney epithelium. Attainment of this goal necessitates a multi- disciplinary group encompassing cell/organ physiology, molecular biology, biochemistry, pharmacology, biophysics and genetics. The program stresses a broad application to the problem of receptors, effectors, and coupling mechanisms to downstream targets employing cells and subcellular organelles and emphasizes and application of state- of-the-art techniques. Studies at a whole animal level will involve continuous infusions, assessments of blood pressure, and selective breeding of transgenic mice. Studies at a cellular level will utilize electrophysiology, fluorescent probes, pH measurement, and confocal microscopy. Studies at a molecular level involve cloning receptor subtypes, transfections of receptors

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Losartan

(wild type and mutants), small G- protein (wild type and mutants), G-protein subunits and constitutively active and dominant negative mutants of phosphatases and kinases. Cores provide administrative support, tissue culture, animal models, biostatistics, and analytical instrumentation measures to enhance the scientific merit of all projects. 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 “losartan” (or synonyms) into the search box. This search gives you access to fulltext articles. The following is a sample of items found for losartan in the PubMed Central database: •

Losartan and angina pectoris. by Ahmad S.; 1995; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=325288

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Losartan and diabetic nephropathy: commentaries on the RENAAL study. by Fisman EZ, Tenenbaum A, Motro M.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=116616

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 losartan, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “losartan” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for losartan (hyperlinks lead to article summaries): 3 4

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print. 6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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A blood pressure independent association between glomerular albumin leakage and electrocardiographic left ventricular hypertrophy. The LIFE Study. Losartan Intervention For Endpoint reduction. Author(s): Olsen MH, Wachtell K, Borch-Johnsen K, Okin PM, Kjeldsen SE, Dahlof B, Devereux RB, Ibsen H. Source: Journal of Human Hypertension. 2002 August; 16(8): 591-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12149666

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A case of exercise-induced acute renal failure in a patient with idiopathic renal hypouricemia developed during antihypertensive therapy with losartan and trichlormethiazide. Author(s): Ito O, Hasegawa Y, Sato K, Mitsui H, Yuda F, Sato H, Ito S, Kudo K. Source: Hypertens Res. 2003 June; 26(6): 509-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12862209

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A comparative evaluation of therapeutic effects of once a day dose of losartan potassium versus enalapril maleate in mild to moderate essential hypertension. Author(s): Neki NS, Arora P. Source: J Indian Med Assoc. 2001 November; 99(11): 640-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12022207

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A comparative trial of controlled-onset, extended-release verapamil, enalapril, and losartan on blood pressure and heart rate changes. Author(s): Bakris G, Sica D, Ram V, Fagan T, Vaitkus PT, Anders RJ. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2002 January; 15(1 Pt 1): 53-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11824861

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A comparison of initial treatment with losartan/HCTZ versus losartan monotherapy in chinese patients with mild to moderate essential hypertension. Author(s): Li Y, Liu G, Jiang B, Gao R, Chen L, Su L, Li J. Source: Int J Clin Pract. 2003 October; 57(8): 673-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627176

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A favourable outcome using oral prednisolone and losartan only in a patient with ANCA-related glomerulonephritis: a discrepancy between histological activity and MPO-ANCA. Author(s): Nakahama H, Sasaki O, Yoshihara F, Nakamura S, Inenaga T, Kawano Y, Ueda H. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 March; 18(3): 610-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12584288

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A forced titration study of antihypertensive efficacy of candesartan cilexetil in comparison to losartan: CLAIM Study II. Author(s): Vidt DG, White WB, Ridley E, Rahman M, Harris S, Vendetti J, Michelson EL, Wang R; CLAIM Study Investigators. Source: Journal of Human Hypertension. 2001 July; 15(7): 475-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11464257

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A low-sodium diet potentiates the effects of losartan in type 2 diabetes. Author(s): Houlihan CA, Allen TJ, Baxter AL, Panangiotopoulos S, Casley DJ, Cooper ME, Jerums G. Source: Diabetes Care. 2002 April; 25(4): 663-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11919122

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A multicenter, randomized, double-blind, placebo-controlled, 8-week trial of the efficacy and tolerability of once-daily losartan 100 mg/hydrochlorothiazide 25 mg and losartan 50 mg/hydrochlorothiazide 12.5 mg in the treatment of moderate-to-severe essential hypertension. Author(s): Gradman AH, Brady WE, Gazdick LP, Lyle P, Zeldin RK. Source: Clinical Therapeutics. 2002 July; 24(7): 1049-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12182251

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A randomised, double-blind, double-dummy comparison of the efficacy and tolerability of lercanidipine tablets and losartan tablets in patients with mild to moderate essential hypertension. Author(s): James IG, Jones A, Davies P. Source: Journal of Human Hypertension. 2002 August; 16(8): 605-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12149668

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A randomised, placebo-controlled, double-blind, crossover study of losartan and enalapril in patients with essential hypertension. Author(s): Fagard R, Lijnen P, Pardaens K, Thijs L, Vinck W. Source: Journal of Human Hypertension. 2001 March; 15(3): 161-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11317199

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A study on the efficacy and safety of losartan in elderly patients with mild to moderate essential hypertension. Author(s): Fernandez-Vega F, Abellan J, Sanz de Castro S, Cucalon JM, Maceira B, Gomez de la Camara A. Source: International Urology and Nephrology. 2001; 32(4): 519-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11989539

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Additive antiproteinuric effect of ACE inhibitor and losartan in IgA nephropathy. Author(s): Bhattacharjee R, Filler G. Source: Pediatric Nephrology (Berlin, Germany). 2002 April; 17(4): 302-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11956889

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Amlodipine and losartan: reaction to comparison. Author(s): Gleim G, Smith RD. Source: Journal of Clinical Hypertension (Greenwich, Conn.). 2003 NovemberDecember; 5(6): 423-4; Author Reply 424. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14688500

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An analysis of cholesterol control and statin use in the Losartan Intervention for Endpoint Reduction in Hypertension Study. Author(s): Kristianson K, Fyhrquist F, Devereux RB, Kjeldsen SE, Lindholm LH, Lyle PA, Nieminen MS, Snapinn SM. Source: Clinical Therapeutics. 2003 April; 25(4): 1186-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12809965

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An economic evaluation of Losartan therapy in type 2 diabetic patients with nephropathy: an analysis of the RENAAL study adapted to France. Author(s): Souchet T, Durand Zaleski I, Hannedouche T, Rodier M, Gaugris S, Passa P; RENAAL study. Source: Diabetes & Metabolism. 2003 February; 29(1): 29-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12629445

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An open comparative clinical trial to assess the efficacy and safety of losartan versus enalapril in mild to moderate hypertension. Author(s): Chowta KN, Chowta MN, Bhat P, Adhikari PM. Source: J Assoc Physicians India. 2002 October; 50: 1236-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12568205

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Angiotensin II receptor-independent antiinflammatory and antiaggregatory properties of losartan: role of the active metabolite EXP3179. Author(s): Kramer C, Sunkomat J, Witte J, Luchtefeld M, Walden M, Schmidt B, Tsikas D, Boger RH, Forssmann WG, Drexler H, Schieffer B. Source: Circulation Research. 2002 April 19; 90(7): 770-6. Erratum In: Circ Res 2002 December 13; 91(12): E65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11964369

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Angiotensin II type 1 receptor antagonist, losartan, causes regression of left ventricular hypertrophy in end-stage renal disease. Author(s): Shibasaki Y, Masaki H, Nishiue T, Nishikawa M, Matsubara H, Iwasaka T. Source: Nephron. 2002 March; 90(3): 256-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11867945

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Angiotensin receptor antagonist losartan improves endothelial function of epicardial coronary arteries in patients with essential hypertension. Author(s): Deng YB, Yang HY, Li CL, Chang Q. Source: Clin Cardiol. 2002 September; 25(9): 422-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12269521

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Angiotensin receptor blocker losartan suppresses platelet activity by interfering with thromboxane signaling. Author(s): Schwemmer M, Sommer O, Bassenge E. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 2001 July; 15(4): 301-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11800413

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Angiotensin-II receptor antagonist losartan reduces microalbuminuria in hypertensive renal transplant recipients. Author(s): Ersoy A, Dilek K, Usta M, Yavuz M, Gullulu M, Oktay B, Yurtkuran M. Source: Clinical Transplantation. 2002 June; 16(3): 202-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12010144

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Antihypertensive effects of losartan and candesartan. Author(s): Messerli FH. Source: Clinical Therapeutics. 2001 March; 23(3): 516-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11318085

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Antihypertensive efficacy and safety of losartan alone and in combination with hydrochlorothiazide in adult African Americans with mild to moderate hypertension. Author(s): Flack JM, Saunders E, Gradman A, Kraus WE, Lester FM, Pratt JH, Alderman M, Green S, Vargas R, Espenshade M, Ceesay P, Alexander J Jr, Goldberg A; Study Group for Losartan in African Americans with Hypertension. Source: Clinical Therapeutics. 2001 August; 23(8): 1193-208. Erratum In: Clin Ther 2001 November; 23(11): 1922. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11558858

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Antihypertensive efficacy and tolerability of low-dose perindopril/indapamide combination compared with losartan in the treatment of essential hypertension. Author(s): Chanudet X, De Champvallins M. Source: Int J Clin Pract. 2001 May; 55(4): 233-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11406907

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Antihypertensive efficacy of candesartan in comparison to losartan: the CLAIM study. Author(s): Bakris G, Gradman A, Reif M, Wofford M, Munger M, Harris S, Vendetti J, Michelson EL, Wang R; CLAIM Study Investigators. Source: Journal of Clinical Hypertension (Greenwich, Conn.). 2001 January-February; 3(1): 16-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11416677

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Anti-proteinuric effect of angiotension II receptor antagonist losartan in cases with glomerular lesions. Author(s): Usta M, Dilek K, Yavuz M, Ersoy A, Gullulu M, Yurtkuran M. Source: Clinical Nephrology. 2001 March; 55(3): 260-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11316250

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Antiproteinuric efficacy of losartan in comparison with amlodipine in non-diabetic proteinuric renal diseases: a double-blind, randomized clinical trial. Author(s): Praga M, Andrade CF, Luno J, Arias M, Poveda R, Mora J, Prat MV, Rivera F, Galceran JM, Ara JM, Aguirre R, Bernis C, Marin R, Campistol JM. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 September; 18(9): 1806-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12937228

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Are angiotensin II receptor blockers more efficacious than placebo in heart failure? Implications of ELITE-2. Evaluation of Losartan In The Elderly. Author(s): Berry C, Norrie J, McMurray JJ. Source: The American Journal of Cardiology. 2001 March 1; 87(5): 606-7, A9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11230847

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Augmentation of myocardial blood flow in hypertensive heart disease by angiotensin antagonists: a comparison of lisinopril and losartan. Author(s): Akinboboye OO, Chou RL, Bergmann SR. Source: Journal of the American College of Cardiology. 2002 August 21; 40(4): 703-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12204500

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Baseline characteristics in relation to electrocardiographic left ventricular hypertrophy in hypertensive patients: the Losartan intervention for endpoint reduction (LIFE) in hypertension study. The Life Study Investigators. Author(s): Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Dahlof B. Source: Hypertension. 2000 November; 36(5): 766-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11082141

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Beneficial effect of losartan against proteinuria from the renal allograft. Author(s): Ishikawa A, Kawabe K. Source: Transplantation Proceedings. 2003 February; 35(1): 289-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591404

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Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients. Author(s): Goldberg MR, Bradstreet TE, McWilliams EJ, Tanaka WK, Lipert S, Bjornsson TD, Waldman SA, Osborne B, Pivadori L, Lewis G, et al. Source: Hypertension. 1995 January; 25(1): 37-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7843751

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Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Author(s): Stearns RA, Chakravarty PK, Chen R, Chiu SH. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 1995 February; 23(2): 207-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7736913

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Blood pressure and renin angiotensin system responses to initiation of treatment with captopril or losartan in heart failure. Author(s): Squire IB, Robb S, Brennan G, O'Kane KP, Dargie HJ, Reid JL. Source: British Journal of Clinical Pharmacology. 1999 September; 48(3): 464-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10576791

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Blood pressure effects of the angiotensin II receptor blocker, losartan. Author(s): Weber MA, Byyny RL, Pratt JH, Faison EP, Snavely DB, Goldberg AI, Nelson EB. Source: Archives of Internal Medicine. 1995 February 27; 155(4): 405-11. Erratum In: Arch Intern Med 1995 April 24; 155(8): 876. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7848024

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Brief report: acute renal failure after losartan treatment in a patient with bilateral renal artery stenosis. Author(s): Holm EA, Randlov A, Strandgaard S. Source: Blood Pressure. 1996 November; 5(6): 360-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8973754

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Can losartan improve cardiac performance during the treadmill exercise test in hypertensive subjects? Author(s): Paterna S, Parrinello G, Amato P, Bologna P, Fornaciari E, Follone G, Di Pasquale P, Di Marco A, Tarantino AM, Ducato G, Accardo Palumbo V, Colomba D, Sciortino A, Bascone F, Licata G. Source: Drugs Exp Clin Res. 2002; 28(4): 155-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12512233

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Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Author(s): Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S; LIFE Study Group. Source: Lancet. 2002 March 23; 359(9311): 1004-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11937179

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Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Author(s): Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group. Source: Lancet. 2002 March 23; 359(9311): 995-1003. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11937178

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Change in diastolic left ventricular filling after one year of antihypertensive treatment: The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Author(s): Wachtell K, Bella JN, Rokkedal J, Palmieri V, Papademetriou V, Dahlof B, Aalto T, Gerdts E, Devereux RB. Source: Circulation. 2002 March 5; 105(9): 1071-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11877357

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Change in systolic left ventricular performance after 3 years of antihypertensive treatment: the Losartan Intervention for Endpoint (LIFE) Study. Author(s): Wachtell K, Palmieri V, Olsen MH, Gerdts E, Papademetriou V, Nieminen MS, Smith G, Dahlof B, Aurigemma GP, Devereux RB. Source: Circulation. 2002 July 9; 106(2): 227-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12105163

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Losartan

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Change of left ventricular geometric pattern after 1 year of antihypertensive treatment: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Author(s): Wachtell K, Dahlof B, Rokkedal J, Papademetriou V, Nieminen MS, Smith G, Gerdts E, Boman K, Bella JN, Devereux RB. Source: American Heart Journal. 2002 December; 144(6): 1057-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12486431

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Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Author(s): Russo D, Minutolo R, Pisani A, Esposito R, Signoriello G, Andreucci M, Balletta MM. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2001 July; 38(1): 18-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11431176

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Combined use of enalapril and losartan to reduce proteinuria: a question of safety. Author(s): Ellis D. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2002 January; 39(1): 209-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11774126

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Comparative cost effectiveness of angiotensin II receptor blockers in a US managed care setting: olmesartan medoxomil compared with losartan, valsartan, and irbesartan. Author(s): Simons WR. Source: Pharmacoeconomics. 2003; 21(1): 61-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12484804

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Comparative effects of candesartan cilexetil and losartan in patients with systemic hypertension. Candesartan Versus Losartan Efficacy Comparison (CANDLE) Study Group. Author(s): Gradman AH, Lewin A, Bowling BT, Tonkon M, Deedwania PC, Kezer AE, Hardison JD, Cushing DJ, Michelson EL. Source: Heart Disease. 1999 May-June; 1(2): 52-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11720604

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Comparative effects of chronic ACE inhibition and AT1 receptor blocked losartan on cardiac hypertrophy and renal function in hypertensive patients. Author(s): De Rosa ML, Cardace P, Rossi M, Baiano A, de Cristofaro A. Source: Journal of Human Hypertension. 2002 February; 16(2): 133-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11850771

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Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. Author(s): Wurzner G, Gerster JC, Chiolero A, Maillard M, Fallab-Stubi CL, Brunner HR, Burnier M. Source: Journal of Hypertension. 2001 October; 19(10): 1855-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11593107

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Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricemia and gout. Author(s): Liberopoulos E, Christides D, Elisaf M. Source: Journal of Hypertension. 2002 February; 20(2): 347. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11821722

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Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. Author(s): Oparil S, Williams D, Chrysant SG, Marbury TC, Neutel J. Source: Journal of Clinical Hypertension (Greenwich, Conn.). 2001 September-October; 3(5): 283-91, 318. Erratum In: J Clin Hypertens (Greenwich) 2001 November-December; 3(6): 395. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11588406

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Comparative pharmacodynamics and pharmacokinetics of candesartan and losartan in man. Author(s): Fuchs B, Breithaupt-Grogler K, Belz GG, Roll S, Malerczyk C, Herrmann V, Spahn-Langguth H, Mutschler E. Source: The Journal of Pharmacy and Pharmacology. 2000 September; 52(9): 1075-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11045887

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Comparison of atenolol, amlodipine, enalapril, hydrochlorothiazide, and losartan for antihypertensive treatment in patients with obstructive sleep apnea. Author(s): Kraiczi H, Hedner J, Peker Y, Grote L. Source: American Journal of Respiratory and Critical Care Medicine. 2000 May; 161(5): 1423-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10806134

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Comparison of effects of losartan versus enalapril on fibrinolysis and coagulation in patients with acute myocardial infarction. Author(s): Soejima H, Ogawa H, Suefuji H, Kaikita K, Takazoe K, Miyamoto S, Kajiwara I, Shimomura H, Sakamoto T, Yoshimura M, Nakamura S. Source: The American Journal of Cardiology. 2001 June 15; 87(12): 1408-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11397366

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Losartan

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Comparison of enalapril and losartan in the treatment of posttransplant erythrocytosis. Author(s): Celik A, Ok E, Unsal A, Toz H, Atabay G. Source: Nephron. 2000 November; 86(3): 394-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11096321

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Comparison of losartan and captopril in ELITE II. Author(s): Lye M. Source: Lancet. 2000 September 2; 356(9232): 852; Author Reply 852-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11022949

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Comparison of losartan and captopril in ELITE II. Author(s): Gansevoort RT, van Veldhuisen DJ. Source: Lancet. 2000 September 2; 356(9232): 851-2; Author Reply 852-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11022948

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Comparison of losartan and captopril in ELITE II. Author(s): Meyer FP. Source: Lancet. 2000 September 2; 356(9232): 851; Author Reply 852-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11022947

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Comparison of losartan and captopril in ELITE II. Author(s): Hall A. Source: Lancet. 2000 September 2; 356(9232): 851; Author Reply 852-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11022946

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Comparison of losartan with ACE inhibitors and dihydropyridine calcium channel antagonists: a pilot study of prescription-event monitoring in Japan. Author(s): Samizo K, Kawabe E, Hinotsu S, Sato T, Kageyama S, Hamada C, Ohashi Y, Kubota K. Source: Drug Safety : an International Journal of Medical Toxicology and Drug Experience. 2002; 25(11): 811-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12222991

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Comparison of the blood pressure-lowering effects and tolerability of Losartan- and Amlodipine-based regimens in patients with isolated systolic hypertension. Author(s): Volpe M, Junren Z, Maxwell T, Rodriguez A, Gamboa R, Gomez-Fernandez P, Ortega-Gonzalez G, Matadamas N, Rodriguez F, Dass B, Kyle C, Clarysse L, Bryce A, Moreno-Heredia E, Germano G, Gilles L, Smith RD, Sanderson JE; CDSP-944 Study Group. Source: Clinical Therapeutics. 2003 May; 25(5): 1469-89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12867222

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Comparison of the effects of amlodipine and losartan on 24-hour ambulatory blood pressure in hypertensive patients. Author(s): Ishimitsu T, Minami J, Yoshii M, Suzuki T, Inada H, Ohta S, Futoh Y, Ono H, Matsuoka H. Source: Clinical and Experimental Hypertension (New York, N.Y. : 1993). 2002 JanuaryFebruary; 24(1-2): 41-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11848168

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Comparison of the effects of enalapril and losartan on posttransplantation erythrocytosis in renal transplant recipients: prospective randomized study. Author(s): Yildiz A, Cine N, Akkaya V, Sahin S, Ismailoglu V, Turk S, Bozfakioglu S, Sever MS. Source: Transplantation. 2001 August 15; 72(3): 542-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11502994

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Comparison of the effects of losartan and atenolol on common carotid artery intimamedia thickness in patients with hypertension: results of a 2-year, double-blind, randomized, controlled study. Author(s): Ludwig M, Stapff M, Ribeiro A, Fritschka E, Tholl U, Smith RD, Stumpe KO. Source: Clinical Therapeutics. 2002 July; 24(7): 1175-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12182261

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Comparison of the efficacy, safety and tolerability of telmisartan with losartan in Indian patients with mild to moderate hypertension: a pilot study. Author(s): Samra SS, Dongre N, Ballary C, Desai A. Source: J Indian Med Assoc. 2003 May; 101(5): 327-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14575232

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Correlates of left atrial size in hypertensive patients with left ventricular hypertrophy: the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Author(s): Gerdts E, Oikarinen L, Palmieri V, Otterstad JE, Wachtell K, Boman K, Dahlof B, Devereux RB; Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Source: Hypertension. 2002 March 1; 39(3): 739-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11897755

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Correlates of pulse pressure reduction during antihypertensive treatment (losartan or atenolol) in hypertensive patients with electrocardiographic left ventricular hypertrophy (the LIFE study). Author(s): Gerdts E, Papademetriou V, Palmieri V, Boman K, Bjornstad H, Wachtell K, Giles TD, Dahlof B, Devereux RB; Losartan Intervention For End (LIFE) point reduction in hypertension study. Source: The American Journal of Cardiology. 2002 February 15; 89(4): 399-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11835919

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Losartan

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Deterioration in renal function with enalapril but not losartan in a patient with renal artery stenosis in a solitary kidney. Author(s): Missouris CG, Ward DE, Eastwood JB, MacGregor GA. Source: Heart (British Cardiac Society). 1997 April; 77(4): 391-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9155634

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Determination of plasma concentrations of losartan in patients by HPLC using solid phase extraction and UV detection. Author(s): Yeung PK, Jamieson A, Smith GJ, Fice D, Pollak PT. Source: International Journal of Pharmaceutics. 2000 August 25; 204(1-2): 17-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11011981

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Differential effects of oral losartan and enalapril on local venous and systemic pressor responses to angiotensin I and II in healthy men. Author(s): Goldberg MR, de Mey C, Wroblewski JM, Li Q, Schroeter V, Belz GG. Source: Clinical Pharmacology and Therapeutics. 1996 January; 59(1): 72-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8549037

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Discovery of losartan, the first angiotensin II receptor antagonist. Author(s): Timmermans PB, Duncia JV, Carini DJ, Chiu AT, Wong PC, Wexler RR, Smith RD. Source: Journal of Human Hypertension. 1995 November; 9 Suppl 5: S3-18. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8583479

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Discovery of losartan, the first specific non-peptide angiotensin II receptor antagonist. Author(s): Siegl PK. Source: Journal of Hypertension. Supplement : Official Journal of the International Society of Hypertension. 1993 April; 11(3): S19-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8315513

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Does angiotensin II receptor antagonist Losartan suppress drinking behavior in hemodialysis patients? Author(s): Shimada N, Hayashi K, Saka S, Nakamura T, Ebihara I, Koide H. Source: Renal Failure. 2001 September; 23(5): 753-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11725925

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Does losartan (Cozaar) slow the progression of renal disease in patients with type 2 diabetes and nephropathy? Author(s): Pierce HL, Stevermer JJ. Source: The Journal of Family Practice. 2001 December; 50(12): 1083. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11742614

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Does losartan decrease all-cause mortality more than placebo or first-generation ACE inhibitors for patients with moderate to severe heart failure? Author(s): LeClair BM. Source: The Journal of Family Practice. 2000 May; 49(5): 397. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10836767

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Does losartan work after all? Author(s): Blendis LM, Wong F. Source: The American Journal of Gastroenterology. 2003 June; 98(6): 1222-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12818261

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Does the addition of losartan improve the beneficial effects of ACE inhibitors in patients with anterior myocardial infarction? A pilot study. Author(s): Di Pasquale P, Bucca V, Scalzo S, Cannizzaro S, Giubilato A, Paterna S. Source: Heart (British Cardiac Society). 1999 June; 81(6): 606-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10336919

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Does the angiotensin II receptor antagonist losartan improve cognitive function? Author(s): Tedesco MA, Ratti G, Di Salvo G, Natale F. Source: Drugs & Aging. 2002; 19(10): 723-32. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12390049

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Dose-dependent blockade of the angiotensin II type 1 receptor with losartan in normal volunteers. Author(s): Berlowitz MS, Latif F, Hankins SR, Ennezat PV, Moskowitz R, Tandon S, Colombo PC, Le Jemtel TH. Source: Journal of Cardiovascular Pharmacology. 2001 June; 37(6): 692-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11392465

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Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man. Author(s): Doig JK, MacFadyen RJ, Sweet CS, Lees KR, Reid JL. Source: Journal of Cardiovascular Pharmacology. 1993 May; 21(5): 732-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7685442

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Double-blind comparison of losartan, lisinopril, and metolazone in elderly hypertensive patients with previous angiotensin-converting enzyme inhibitorinduced cough. Author(s): Chan P, Tomlinson B, Huang TY, Ko JT, Lin TS, Lee YS. Source: Journal of Clinical Pharmacology. 1997 March; 37(3): 253-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9089428

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Losartan

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Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist. Author(s): Munafo A, Christen Y, Nussberger J, Shum LY, Borland RM, Lee RJ, Waeber B, Biollaz J, Brunner HR. Source: Clinical Pharmacology and Therapeutics. 1992 May; 51(5): 513-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1587065

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DuP 532, an angiotensin II receptor antagonist: first administration and comparison with losartan. Author(s): Goldberg MR, Lo MW, Christ DD, Chiou R, Furtek CI, Amit O, Carides A, Biollaz J, Piguet V, Nussberger J, Brunner HR. Source: Clinical Pharmacology and Therapeutics. 1997 January; 61(1): 59-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9024174

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Effect of amlodipine, quinapril, and losartan on pulse wave velocity and plasma collagen markers in patients with mild-to-moderate arterial hypertension. Author(s): Rajzer M, Klocek M, Kawecka-Jaszcz K. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2003 June; 16(6): 439-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12799091

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Effect of losartan and amlodipine on proteinuria and transforming growth factorbeta1 in patients with IgA nephropathy. Author(s): Park HC, Xu ZG, Choi S, Goo YS, Kang SW, Choi KH, Ha SK, Lee HY, Han DS. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 June; 18(6): 1115-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12748343

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Effect of losartan on circulating TNFalpha levels and left ventricular systolic performance in patients with heart failure. Author(s): Gurlek A, Kilickap M, Dincer I, Dandachi R, Tutkak H, Oral D. Source: Journal of Cardiovascular Risk. 2001 October; 8(5): 279-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11702033

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Effect of losartan on microalbuminuria in normotensive patients with type 2 diabetes mellitus. A randomized clinical trial. Author(s): Zandbergen AA, Baggen MG, Lamberts SW, Bootsma AH, de Zeeuw D, Ouwendijk RJ. Source: Annals of Internal Medicine. 2003 July 15; 139(2): 90-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12859158

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Effect of losartan on nocturnal blood pressure in patients with stroke: comparison with angiotensin converting enzyme inhibitor. Author(s): Okuguchi T, Osanai T, Fujiwara N, Kato T, Metoki N, Konta Y, Okumura K. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2002 November; 15(11): 998-1002. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12441222

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Effect of losartan on sudden cardiac death in people with diabetes: data from the LIFE study. Author(s): Lindholm LH, Dahlof B, Edelman JM, Ibsen H, Borch-Johnsen K, Olsen MH, Snapinn S, Wachtell K; LIFE study group. Source: Lancet. 2003 August 23; 362(9384): 619-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12944063

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Effect of losartan treatment on the proteinuria in normotensive patients having proteinuria due to secondary amyloidosis. Author(s): Odabas AR, Cetinkaya R, Selcuk Y, Bilen H. Source: Upsala Journal of Medical Sciences. 2001; 106(3): 183-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12166510

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Effect of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism in healthy subjects. Author(s): Hamada T, Hisatome I, Kinugasa Y, Matsubara K, Shimizu H, Tanaka H, Furuse M, Sonoyama K, Yamamoto Y, Ohtahara A, Igawa O, Shigemasa C, Yamamoto T. Source: Intern Med. 2002 October; 41(10): 793-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12412998

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Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects. Author(s): Sekino K, Kubota T, Okada Y, Yamada Y, Yamamoto K, Horiuchi R, Kimura K, Iga T. Source: European Journal of Clinical Pharmacology. 2003 November; 59(8-9): 589-92. Epub 2003 September 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504849

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Effects of combination treatment using anti-hyperuricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Author(s): Takahashi S, Moriwaki Y, Yamamoto T, Tsutsumi Z, Ka T, Fukuchi M. Source: Annals of the Rheumatic Diseases. 2003 June; 62(6): 572-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759298

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Losartan

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Effects of enalapril and losartan on circulating adhesion molecules and monocyte chemotactic protein-1. Author(s): Jilma B, Li-Saw-Hee FL, Wagner OF, Beevers DG, Lip GY. Source: Clinical Science (London, England : 1979). 2002 August; 103(2): 131-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12149103

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Effects of losartan and atenolol on left ventricular mass and neurohormonal profile in patients with essential hypertension and left ventricular hypertrophy. Author(s): Dahlof B, Zanchetti A, Diez J, Nicholls MG, Yu CM, Barrios V, Aurup P, Smith RD, Johansson M; For the REGAAL Study Investigators. Source: Journal of Hypertension. 2002 September; 20(9): 1855-64. Erratum In: J Hypertens. 2002 November; 20(11): 2315. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12195129

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Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Author(s): Dickstein K, Kjekshus J; OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Source: Lancet. 2002 September 7; 360(9335): 752-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12241832

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Effects of losartan in patients with a systemically functioning morphologic right ventricle after atrial repair of transposition of the great arteries. Author(s): Lester SJ, McElhinney DB, Viloria E, Reddy GP, Ryan E, Tworetzky W, Schiller NB, Foster E. Source: The American Journal of Cardiology. 2001 December 1; 88(11): 1314-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11728365

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Effects of losartan on blood pressure and humoral factors in a patient who suffered from anaphylactoid reactions when treated with ACE inhibitors during LDL apheresis. Author(s): Kojima S, Shida M, Takano H, Inami S, Yodogawa K, Yokoyama H, Kuramochi M. Source: Hypertens Res. 2001 September; 24(5): 595-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11675956

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Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. Author(s): Kjeldsen SE, Dahlof B, Devereux RB, Julius S, Aurup P, Edelman J, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristianson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Snapinn S, Wedel H; LIFE (Losartan Intervention for Endpoint Reduction) Study Group. Source: Jama : the Journal of the American Medical Association. 2002 September 25; 288(12): 1491-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12243636

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Effects of losartan on diabetic maculopathy in type 2 diabetic patients. Author(s): Gleim GW, Tressler CS. Source: Journal of Internal Medicine. 2004 February; 255(2): 304-5; Author Reply 306-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14746571

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Effects of losartan on diabetic maculopathy in type 2 diabetic patients: a randomized, double-masked study. Author(s): Knudsen ST, Bek T, Poulsen PL, Hove MN, Rehling M, Mogensen CE. Source: Journal of Internal Medicine. 2003 August; 254(2): 147-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12859696

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Effects of losartan or atenolol in hypertensive patients without clinically evident vascular disease: a substudy of the LIFE randomized trial. Author(s): Devereux RB, Dahlof B, Kjeldsen SE, Julius S, Aurup P, Beevers G, Edelman JM, de Faire U, Fyhrquist F, Helle Berg S, Ibsen H, Kristianson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Snapinn S, Wedel H; LIFE Study Group. Source: Annals of Internal Medicine. 2003 August 5; 139(3): 169-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899584

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Effects of losartan/diuretic combination treatment on serum uric acid levels in hypertensive patients. Author(s): Milionis HJ, Nikas S, Elisaf MS. Source: The American Journal of Cardiology. 2001 November 1; 88(9): 1084. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11704020

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Effects of low-dose losartan treatment on persistent microalbuminuria in normotensive type 1 diabetic subjects. Author(s): Acbay O. Source: J Endocrinol Invest. 2001 September; 24(8): 608-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11686543

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Effects of telmisartan and losartan on left ventricular mass in mild-to-moderate hypertension. A randomized, double-blind trial. Author(s): Martina B, Dieterle T, Sigle JP, Surber C, Battegay E. Source: Cardiology. 2003; 99(3): 169-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12824726

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Efficacy and safety of losartan in patients with proteinuria. Author(s): Leu JG, Huang CM, Kao SJ, Jiang WW. Source: Nephron. 2002 July; 91(3): 496-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12119484

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Efficacy and safety of losartan-amplodipine combination--an Indian postmarketing surveillance experience. Author(s): Gokhale N, Shahani S, Pawar D. Source: J Indian Med Assoc. 2002 March; 100(3): 207-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12408291

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Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients. Author(s): Flack JM, Oparil S, Pratt JH, Roniker B, Garthwaite S, Kleiman JH, Yang Y, Krause SL, Workman D, Saunders E. Source: Journal of the American College of Cardiology. 2003 April 2; 41(7): 1148-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679215

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Efficacy and tolerability of fixed-dose combinations of telmisartan plus HCTZ compared with losartan plus HCTZ in patients with essential hypertension. Author(s): Lacourciere Y, Gil-Extremera B, Mueller O, Byrne M, Williams L. Source: Int J Clin Pract. 2003 May; 57(4): 273-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12800457

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Efficacy of losartan in patients with primary focal segmental glomerulosclerosis resistant to immunosuppressive treatment. Author(s): Usta M, Ersoy A, Dilek K, Ozdemir B, Yavuz M, Gullulu M, Yurtkuran M. Source: Journal of Internal Medicine. 2003 March; 253(3): 329-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12603500

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Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure. Author(s): Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Source: Journal of the American Society of Nephrology : Jasn. 2003 February; 14(2): 42530. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12538743

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Ethnic differences in electrocardiographic criteria for left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint. Author(s): Okin PM, Wright JT, Nieminen MS, Jern S, Taylor AL, Phillips R, Papademetriou V, Clark LT, Ofili EO, Randall OS, Oikarinen L, Viitasalo M, Toivonen L, Julius S, Dahlof B, Devereux RB. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2002 August; 15(8): 663-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12160187

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Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers. Author(s): Fischer TL, Pieper JA, Graff DW, Rodgers JE, Fischer JD, Parnell KJ, Goldstein JA, Greenwood R, Patterson JH. Source: Clinical Pharmacology and Therapeutics. 2002 September; 72(3): 238-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12235444

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Failure of losartan to control blood pressure in scleroderma renal crisis. Author(s): Caskey FJ, Thacker EJ, Johnston PA, Barnes JN. Source: Lancet. 1997 March 1; 349(9052): 620. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9057740

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Fenofibrate and losartan. Author(s): Bardin T. Source: Annals of the Rheumatic Diseases. 2003 June; 62(6): 497-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759281

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First dose hypotension after angiotensin converting enzyme inhibitor captopril and angiotensin II blocker losartan in patients with acute myocardial infarction. Author(s): Spinar J, Vitovec J, Pluhacek L, Spinarova L, Fischerova B, Toman J. Source: International Journal of Cardiology. 2000 September 15; 75(2-3): 197-204. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11077134

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Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Author(s): Kaukonen KM, Olkkola KT, Neuvonen PJ. Source: European Journal of Clinical Pharmacology. 1998 February; 53(6): 445-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9551703

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Four-Year persistence patterns among patients initiating therapy with the angiotensin II receptor antagonist losartan versus other artihypertensive drug classes. Author(s): Conlin PR, Gerth WC, Fox J, Roehm JB, Boccuzzi SJ. Source: Clinical Therapeutics. 2001 December; 23(12): 1999-2010. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11813934

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Global efficacy and tolerability of losartan, an angiotensin II subtype 1-receptor antagonist, in the treatment of hypertension. Author(s): Mallion JM, Goldberg AI. Source: Blood Pressure. Supplement. 1996; 2: 82-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8913546

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Haemodynamic and renal responses to oral losartan potassium during salt depletion or salt repletion in normal human volunteers. Author(s): Doig JK, MacFadyen RJ, Sweet CS, Reid JL. Source: Journal of Cardiovascular Pharmacology. 1995 April; 25(4): 511-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7596116

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Haemodynamic, neurohumoral and exercise effects of losartan vs. captopril in chronic heart failure: results of an ELITE trial substudy. Evaluation of Losartan in the Elderly. Author(s): Houghton AR, Harrison M, Cowley AJ. Source: European Journal of Heart Failure : Journal of the Working Group on Heart Failure of the European Society of Cardiology. 1999 December; 1(4): 385-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10937952

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Haemodynamic, renal sodium handling, and neurohormonal effects of acute administration of low dose losartan, an angiotensin II receptor antagonist, in preascitic cirrhosis. Author(s): Girgrah N, Liu P, Collier J, Blendis L, Wong F. Source: Gut. 2000 January; 46(1): 114-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10601066

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Haemorheological effects of losartan and enalapril in patients with renal parenchymal disease and hypertension. Author(s): Shand BI. Source: Journal of Human Hypertension. 2000 May; 14(5): 305-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10822316

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Hemodynamic and humoral effects of the angiotensin II antagonist losartan in essential hypertension. Author(s): Grossman E, Peleg E, Carroll J, Shamiss A, Rosenthal T. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 1994 December; 7(12): 1041-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7702796

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Hemodynamic and neurohormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Author(s): Gottlieb SS, Dickstein K, Fleck E, Kostis J, Levine TB, LeJemtel T, DeKock M. Source: Circulation. 1993 October; 88(4 Pt 1): 1602-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8403307

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Hemodynamic and neurohumoral effects of the angiotensin II antagonist losartan in patients with heart failure. Author(s): Dickstein K, Gottlieb S, Fleck E, Kostis J, Levine B, DeKock M, LeJemtel T. Source: Journal of Hypertension. Supplement : Official Journal of the International Society of Hypertension. 1994 July; 12(2): S31-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7965263

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Hemodynamic and renal effects of indomethacin in losartan-treated hypertensive individuals. Author(s): Olsen ME, Thomsen T, Hassager C, Ibsen H, Dige-Petersen H. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 1999 February; 12(2 Pt 1): 209-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10090350

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Henoch-Schonlein purpura induced by losartan therapy. Author(s): Bosch X. Source: Archives of Internal Medicine. 1998 January 26; 158(2): 191-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9448560

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Hepatic injury associated with losartan. Author(s): Andrade RJ, Lucena MI, Santalla F. Source: The Annals of Pharmacotherapy. 1998 December; 32(12): 1371. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9876824

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Historical development of losartan (DuP 753) and angiotensin II receptor subtypes. Author(s): Wong PC, Timmermans PB. Source: Blood Pressure. Supplement. 1996; 3: 11-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8973760

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How well have animal studies with losartan predicted responses in humans? Author(s): Sweet CS, Nelson EB. Source: Journal of Hypertension. Supplement : Official Journal of the International Society of Hypertension. 1993 April; 11(3): S63-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8315522

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Losartan

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HPLC assays to simultaneously determine the angiotensin-AT1 antagonist losartan as well as its main and active metabolite EXP 3174 in biological material of humans and rats. Author(s): Soldner A, Spahn-Langguth H, Mutschler E. Source: Journal of Pharmaceutical and Biomedical Analysis. 1998 January; 16(5): 863-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9535198

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Human plasma protein binding of the angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) and its pharmacologically active metabolite EXP3174. Author(s): Christ DD. Source: Journal of Clinical Pharmacology. 1995 May; 35(5): 515-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7657853

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Hypotensive effect of losartan, a nonpeptide angiotensin II receptor antagonist, in essential hypertension. Author(s): Tsunoda K, Abe K, Hagino T, Omata K, Misawa S, Imai Y, Yoshinaga K. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 1993 January; 6(1): 28-32. Erratum In: Am J Hypertens 1993 May; 6(5 Pt 1): 451. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8427658

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Immune thrombocytopenia after losartan therapy. Author(s): Ada S, Yalamanchili M, Friedenberg W. Source: Annals of Internal Medicine. 2002 October 15; 137(8): 704. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12379089

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Improved exercise tolerance after losartan and enalapril in heart failure: correlation with changes in skeletal muscle myosin heavy chain composition. Author(s): Vescovo G, Dalla Libera L, Serafini F, Leprotti C, Facchin L, Volterrani M, Ceconi C, Ambrosio GB. Source: Circulation. 1998 October 27; 98(17): 1742-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9788828

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Increased efficacy and tolerability with losartan plus hydrochlorothiazide in patients with uncontrolled hypertension and therapy-related symptoms receiving two monotherapies. Author(s): Naidoo DP, Sareli P, Marin F, Aroca-Martinez G, Maritz FJ, Jardim PC, Guerrero AA, Thompson CA, Bero T, Drazka J, Kosmalova V, Dumortier T, Smith RD. Source: Adv Ther. 1999 September-October; 16(5): 187-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10915394

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Increased left-ventricular mass after losartan treatment. Author(s): Cheung B. Source: Lancet. 1997 June 14; 349(9067): 1743-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9193389

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Influence of losartan and nicardipine on the contractile responses of human subcutaneous arteries and veins to angiotensin II. Author(s): Baan J Jr, Pfaffendorf M, van der Wal AC, Chang PC, van Zwieten PA. Source: Fundamental & Clinical Pharmacology. 1999; 13(1): 43-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10027087

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Influence of losartan on alpha-adrenoceptor-mediated vasoconstrictor response in humans. Author(s): Harada K, Kawaguchi A, Ohmori M, Fujimura A. Source: Journal of Cardiovascular Pharmacology. 2000 July; 36(1): 45-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10892659

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Influence of Losartan, an angiotensin receptor antagonist, on neointimal proliferation in cultured human saphenous vein. Author(s): Varty K, Allen KE, Jones L, Sayers RD, Bell PR, London NJ. Source: The British Journal of Surgery. 1994 June; 81(6): 819-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8044591

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Influence of self-measurement of blood pressure on the responder rate in hypertensive patients treated with losartan: results of the SVATCH Study. Standard vs Automatic Treatment Control of COSAAR in Hypertension. Author(s): Vetter W, Hess L, Brignoli R. Source: Journal of Human Hypertension. 2000 April; 14(4): 235-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10805048

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Influence of the angiotensin II receptor antagonist losartan on diuretic-induced metabolic effects in elderly hypertensive patients: comparison with a calcium channel blocker. Author(s): Ohnishi K, Kohno M, Yukiiri K, Masugata H, Wada Y, Takagi Y, Ohmori K. Source: Int J Clin Pharmacol Ther. 2001 October; 39(10): 417-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11680666

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Inhibition of angiotensin II pressor response and ex vivo angiotensin II radioligand binding by candesartan cilexetil and losartan in healthy human volunteers. Author(s): Belz GG, Fuchs B, Malerczyk C, Magin SG, Roll S, Mutschler E. Source: Journal of Human Hypertension. 1997 September; 11 Suppl 2: S45-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9331006

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Inhibition of angiotensin II-induced contraction by losartan in human coronary arteries. Author(s): Holmgren A, Pantev E, Erlinge D, Edvinsson L. Source: Journal of Cardiovascular Pharmacology. 1998 October; 32(4): 662-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9781937

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Inhibition of platelet activation in stroke-prone spontaneously hypertensive rats: comparison of losartan, candesartan, and valsartan. Author(s): Jimenez AM, Monton M, Garcia R, Nunez A, Gomez J, Rico L, Garcia-Colis E, de Miguel LS, Arriero MM, Cabestrero F, Farre J, Casado S, Lopez-Farre A. Source: Journal of Cardiovascular Pharmacology. 2001 April; 37(4): 406-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11300653

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Inhibition of platelet aggregability by losartan in essential hypertension. Author(s): Levy PJ, Yunis C, Owen J, Brosnihan KB, Smith R, Ferrario CM. Source: The American Journal of Cardiology. 2000 December 1; 86(11): 1188-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11090789

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Interim evidence of the renoprotective effect of the angiotensin II receptor antagonist losartan versus the calcium channel blocker amlodipine in patients with chronic kidney disease and hypertension: a report of the Japanese Losartan Therapy Intended for Global Renal Protection in Hypertensive Patients (JLIGHT) Study. Author(s): Iino Y, Hayashi M, Kawamura T, Shiigai T, Tomino Y, Yamada K, Kitajima T, Ideura T, Koyama A, Sugisaki T, Suzuki H, Umemura S, Kawaguchi Y, Uchida S, Kuwahara M, Yamazaki T; Japanese Lasartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) Study Investigators. Source: Clinical and Experimental Nephrology. 2003 September; 7(3): 221-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14586719

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Intra-individual variability in urinary losartan oxidation ratio, an in vivo marker of CYP2C9 activity. Author(s): Yasar U, Dahl ML, Christensen M, Eliasson E. Source: British Journal of Clinical Pharmacology. 2002 August; 54(2): 183-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12207639

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Intrinsic properties of the nonpeptide angiotensin II antagonist losartan in glomeruli and mesangial cells at high concentrations. Author(s): Chansel D, Badre L, Czekalski S, Vandermeersch S, Cambar J, Ardaillou R. Source: The Journal of Pharmacology and Experimental Therapeutics. 1993 June; 265(3): 1534-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8510026

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Irbesartan substitution for valsartan or losartan in treating hypertension. Author(s): Graham MR, Allcock NM. Source: The Annals of Pharmacotherapy. 2002 December; 36(12): 1840-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12452741

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Is cardiovascular remodeling in patients with essential hypertension related to more than high blood pressure? A LIFE substudy. Losartan Intervention For EndpointReduction in Hypertension. Author(s): Olsen MH, Wachtell K, Hermann KL, Frandsen E, Dige-Petersen H, Rokkedal J, Devereux RB, Ibsen H. Source: American Heart Journal. 2002 September; 144(3): 530-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12228792

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Is losartan as effective as enalapril on posttransplant persistent proteinuria? Author(s): Altiparmak MR, Trablus S, Apaydin S, Basar O, Sariyar M, Serdengecti K, Erek E. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3368-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750440

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Is losartan superior to captopril in reducing all-cause mortality in elderly patients with symptomatic heart failure? Author(s): Trojian TH, Jackson EA. Source: The Journal of Family Practice. 2000 August; 49(8): 759-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10947144

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LIFE: losartan versus atenolol. Author(s): Chong AY, Lip GY. Source: Lancet. 2003 October 25; 362(9393): 1416. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14585648

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LIFE: losartan versus atenolol. Author(s): Ong HT. Source: Lancet. 2003 October 25; 362(9393): 1416. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14585647

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Long-term antiproteinuric and renoprotective efficacy and safety of losartan in children with proteinuria. Author(s): Ellis D, Vats A, Moritz ML, Reitz S, Grosso MJ, Janosky JE. Source: The Journal of Pediatrics. 2003 July; 143(1): 89-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915830

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Long-term effects of losartan on proteinuria and renal function in patients with renal amyloidosis. Author(s): Dilek K, Usta M, Ersoy A, Ozdemir B, Yavuz M, Gullulu M, Yurtkuran M. Source: Scandinavian Journal of Urology and Nephrology. 2002; 36(6): 443-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12623509

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Long-term renoprotective effects of losartan in diabetic nephropathy: interaction with ACE insertion/deletion genotype? Author(s): Andersen S, Tarnow L, Cambien F, Rossing P, Juhl TR, Deinum J, Parving HH. Source: Diabetes Care. 2003 May; 26(5): 1501-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716812

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Losartan and E3174 pharmacokinetics in cytochrome P450 2C9*1/*1, *1/*2, and *1/*3 individuals. Author(s): Lee CR, Pieper JA, Hinderliter AL, Blaisdell JA, Goldstein JA. Source: Pharmacotherapy. 2003 June; 23(6): 720-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12820813

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Losartan and lercanidipine attenuate low-density lipoprotein oxidation in patients with hypertension and type 2 diabetes mellitus: a randomized, prospective crossover study. Author(s): Rachmani R, Levi Z, Zadok BS, Ravid M. Source: Clinical Pharmacology and Therapeutics. 2002 September; 72(3): 302-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12235451

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Losartan and perindopril effects on plasma plasminogen activator inhibitor-1 and fibrinogen in hypertensive type 2 diabetic patients. Author(s): Fogari R, Mugellini A, Zoppi A, Corradi L, Preti P, Lazzari P, Derosa G. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2002 April; 15(4 Pt 1): 316-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11991216

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Losartan and the meaning of LIFE. Author(s): Lip GY. Source: Journal of Human Hypertension. 2002 May; 16(5): 289-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12082487

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Losartan attenuates symptomatic and hormonal responses to hypoglycemia in humans. Author(s): Deininger E, Oltmanns KM, Wellhoener P, Fruehwald-Schultes B, Kern W, Heuer B, Dominiak P, Born J, Fehm HL, Peters A. Source: Clinical Pharmacology and Therapeutics. 2001 October; 70(4): 362-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11673752

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Losartan for cardiovascular disease in patients with and without diabetes in the LIFE study. Author(s): Poole-Wilson PA, Lubsen J. Source: Lancet. 2002 June 22; 359(9324): 2199; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091001

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Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Author(s): Cruickshank JM. Source: Lancet. 2002 June 22; 359(9324): 2200-1; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091004

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Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Author(s): Hamon M. Source: Lancet. 2002 June 22; 359(9324): 2199-200; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091003

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Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Author(s): Wiedermann CJ. Source: Lancet. 2002 June 22; 359(9324): 2199; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091002

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Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Author(s): Fuchs FD. Source: Lancet. 2002 June 22; 359(9324): 2203; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091010

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Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Author(s): Montastruc JL, Pathak A, Lapeyre-Mestre M. Source: Lancet. 2002 June 22; 359(9324): 2202; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091009

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Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Author(s): Cockcroft JR, Brown MJ. Source: Lancet. 2002 June 22; 359(9324): 2202; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091008

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Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Author(s): Hjelmesaeth J, Carlsson PO. Source: Lancet. 2002 June 22; 359(9324): 2201-2; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091007

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Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Author(s): Bursztyn M. Source: Lancet. 2002 June 22; 359(9324): 2201; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091006

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Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Author(s): Bloom JM. Source: Lancet. 2002 June 22; 359(9324): 2201; Author Reply 2203-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12091005

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Losartan in diabetic nephropathy. Author(s): Carswell CI, Goa KL. Source: Drugs. 2003; 63(4): 407-14; Discussion 415-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12558462

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Losartan induced fetal toxicity. Author(s): Nayar B, Singhal A, Aggarwal R, Malhotra N. Source: Indian J Pediatr. 2003 November; 70(11): 923-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14703235

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Losartan inhibits in vitro platelet activation: comparison with candesartan and valsartan. Author(s): Nunez A, Gomez J, Zalba LR, Monton M, Jimenez A, Velasco S, Lopez-Blaya A, Uriarte AC, Casado S, Lopez-Farre A. Source: J Renin Angiotensin Aldosterone Syst. 2000 June; 1(2): 175-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11967810

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Losartan inhibits the angiotensin II-induced modifications on fibrinolysis and matrix deposition by primary human vascular smooth muscle cells. Author(s): Papakonstantinou E, Roth M, Kokkas B, Papadopoulos C, Karakiulakis G. Source: Journal of Cardiovascular Pharmacology. 2001 November; 38(5): 715-28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11602818

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Losartan potassium (Cozaar). Author(s): Lindenfeld J, Borer J, Armstrong PW. Source: Circulation. 2002 April 23; 105(16): E9100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11997294

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Losartan reduces the costs associated with diabetic end-stage renal disease: the RENAAL study economic evaluation. Author(s): Herman WH, Shahinfar S, Carides GW, Dasbach EJ, Gerth WC, Alexander CM, Cook JR, Keane WF, Brenner BM. Source: Diabetes Care. 2003 March; 26(3): 683-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12610022

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Losartan vs atenolol in prevention of stroke and cardiovascular disease. Author(s): Fournier A, Oprisiu R, Andrejak M, Fernandez L, Achard JM. Source: Jama : the Journal of the American Medical Association. 2003 February 12; 289(6): 700; Author Reply 701. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12585946

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Losartan vs atenolol in prevention of stroke and cardiovascular disease. Author(s): Messerli FH, Grossman E, Fournier A. Source: Jama : the Journal of the American Medical Association. 2003 February 12; 289(6): 700-1; Author Reply 701. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12585945

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Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Author(s): Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL. Source: Circulation. 2002 May 28; 105(21): 2512-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12034658

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Losartan-induced hepatic injury. Author(s): Tabak F, Mert A, Ozaras R, Biyikli M, Ozturk R, Ozbay G, Senturk H, Aktuglu Y. Source: Journal of Clinical Gastroenterology. 2002 May-June; 34(5): 585-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11960076

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Main results of the losartan versus amlodipine (LOA) study on drug tolerability and psychological general well-being. LOA Study Group. Author(s): Dahlof B, Lindholm LH, Carney S, Pentikainen PJ, Ostergren J. Source: Journal of Hypertension. 1997 November; 15(11): 1327-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9383183

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Mannitol-induced toxicity in a diabetic patient receiving losartan. Author(s): Matsumura M. Source: The American Journal of Medicine. 2001 March; 110(4): 331. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11247599

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Marked hepatotoxicity associated with losartan treatment. Author(s): Nygaard B, Strandgaard S. Source: Blood Pressure. 1996 May; 5(3): 190-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8790930

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Maximal exercise capacity is related to cardiovascular structure in patients with longstanding hypertension. A LIFE substudy. Losartan Intervention For EndpointReduction in Hypertension. Author(s): Olsen MH, Wachtell K, Hermann KL, Bella JN, Andersen UB, Dige-Petersen H, Rokkedal J, Ibsen H. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2001 December; 14(12): 1205-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11775128

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Medical and cost-economy aspects of modern antihypertensive therapy--with special reference to 2 years of clinical experience with losartan. Author(s): Hansson L. Source: Blood Pressure. Supplement. 1997; 1: 52-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9285110

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Meta-analysis of observed mortality data from all-controlled, double-blind, multipledose studies of losartan in heart failure. Losartan Heart Failure Mortality Metaanalysis Study Group. Author(s): Sharma D, Buyse M, Pitt B, Rucinska EJ. Source: The American Journal of Cardiology. 2000 January 15; 85(2): 187-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10955375

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Method for the simultaneous determination of losartan and its major metabolite, EXP-3174, in human plasma by liquid chromatography-electrospray ionization tandem mass spectrometry. Author(s): Iwasa T, Takano T, Hara K, Kamei T. Source: J Chromatogr B Biomed Sci Appl. 1999 November 12; 734(2): 325-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10595730

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Might losartan reduce sudden cardiac death in diabetic patients with hypertension? Author(s): Aronow WS. Source: Lancet. 2003 August 23; 362(9384): 591-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12944056

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Modulation of alveolar-capillary sodium handling as a mechanism of protection of gas transfer by enalapril, and not by losartan, in chronic heart failure. Author(s): Guazzi M, Agostoni P, Guazzi MD. Source: Journal of the American College of Cardiology. 2001 February; 37(2): 398-406. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11216953

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No acute additive effect of losartan in a patient already on an ACE inhibitor for heart failure. Author(s): Missouris CG, Patel SJ, Morton JJ, MacGregor GA. Source: Journal of Human Hypertension. 1999 November; 13(11): 797-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10578227

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No effect of losartan on response to erythropoietin therapy in patients undergoing hemodialysis. Author(s): Kato A, Takita T, Furuhashi M, Takahashi T, Maruyama Y, Hishida A. Source: Nephron. 2000 December; 86(4): 538-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11124620

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Novel AT(1) receptor-independent functions of losartan. Author(s): Sadoshima J. Source: Circulation Research. 2002 April 19; 90(7): 754-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11964366

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One-week losartan administration increases sodium excretion in cirrhotic patients with and without ascites. Author(s): Yang YY, Lin HC, Lee WC, Hou MC, Lee FY, Chang FY, Lee SD. Source: Journal of Gastroenterology. 2002; 37(3): 194-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11931532

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Optimal antiproteinuric dose of losartan in nondiabetic patients with nephrotic range proteinuria. Author(s): Laverman GD, Henning RH, de Jong PE, Navis G, de Zeeuw D. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2001 December; 38(6): 1381-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11728979

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Optimal dose of losartan for renoprotection in diabetic nephropathy. Author(s): Andersen S, Rossing P, Juhl TR, Deinum J, Parving HH. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2002 August; 17(8): 1413-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12147788

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Oxidation of the angiotensin II receptor antagonist losartan (DuP 753) in human liver microsomes. Role of cytochrome P4503A(4) in formation of the active metabolite EXP3174. Author(s): Yun CH, Lee HS, Lee H, Rho JK, Jeong HG, Guengerich FP. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 1995 February; 23(2): 285-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7736926

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Pancreatitis after losartan. Author(s): Birck R, Keim V, Fiedler F, van der Woude FJ, Rohmeiss P. Source: Lancet. 1998 April 18; 351(9110): 1178. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9643695

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Part 1. Uric acid and losartan. Author(s): Sica DA, Schoolwerth AC. Source: Current Opinion in Nephrology and Hypertension. 2002 September; 11(5): 47582. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12187310

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Pharmacoeconomic aspects of losartan treatment to delay progression of renal disease in patients with Type 2 diabetes. Author(s): Postma MJ, Kruidhof H, de Jong-van den Berg LT, de Zeeuw D. Source: Expert Opinion on Pharmacotherapy. 2003 September; 4(9): 1543-50. Review. Erratum In: Expert Opin Pharmacother. 2003 October; 4(10): 1887. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943484

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Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and losartan. Author(s): Azizi M, Chatellier G, Guyene TT, Menard J. Source: Journal of Hypertension. 1999 April; 17(4): 561-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10404959

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Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans. Author(s): Ohtawa M, Takayama F, Saitoh K, Yoshinaga T, Nakashima M. Source: British Journal of Clinical Pharmacology. 1993 March; 35(3): 290-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8471405

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Pharmacokinetics and blood pressure response of losartan in end-stage renal disease. Author(s): Sica DA, Halstenson CE, Gehr TW, Keane WF. Source: Clinical Pharmacokinetics. 2000 June; 38(6): 519-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10885588

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Pharmacokinetics of intravenous and oral losartan in patients with heart failure. Author(s): Lo MW, Toh J, Emmert SE, Ritter MA, Furtek CI, Lu H, Colucci WS, Uretsky BF, Rucinska E. Source: Journal of Clinical Pharmacology. 1998 June; 38(6): 525-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9650542

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Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype. Author(s): Yasar U, Forslund-Bergengren C, Tybring G, Dorado P, Llerena A, Sjoqvist F, Eliasson E, Dahl ML. Source: Clinical Pharmacology and Therapeutics. 2002 January; 71(1): 89-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11823761

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Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans. Author(s): Lo MW, Goldberg MR, McCrea JB, Lu H, Furtek CI, Bjornsson TD. Source: Clinical Pharmacology and Therapeutics. 1995 December; 58(6): 641-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8529329

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Pharmacokinetics, safety, and antihypertensive efficacy of losartan in combination with hydrochlorothiazide in hypertensive patients with renal impairment. Author(s): Dickson TZ, Zagrobelny J, Lin CC, Ritter MA, Snavely D, Ramjit D, Shahinfar S, Lo MW. Source: Journal of Clinical Pharmacology. 2003 June; 43(6): 591-603. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12817522

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Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. Author(s): Goldberg MR, Lo MW, Deutsch PJ, Wilson SE, McWilliams EJ, McCrea JB. Source: Clinical Pharmacology and Therapeutics. 1996 March; 59(3): 268-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8653989

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Phenotypic and genotypic investigations of a healthy volunteer deficient in the conversion of losartan to its active metabolite E-3174. Author(s): McCrea JB, Cribb A, Rushmore T, Osborne B, Gillen L, Lo MW, Waldman S, Bjornsson T, Spielberg S, Goldberg MR. Source: Clinical Pharmacology and Therapeutics. 1999 March; 65(3): 348-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10096267

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Portal pressure response to losartan compared with propranolol in patients with cirrhosis. Author(s): De BK, Bandyopadhyay K, Das TK, Das D, Biswas PK, Majumdar D, Mandal SK, Ray S, Dasgupta S. Source: The American Journal of Gastroenterology. 2003 June; 98(6): 1371-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12818283

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Possible losartan-induced rash. Author(s): Haddad AM, Scholer SG. Source: American Journal of Health-System Pharmacy : Ajhp : Official Journal of the American Society of Health-System Pharmacists. 1997 June 1; 54(11): 1333-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9179355

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Preventing increases in early-morning blood pressure, heart rate, and the ratepressure product with controlled onset extended release verapamil at bedtime versus enalapril, losartan, and placebo on arising. Author(s): White WB, Sica DA, Calhoun D, Mansoor GA, Anders RJ. Source: American Heart Journal. 2002 October; 144(4): 657-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12360162

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Problems with interpreting the data in Kassler-Taub et al's article comparing irbesartan and losartan. Author(s): Bunt T. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 1999 January; 12(1 Pt 1): 79-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10075390

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Progression of renal failure delayed by use of losartan in a case of IgA nephropathy. Author(s): Iseki K, Takishita S. Source: Intern Med. 2002 December; 41(12): 1167-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12521208

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Progressive hypertrophy regression with sustained pressure reduction in hypertension: the Losartan Intervention For Endpoint Reduction study. Author(s): Devereux RB, Palmieri V, Liu JE, Wachtell K, Bella JN, Boman K, Gerdts E, Nieminen MS, Papademetriou V, Dahlof B. Source: Journal of Hypertension. 2002 July; 20(7): 1445-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131543

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Prospective evaluation comparing the effects of enalapril and losartan in left ventricular remodeling after acute myocardial infarction. Author(s): Maia LN, Nicolau JC, Vitola JV, Santos M, Brandi JM, Joaquim MR, Baggi JM Jr, Cordeiro JA, de Godoy MF. Source: American Heart Journal. 2003 June; 145(6): E21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12796769

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Randomised comparison of losartan vs. captopril on quality of life in elderly patients with symptomatic heart failure: the losartan heart failure ELITE quality of life substudy. Author(s): Cowley AJ, Wiens BL, Segal R, Rich MW, Santanello NC, Dasbach EJ, Pitt B; ELITE Investigators. Evaluation of Losartan in the Elderly. Source: Quality of Life Research : an International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation. 2000; 9(4): 377-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11131930

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Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE) Author(s): Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI. Source: Lancet. 1997 March 15; 349(9054): 747-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9074572

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Randomised, double-blind, parallel study of the anti-hypertensive efficacy and safety of losartan potassium compared with felodipine ER in elderly patients with mild to moderate hypertension. Author(s): Chan JC, Critchley JA, Lappe JT, Raskin SJ, Snavely D, Goldberg AI, Sweet CS. Source: Journal of Human Hypertension. 1995 September; 9(9): 765-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8551492

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Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis. Author(s): Gonzalez-Abraldes J, Albillos A, Banares R, Del Arbol LR, Moitinho E, Rodriguez C, Gonzalez M, Escorsell A, Garcia-Pagan JC, Bosch J. Source: Gastroenterology. 2001 August; 121(2): 382-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11487547

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Reduction in left ventricular hypertrophy in hypertensive patients treated with enalapril, losartan or the combination of enalapril and losartan. Author(s): Avanza AC Jr, El Aouar LM, Mill JG. Source: Arquivos Brasileiros De Cardiologia. 2000 February; 74(2): 103-17. English, Portuguese. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10904284

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Reduction of resistance artery stiffness by treatment with the AT(1)-receptor antagonist losartan in essential hypertension. Author(s): Park JB, Intengan HD, Schiffrin EL. Source: J Renin Angiotensin Aldosterone Syst. 2000 March; 1(1): 40-5. Erratum In: J Renin Angiotensin Aldosterone Syst 2000 June; 1(2): 124. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11967798

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Regression of electrocardiographic left ventricular hypertrophy by losartan versus atenolol: The Losartan Intervention for Endpoint reduction in Hypertension (LIFE) Study. Author(s): Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Nieminen MS, Snapinn S, Harris KE, Aurup P, Edelman JM, Dahlof B; Losartan Intervention for Endpoint reduction in hypertension Study Investigations. Source: Circulation. 2003 August 12; 108(6): 684-90. Epub 2003 July 28. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12885747

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Relation of left ventricular geometry and function to systemic hemodynamics in hypertension: the LIFE Study. Losartan Intervention For Endpoint Reduction in Hypertension Study. Author(s): Bella JN, Wachtell K, Palmieri V, Liebson PR, Gerdts E, Ylitalo A, Koren MJ, Pedersen OL, Rokkedal J, Dahlof B, Roman MJ, Devereux RB. Source: Journal of Hypertension. 2001 January; 19(1): 127-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11204292

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Relation of QT interval and QT dispersion to echocardiographic left ventricular hypertrophy and geometric pattern in hypertensive patients. The LIFE study. The Losartan Intervention For Endpoint Reduction. Author(s): Oikarinen L, Nieminen MS, Viitasalo M, Toivonen L, Wachtell K, Papademetriou V, Jern S, Dahlof B, Devereux RB, Okin PM. Source: Journal of Hypertension. 2001 October; 19(10): 1883-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11593111

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Relation of QT interval and QT dispersion to regression of echocardiographic and electrocardiographic left ventricular hypertrophy in hypertensive patients: the Losartan Intervention For Endpoint Reduction (LIFE) study. Author(s): Oikarinen L, Nieminen MS, Toivonen L, Viitasalo M, Wachtell K, Papademetriou V, Jern S, Dahlof B, Devereux RB, Okin PM; LIFE Study Investigators. Source: American Heart Journal. 2003 May; 145(5): 919-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766755

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Relationship of the electrocardiographic strain pattern to left ventricular structure and function in hypertensive patients: the LIFE study. Losartan Intervention For End point. Author(s): Okin PM, Devereux RB, Nieminen MS, Jern S, Oikarinen L, Viitasalo M, Toivonen L, Kjeldsen SE, Julius S, Dahlof B. Source: Journal of the American College of Cardiology. 2001 August; 38(2): 514-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11499746

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Renal effects of losartan and amlodipine in hypertensive patients with non-diabetic nephropathy. Author(s): Holdaas H, Hartmann A, Berg KJ, Lund K, Fauchald P. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1998 December; 13(12): 3096-102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9870472

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Renal hemodynamics in essential hypertensives treated with losartan. Author(s): Erley CM, Bader B, Scheu M, Wolf S, Braun N, Risler T. Source: Clinical Nephrology. 1995 January; 43 Suppl 1: S8-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7781206

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Renal impairment associated with losartan. Author(s): Saine DR, Ahrens ER. Source: Annals of Internal Medicine. 1996 April 15; 124(8): 775. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8633842

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Renoprotective effect of small doses of losartan and enalapril in patients with primary glomerulonephritis. Short-term observation. Author(s): Tylicki L, Rutkowski P, Renke M, Rutkowski B. Source: American Journal of Nephrology. 2002 July-August; 22(4): 356-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12169868

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Renoprotective effects of losartan in diabetic nephropathy: interaction with ACE insertion/deletion genotype? Author(s): Andersen S, Tarnow L, Cambien F, Rossing P, Juhl TR, Deinum J, Parving HH. Source: Kidney International. 2002 July; 62(1): 192-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12081578

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Repeated transient anuria following losartan administration in a patient with a solitary kidney. Author(s): Maillard JO, Descombes E, Fellay G, Regamey C. Source: Renal Failure. 2001 January; 23(1): 143-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11256525

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Reversible acute renal failure induced by losartan in a renal transplant recipient. Author(s): Ostermann M, Goldsmith DJ, Doyle T, Kingswood JC, Sharpstone P. Source: Postgraduate Medical Journal. 1997 February; 73(856): 105-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9122087

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Reversible ageusia associated with losartan. Author(s): Schlienger RG, Saxer M, Haefeli WE. Source: Lancet. 1996 February 17; 347(8999): 471-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8618505

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Reversible ageusia induced by losartan: a case report. Author(s): Ohkoshi N, Shoji S. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2002 May; 9(3): 315. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11985643

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Reversible dysgeusia attributed to losartan. Author(s): Heeringa M, van Puijenbroek EP. Source: Annals of Internal Medicine. 1998 July 1; 129(1): 72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9653007

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Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. Author(s): Lindholm LH, Ibsen H, Borch-Johnsen K, Olsen MH, Wachtell K, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristianson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman JM, Snapinn S; For the LIFE study group. Source: Journal of Hypertension. 2002 September; 20(9): 1879-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12195132

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Role of bradykinin in the vasodilator effects of losartan and enalapril in patients with heart failure. Author(s): Davie AP, Dargie HJ, McMurray JJ. Source: Circulation. 1999 July 20; 100(3): 268-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10411851

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Role of CYP2C9 polymorphism in losartan oxidation. Author(s): Yasar U, Tybring G, Hidestrand M, Oscarson M, Ingelman-Sundberg M, Dahl ML, Eliasson E. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2001 July; 29(7): 1051-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11408373

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Role of erythropoietin in pathogenesis of post transplant erythrocytosis (PTE) and mechanism of losartan's efficiency. Author(s): Altun B, Arici M, Yasavul U, Turgan C, Caglar S. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1997 March; 12(3): 626-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9075166

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Role of losartan therapy in the management of diabetic hypertension. Author(s): Paul B, Sapra B, Maheshwari S, Goyal RK. Source: J Assoc Physicians India. 2000 May; 48(5): 514-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11273147

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Safe and effective management of hypertension with fixed-dose combination therapy: focus on losartan plus hydrochlorothiazide. Author(s): Benedict CR. Source: Int J Clin Pract. 2000 January-February; 54(1): 48-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10750261

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Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, and angiotensinconverting enzyme inhibitors for the treatment of systemic hypertension. Author(s): Goldberg AI, Dunlay MC, Sweet CS. Source: The American Journal of Cardiology. 1995 April 15; 75(12): 793-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7717281

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Safety of losartan in hypertensive patients with thiazide-induced hyperuricemia. Author(s): Shahinfar S, Simpson RL, Carides AD, Thiyagarajan B, Nakagawa Y, Umans JG, Parks JH, Coe FL. Source: Kidney International. 1999 November; 56(5): 1879-85. Erratum In: Kidney Int 2000 January; 57(1): 370. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10571797

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Safety, tolerability, and neurohormonal changes of the combination captopril plus losartan in the early postinfarction period: a pilot study. Author(s): Di Pasquale P, Bucca V, Scalzo S, Paterna S. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 1998 May; 12(2): 211-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9652880

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Schonlein-Henoch purpura associated with losartan treatment and presence of antineutrophil cytoplasmic antibodies of x specificity. Author(s): Brouard M, Piguet V, Chavaz P, Borradori L. Source: The British Journal of Dermatology. 2001 August; 145(2): 362-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11531817

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Sexual dysfunction in hypertensive patients treated with losartan. Author(s): Llisterri JL, Lozano Vidal JV, Aznar Vicente J, Argaya Roca M, Pol Bravo C, Sanchez Zamorano MA, Ferrario CM. Source: The American Journal of the Medical Sciences. 2001 May; 321(5): 336-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11370797

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Simple high-performance liquid chromatographic method for determination of losartan and E-3174 metabolite in human plasma, urine and dialysate. Author(s): Farthing D, Sica D, Fakhry I, Pedro A, Gehr TW. Source: J Chromatogr B Biomed Sci Appl. 1997 December 19; 704(1-2): 374-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9518174

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Simultaneous determination of a novel angiotensin II receptor blocking agent, losartan, and its metabolite in human plasma and urine by high-performance liquid chromatography. Author(s): Furtek CI, Lo MW. Source: Journal of Chromatography. 1992 January 17; 573(2): 295-301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1601963

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Simultaneous determination of losartan and EXP3174 in human plasma and urine utilizing liquid chromatography/tandem mass spectrometry. Author(s): Polinko M, Riffel K, Song H, Lo MW. Source: Journal of Pharmaceutical and Biomedical Analysis. 2003 September 15; 33(1): 73-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12946533

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Simultaneous determination of losartan and hydrochlorothiazide in combined dosage forms by first-derivative spectroscopy and high-performance thin-layer chromatography. Author(s): Shah SA, Rathod IS, Suhagia BN, Savale SS, Patel JB. Source: J Aoac Int. 2001 November-December; 84(6): 1715-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11767136

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Site-directed mutagenesis of the gerbil and human angiotensin II AT(1) receptors identifies amino acid residues attributable to the binding affinity for the nonpeptidic antagonist losartan. Author(s): Hoe KL, Saavedra JM. Source: Molecular Pharmacology. 2002 June; 61(6): 1404-15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12021402

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Start of therapy with the angiotensin II antagonist losartan after immediate switch from pretreatment with an ACE inhibitor. Author(s): Scholze J, Stapff M. Source: British Journal of Clinical Pharmacology. 1998 August; 46(2): 169-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9723827

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Successful long-term treatment of post-transplant erythrocytosis with losartan. Author(s): Midtvedt K, Stokke ES, Hartmann A. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1996 December; 11(12): 2495-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9017632

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Successful treatment of post-renal transplant erythrocytosis with losartan. Author(s): Cachat F, Guignard JP. Source: Pediatric Nephrology (Berlin, Germany). 1999 October; 13(8): 718-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10576794

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Synergistic efficacy of enalapril and losartan on exercise performance and oxygen consumption at peak exercise in congestive heart failure. Author(s): Guazzi M, Palermo P, Pontone G, Susini F, Agostoni P. Source: The American Journal of Cardiology. 1999 November 1; 84(9): 1038-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10569660

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Telmisartan vs losartan plus hydrochlorothiazide in the treatment of mild-tomoderate essential hypertension--a randomised ABPM study. Author(s): Neutel JM, Kolloch RE, Plouin PF, Meinicke TW, Schumacher H; OTELLOH Study Group. Source: Journal of Human Hypertension. 2003 August; 17(8): 569-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12874615

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The angiotensin II-receptor antagonist losartan does not prevent hemodynamic or vascular tolerance to nitroglycerin. Author(s): Milone SD, Azevedo ER, Forster C, Parker JD. Source: Journal of Cardiovascular Pharmacology. 1999 November; 34(5): 645-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10547079

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The antiarrhythmic potential of angiotensin II antagonism: experience with losartan. Author(s): Gavras I, Gavras H. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2000 May; 13(5 Pt 1): 512-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10826402

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The antiproteinuric effect of losartan is systemic blood pressure dependent. Author(s): Crowe AV, Howse M, Vinjamuri S, Kemp GJ, Williams PS. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 October; 18(10): 2160-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13679496

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The DASH diet enhances the blood pressure response to losartan in hypertensive patients. Author(s): Conlin PR, Erlinger TP, Bohannon A, Miller ER 3rd, Appel LJ, Svetkey LP, Moore TJ. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2003 May; 16(5 Pt 1): 337-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12745193

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The effect of a losartan-based treatment regimen on isolated systolic hypertension. Author(s): Cushman WC, Brady WE, Gazdick LP, Zeldin RK. Source: Journal of Clinical Hypertension (Greenwich, Conn.). 2002 March-April; 4(2): 101-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11927789

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The effect of high dose losartan on erythropoietin resistance in patients undergoing haemodialysis. Author(s): Odabas AR, Cetinkaya R, Selcuk Y, Keles S, Bilen H. Source: Panminerva Medica. 2003 March; 45(1): 59-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12682621

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The effect of Losartan on insulin resistance and beta cell function in chronic hemodialysis patients. Author(s): Fishman S, Rapoport MJ, Weissgarten J, Zaidenstein R, Dishi V, Hartzeanu I, Golik A. Source: Renal Failure. 2001 September; 23(5): 685-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11725915

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The effect of losartan potassium on choroidal hemodynamics in healthy subjects. Author(s): Spicher T, Orgul S, Gugleta K, Teuchner B, Flammer J. Source: Journal of Glaucoma. 2002 June; 11(3): 177-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12140392

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The effects of amlodipine compared to losartan in patients with mild to moderately severe hypertension. Author(s): Phillips RA, Kloner RA, Grimm RH Jr, Weinberger M. Source: Journal of Clinical Hypertension (Greenwich, Conn.). 2003 January-February; 5(1): 17-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12556649

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The effects of losartan and enalapril therapies on the levels of nitric oxide, malondialdehyde, and glutathione in patients with essential hypertension. Author(s): Donmez G, Derici U, Erbas D, Arinsoy T, Onk A, Sindel S, Hasanoglu E. Source: Japanese Journal of Physiology. 2002 October; 52(5): 435-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12533248

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The effects of losartan and fosinopril in hypertensive type 2 diabetic patients. Author(s): Kavgaci H, Sahin A, Onder Ersoz H, Erem C, Ozdemir F. Source: Diabetes Research and Clinical Practice. 2002 October; 58(1): 19-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12161053

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The effects of the addition of losartan on uric acid metabolism in patients receiving indapamide. Author(s): Nikas S, Rizos E, Milionis H, Bairaktari E, Kalaitzidis R, Siamopoulos K, Elisaf M. Source: J Renin Angiotensin Aldosterone Syst. 2000 September; 1(3): 289-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11881040

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The Losartan Intervention for Endpoint Reduction (LIFE) trial-have angiotensinreceptor blockers come of age? Author(s): Sica DA, Weber M. Source: Journal of Clinical Hypertension (Greenwich, Conn.). 2002 July-August; 4(4): 301-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12147937

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The losartan renal protection study--rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan). Author(s): Brenner BM, Cooper ME, Zeeuw Dd D, Grunfeld JP, Keane WF, Kurokawa K, McGill JB, Mitch WE, Parving HH, Remuzzi G, Ribeiro AB, Schluchter MD, Snavely D, Zhang Z, Simps R, Shahinar S; RENAAL Study Invstigators. Source: J Renin Angiotensin Aldosterone Syst. 2000 December; 1(4): 328-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11967819

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The mechanism of improved sodium homeostasis of low-dose losartan in preascitic cirrhosis. Author(s): Wong F, Liu P, Blendis L. Source: Hepatology (Baltimore, Md.). 2002 June; 35(6): 1449-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12029630

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The OPTIMAAL trial: losartan or captopril after acute myocardial infarction. Author(s): Gayet JL; Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan. Source: Lancet. 2002 December 7; 360(9348): 1884-5; Author Reply 1885. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480392

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The OPTIMMAL trial: losartan or captopril after acute myocardial infarction. Author(s): Hamon M, Filippi-Codaccioni E; Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan. Source: Lancet. 2002 December 7; 360(9348): 1886-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480397

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The OPTIMMAL trial: losartan or captopril after acute myocardial infarction. Author(s): Chowdhary S, Townend JN; Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan. Source: Lancet. 2002 December 7; 360(9348): 1886. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480396

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The OPTIMMAL trial: losartan or captopril after acute myocardial infarction. Author(s): Martinez-Selles M; Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan. Source: Lancet. 2002 December 7; 360(9348): 1885; Author Reply 1885. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480394

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The OPTIMMAL trial: losartan or captopril after acute myocardial infarction. Author(s): Fournier A, Andrejak M, Slama M, Godefroy O, Achard JM; Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan. Source: Lancet. 2002 December 7; 360(9348): 1885-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12480393

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The pharmacokinetics and pharmacodynamics of losartan in continuous ambulatory peritoneal dialysis. Author(s): Pedro AA, Gehr TW, Brophy DF, Sica DA. Source: Journal of Clinical Pharmacology. 2000 April; 40(4): 389-95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10761166

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The potential economic consequences of cognitive improvement with losartan. Author(s): Jonsson L, Gerth W, Fastbom J. Source: Blood Pressure. 2002; 11(1): 46-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11926351

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The role of losartan in cost-effective hypertension control. Author(s): McIntyre H, Costa FV, Dusing R, Ambrosioni E, Gerth W. Source: Current Medical Research and Opinion. 2002; 18(3): 139-45. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12094823

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The role of losartan in the management of patients with heart failure. Author(s): Dickstein K. Source: Clinical Therapeutics. 2001 September; 23(9): 1456-77. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11589260

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Thromboxane receptor density is increased in human cardiovascular disease with evidence for inhibition at therapeutic concentrations by the AT(1) receptor antagonist losartan. Author(s): Katugampola SD, Davenport AP. Source: British Journal of Pharmacology. 2001 December; 134(7): 1385-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11724743

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Time course of the antiproteinuric and antihypertensive effect of losartan in diabetic nephropathy. Author(s): Andersen S, Jacobsen P, Tarnow L, Rossing P, Juhl TR, Parving HH. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 February; 18(2): 293-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12543883

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T-lymphocyte and plasma angiotensin-converting enzyme activity during enalapril and losartan administration in humans. Author(s): Petrov VV, Fagard RH, Lijnen PJ. Source: Journal of Cardiovascular Pharmacology. 2001 October; 38(4): 578-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11588528

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Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans. Author(s): Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA. Source: Journal of Clinical Pharmacology. 2003 January; 43(1): 84-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12520632

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Trough-to-peak ratio, smoothness index, and circadian blood pressure profile after treatment with once-daily fixed combination of losartan 100 and hydrochlorothiazide 25 in essential hypertension. Author(s): Coca A, Sobrino J, Soler J, Felip A, Pelegri A, Minguez A, Vila J, de la Sierra A, Plana J. Source: Journal of Cardiovascular Pharmacology. 2002 June; 39(6): 824-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12021576

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Uricosuric effect of losartan in patients with renal transplants. Author(s): Kamper AL, Nielsen AH. Source: Transplantation. 2001 August 27; 72(4): 671-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11544429

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Uricosuric effect of losartan in renal transplanted patients. Author(s): Kamper A, Nielsen AH. Source: Transplantation Proceedings. 2001 February-March; 33(1-2): 1201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11267257

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Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients. Author(s): Minghelli G, Seydoux C, Goy JJ, Burnier M. Source: Transplantation. 1998 July 27; 66(2): 268-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9701277

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Urine albumin/creatinine ratio and echocardiographic left ventricular structure and function in hypertensive patients with electrocardiographic left ventricular hypertrophy: the LIFE study. Losartan Intervention for Endpoint Reduction. Author(s): Wachtell K, Palmieri V, Olsen MH, Bella JN, Aalto T, Dahlof B, Gerdts E, Wright JT Jr, Papademetriou V, Mogensen CE, Borch-Johnsen K, Ibsen H, Devereux RB. Source: American Heart Journal. 2002 February; 143(2): 319-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11835038

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Use of ambulatory blood pressure monitoring to compare antihypertensive efficacy and safety of two angiotensin II receptor antagonists, losartan and valsartan. Losartan Trial Investigators. Author(s): Monterroso VH, Rodriguez Chavez V, Carbajal ET, Vogel DR, Aroca Martinez GJ, Garcia LH, Cuevas JH, Lara Teran J, Hitzenberger G, Leao Neves P, Middlemost SJ, Dumortier T, Bunt AM, Smith RD. Source: Adv Ther. 2000 March-April; 17(2): 117-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11010055

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Use of losartan in FH patients during treatment with DSC-LDL apheresis. Author(s): Pintus S, Pintus P, Maxia P, Anedda S. Source: Journal of Clinical Apheresis. 1997; 12(3): 156. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9365870

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Use of losartan in the treatment of hypertensive patients with a history of cough induced by angiotensin-converting enzyme inhibitors. Author(s): Paster RZ, Snavely DB, Sweet AR, Draper RA, Goldberg AI, Soffer BA, Sweet CS. Source: Clinical Therapeutics. 1998 September-October; 20(5): 978-89. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9829449

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Usefulness of losartan, captopril, and furosemide in preventing nitrate tolerance and improving control of unstable angina pectoris. Author(s): Cotter G, Metzkor-Cotter E, Kaluski E, Blatt A, Litinsky I, Baumohl Y, Moshkovitz Y, Vered Z, Zaidenstein R, Golik A. Source: The American Journal of Cardiology. 1998 November 1; 82(9): 1024-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9817475

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Vasodilatory capacity and vascular structure in long-standing hypertension: a LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension. Author(s): Olsen MH, Wachtell K, Aalkjaer C, Dige-Petersen H, Rokkedal J, Ibsen H. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2002 May; 15(5): 398-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12022241

•

Venoconstriction by angiotensin II in the human forearm is inhibited by losartan but not by nicardipine. Author(s): Baan J Jr, Chang PC, Vermeij P, Pfaffendorf M, van Zwieten PA. Source: Journal of Cardiovascular Pharmacology. 1998 January; 31(1): 50-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9456277

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

Finding Nutrition Studies on Losartan 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 “losartan” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

7

Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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

A comparison of intervention with losartan or captopril in acute myocardial infarction. Author(s): 2nd Department of Medicine, St. Anne's University Hospital, Pekarska 53, 656 91, Brno, Czech Republic. [email protected] Source: Spinar, J Vitovec, J Spinarova, L Pluhacek, L Fischerova, B Toman, J Eur-J-HeartFail. 2000 March; 2(1): 91-100 1388-9842

•

A randomized, double-blind comparison of the antihypertensive efficacy and safety of once-daily losartan compared to twice-daily captopril in mild to moderate essential hypertension. Author(s): Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Spain. Source: Roca Cusachs, A Oigman, W Lepe, L Cifkova, R Karpov, Y A Harron, D W ActaCardiol. 1997; 52(6): 495-506 0001-5385

•

Angiotensin II and monocrotaline-induced pulmonary hypertension: effect of losartan (DuP 753), a nonpeptide angiotensin type 1 receptor antagonist. Author(s): Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, University of Kentucky, Lexington. Source: Cassis, L A Rippetoe, P E Soltis, E E Painter, D J Fitz, R Gillespie, M N JPharmacol-Exp-Ther. 1992 September; 262(3): 1168-72 0022-3565

•

AT1 receptors and cell proliferation in rat adrenals: effects of angiotensin infusion, low sodium diet and losartan. Author(s): Molecular Medicine Centre, Western General Hospital, Edinburgh, UK. Source: McEwan, P E Vinson, G P Kenyon, C J Endocr-Res. 1996 November; 22(4): 36971 0743-5800

•

Captopril plus losartan in early post-infarction. Neurohormonal effects: a pilot study. Author(s): Coronary Care Unit, Ingrassia Hospital Palermo. Source: Di Pasquale, P Cannizzaro, S Longo, A M Maringhini, G Iachininoto, R Paterna, S G-Ital-Cardiol. 1997 December; 27(12): 1256-63 0046-5968

•

Chronic effect of losartan in a murine model of dilated cardiomyopathy: comparison with captopril. Author(s): Department of Laboratory Medicine, Gunma University School of Medicine, Maebashi, Japan. Source: Kanda, T Araki, M Nakano, M Imai, S Suzuki, T Murata, K Kobayashi, I JPharmacol-Exp-Ther. 1995 May; 273(2): 955-8 0022-3565

•

Comparative studies on the memory-enhancing actions of captopril and losartan in mice using inhibitory shock avoidance paradigm. Author(s): Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Source: Raghavendra, V Chopra, K Kulkarni, S K Neuropeptides. 2001 February; 35(1): 65-9 0143-4179

•

Differential inhibition of the prejunctional actions of angiotensin II in rat atria by valsartan, irbesartan, eprosartan, and losartan. Author(s): Novartis Institute for Biomedical Research, Metabolic and Cardiovascular Diseases, Summit, New Jersey 07901-1027, USA. [email protected] Source: Shetty, S S DelGrande, D J-Pharmacol-Exp-Ther. 2000 July; 294(1): 179-86 00223565

Nutrition

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•

Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. Author(s): Department of Internal Medicine A, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel-Aiv University, Zerifin, Israel. Source: Zaidenstein, R Soback, S Gips, M Avni, B Dishi, V Weissgarten, Y Golik, A Scapa, E Ther-Drug-Monit. 2001 August; 23(4): 369-73 0163-4356

•

Effects of losartan versus captopril on mortality in patients with symptomatic heart failure: rationale, design, and baseline characteristics of patients in the Losartan Heart Failure Survival Study--ELITE II. Author(s): Division of Cardiology, University of Mechigan School of Medicine, Ann Arbor 48109-0366, USA. Source: Pitt, B Poole Wilson, P Segal, R Martinez, F A Dickstein, K Camm, A J Konstam, M A Riegger, G Klinger, G H Neaton, J Sharma, D ThiyagaraJanuary, B J-Card-Fail. 1999 June; 5(2): 146-54 1071-9164

•

Expression of immunoreactive nitric oxide synthase isoforms in rat kidney. Effects of dietary salt and losartan. Author(s): Division of Nephrology, Hypertension and Transplantation, University of Florida, College of Medicine, Gainesville, USA. Source: Tojo, A Madsen, K M Wilcox, C S Jpn-Heart-J. 1995 May; 36(3): 389-98 0021-4868

•

Hormonal and cardiovascular effects of losartan (DuP753), an angiotensin receptor antagonist, in nonhuman primates. Author(s): Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Michigan. Source: DeGraaf, G L Pals, D T Couch, S J Lawson, J A J-Pharmacol-Exp-Ther. 1993 January; 264(1): 6-10 0022-3565

•

Intracerebroventricular angiotensin II-induced thirst and sodium appetite in rat are blocked by the AT1 receptor antagonist, Losartan (DuP 753), but not by the AT2 antagonist, CGP 42112B. Author(s): Physiological Laboratory, Cambridge. Source: Beresford, M J Fitzsimons, J T Exp-Physiol. 1992 September; 77(5): 761-4 09580670

•

Involvement of cholinergic system in losartan-induced facilitation of spatial and short-term working memory. Author(s): Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Source: Raghavendra, V Chopra, K Kulkarni, S K Neuropeptides. 1998 October; 32(5): 417-21 0143-4179

•

Losartan may modulate erythropoietin production. Author(s): St. Michael's Hospital, Toronto, Ontario, Canada. [email protected] Source: Donnelly, S M Miller, J A J-Renin-Angiotensin-Aldosterone-Syst. 2001 December; 2(4): 255-60 1470-3203

•

Modulation of motor functions involving the dopaminergic system by AT1 receptor antagonist, losartan. Author(s): Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Source: Raghavendra, V Chopra, K Kulkarni, S K Neuropeptides. 1998 June; 32(3): 27580 0143-4179

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•

Nonpeptide angiotensin II antagonist losartan inhibits thromboxane A2-induced contractions in canine coronary arteries. Author(s): The Hypertension Center, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157-1032, USA. Source: Li, P Ferrario, C M Brosnihan, K B J-Pharmacol-Exp-Ther. 1997 June; 281(3): 1065-70 0022-3565

•

Synergistic effects of mycophenolate mofetil and losartan in a model of chronic cyclosporine nephropathy. Author(s): Cell Death Disease Research Center, Division of Nephrology, Department of Internal Medicine, Kangnam St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea. Source: Woo Yang, C Jong Ahn, H Young Kim, W Li, C Young Jung, J Ae Yoon, S Soo Kim, Y Ho Cha, J Kim, J Kee Bang, B Transplantation. 2003 February 15; 75(3): 309-15 0041-1337

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

•

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

•

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

•

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

•

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/

•

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

•

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

•

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

Nutrition

•

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

•

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

•

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

•

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

•

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

•

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

•

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

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The following is a specific Web list relating to losartan; 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 Potassium Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. CLINICAL TRIALS AND LOSARTAN Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning losartan.

Recent Trials on Losartan The following is a list of recent trials dedicated to losartan.8 Further information on a trial is available at the Web site indicated. •

Long Term Effects of Enalapril and Losartan on Genetic Heart Disease Condition(s): Hypertrophic Myocardial Ischemia

Cardiomyopathy;

Left

Ventricular

Hypertrophy;

Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: The human heart is divided into four chambers. One of the four chambers, the left ventricle, is the chamber mainly responsible for pumping blood out of the heart into circulation. Hypertrophic cardiomyopathy (HCM) is a genetically inherited disease causing an abnormal thickening of the heart muscle, especially the muscle making up the left ventricle. When the left ventricle becomes abnormally large it is called left ventricular hypertrophy (LVH). This condition can cause symptoms of chest pain, shortness of breath, fatigue, and heart beat palpitations. This study is designed to compare the ability of two drugs (enalapril and losartan) to improve symptoms and heart function of patients diagnosed with hypertrophic cardiomyopathy (HCM). Researchers have decided to compare these drugs because each one has been used to treat patients with other diseases causing thickening of the heart muscle. In these other conditions, enalapril and losartan have improved symptoms, decreased the thickness of heart muscle, improved blood flow and supply to the heart muscle, and improved the pumping action of the heart muscle. In this study researchers will compare the effectiveness of enalapril and losartan when given separately and together to patients with hypertrophic cardiomyopathy (HCM). 8

These are listed at www.ClinicalTrials.gov.

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Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001534

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “losartan” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

•

For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

•

For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

•

For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

•

For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

•

For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

•

For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

•

For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

•

For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

•

For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

•

For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

Clinical Trials 87

•

For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

•

For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

•

For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

•

For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 4. PATENTS ON LOSARTAN 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.9 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 “losartan” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on losartan, we have not necessarily excluded non-medical patents in this bibliography.

Patents on Losartan By performing a patent search focusing on losartan, 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

9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on losartan: •

Composition of enalapril and losartan Inventor(s): Chen; Tzyy-Show H. (Lansdale, PA), Grossman; William (San Francisco, CA), Iskandarani; Bassel (Lansdowne, PA), Krammer; Kenneth A. (Green Lane, PA), Sweet; Charles S. (Doylestown, PA) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 6,087,386 Date filed: June 17, 1997 Abstract: The present invention discloses a pharmaceutical composition of enalapril and losartan and a pharmaceutically acceptable carrier. Excerpt(s): Angiotensin II (AII) is a potent vasoconstrictor. Its generation in the reninangiotensin cascade results from the enzymatic action of renin on a blood plasma.alpha.2-globulin, angiotensinogen, to produce angiotensin I (AI). AI is then converted by angiotensin converting enzyme (ACE) to the octapeptide hormone AII. AII has been implicated as a causitive agent in hypertension. Therefore, ACE inhibitiors, which inhibit the production of AII via angiotensin converting enzyme, and AII receptor antagonists, which inhibit the function of AII, no matter the pathway of biosynthesis, are useful in the treatment of hypertension. The efficacy of these compounds in the treatment of heart failure is also being studied. Pals, et al., Circulation Research, 29, 673 (1971) describe the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone AII to yield an octapeptide that blocks the effects of AII on the blood pressure of pithed rats. This analog, [Sar.sup.1, Ala.sup.8 ] AII, initially called "P-113" and subsequently "saralasin," was found to be one of the most potent competitive antagonists of the actions of AII, although, like most of the so-called peptide-AII-antagonists, it also possesses agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating AII (Pals et al., Circulation Research, 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B. V., p. 246 (1984)). However, due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AII. Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are severely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard. Some known non-peptide antihypertensive agents act by inhibiting an enzyme, called angiotensin converting enzyme (ACE), which is responsible for conversion of angiotensin I to AII. Captopril and enalapril are commercially available ACE inhibitors (ACEI's). Based on experimental and clinical evidence, about 40% of hypertensive patients are non-responsive to treatment with ACEI's. But when a diuretic such as furosemide or hydrochlorothiazide is given together with an ACEI, the blood pressure of most hypertensive patients is effectively normalized. Diuretic treatment converts the non-renin dependent state in regulating blood pressure to a renin-dependent state. Although AII antagonist compounds act by a different mechanism, i.e., by blocking the AII receptor rather than by inhibiting the angiotensin converting enzyme, both mechanisms involve interference with the renin-

Patents 91

angiotensin cascade. A combination of the ACEI enalapril maleate and the diruetic hydrochlorothiazide is commercially available under the trademark Vaseretic.RTM. from Merck & Co. Publications which relate to the use of diuretics with ACEI's to treat hypertension, in either a diuretic-first, stepwise approach or in physical combination, include Keeton, T. K. and Campbell, W. B., Pharmacol. Rev., 31:81 (1981) and Weinberger, M. H., Medical Clinics N. America, 71:979 (1987). Diuretics have also been administered in combination with saralasin to enhance the antihypertensive effect. Web site: http://www.delphion.com/details?pn=US06087386__ •

Crystalline or crystallized acid addition salt of losartan and purification method of losartan Inventor(s): Itaya; Nobushige (Osaka, JP), Katsura; Tadashi (Osaka, JP), Shiratani; Hiroshi (Osaka, JP) Assignee(s): Sumika Fine Chemicals Co., Ltd. (osaka, Jp) Patent Number: 6,350,880 Date filed: November 16, 2000 Abstract: The present invention provides a crystalline or crystallized acid addition salt of Losartan useful for obtaining highly pure 2-n-butyl-4-chloro-1-[[2'-(1H-tetrazol-5yl)[1,1'-biphenyl]-4-yl]methyl]-1 H-imidazole-5-methanol (Losartan), and a purification method of Losartan that includes production of the crystalline or crystallized acid addition salt. Excerpt(s): The present invention relates to a novel crystalline or crystallized acid addition salt of Losartan, which has a superior antagonistic activity against angiotensin II, and to a purification method of Losartan, which comprises producing the crystalline or crystallized acid addition salt. (hereinafter to be also referred to as Losartan) is a useful antihypertensive agent having a superior antagonistic activity against angiotensin II. Losartan is generally used in the form of a potassium salt. Inasmuch as purification of a potassium salt is not feasible, it is a typical practice to purify free Losartan to a high degree first and then convert it to a potassium salt. However, purification of Losartan itself is also difficult and there are some purification methods proposed to achieve a higher purity of Losartan (WO93/10106, WO95/17396 etc.). These methods, nevertheless, are not entirely satisfactory and a feasible purification method to increase the purity of Losartan has been demanded. Web site: http://www.delphion.com/details?pn=US06350880__

•

Enhanced functional recovery of the heart by losartan treatment after an ischemic attach Inventor(s): Cohen; Sheila M. (Cranford, NJ), Werrmann; Jeffrey G. (Pittstown, NJ) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 5,795,904 Date filed: December 6, 1996 Abstract: Losartan, its active metabolite, EXP3174, or the pharmaceutically acceptable salts of these compounds for use in enhancing the functional recovery of the heart after an ischemic attack.

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Excerpt(s): The discovery of orally active, nonpeptide angiotensin II (AII) receptor antagonists ›See Wong, P. C., et al., "Nonpeptide Angiotensin II Receptor Antagonists, IV EXP6155 and EXP6803", Hypertension 1989, Vol. 13, pp. 489-97! has provided important new tools to help decipher the complex role of the renin-angiotensin system in the development of myocardial dysfunction during ischemia and subsequent reperfusion. The identification and classification of two AII receptor subtypes AT.sub.1 and AT.sub.2 were early results of this discovery ›See a) Blankley, C. J., et al., "Synthesis and Structure-activity Relationships of a Novel Series of Nonpeptide Angiotensin II Receptor Binding Inhibitors Specific for the AT-2 Subtype", J. Med. Chem., 1991, Vol. 34, pp. 3248-60; b) Chang, R. S. L., et al., "Angiotensin Receptor Subtypes in Rat, Rabbit and Monkey Tissues: Relative Distribution and Species Dependency", Life Sci., 1991, Vol. 49, pp. 1485-90; and c) Hodges, J. C., et al., "Angiotensin II Receptor Binding Inhibitors", Drug Fut., 1992, Vol. 17, pp. 575-93!. Treatment with the AII AT.sub.1 receptor antagonist losartan following myocardial infarction (MI) has been reported to improve cardiac pump performance ›See a) Raya, T. E. et al., "Hemodynamic Effects of Direct Angiotensin II Blockade Compared to Converting Enzyme Inhibition in Rat Model of Heart Failure", Am. J. Hypertens., 1991, Vol. 4, pp. 334S-40S; and b) Capasso, J. M., et al., "Efficacy of Angiotensin-Converting Enzyme Inhibition and AT.sub.1 Receptor Blockade on Cardiac Pump Performance After Myocardial Infections in Rats", J. Cardiovasc. Pharmacol., 1994, Vol. 23, pp. 584-93! and to attenuate ventricular remodeling ›See Schieffer, B., et al., "Comparative Effects of Chronic Angiotensin-Converting Enzyme Inhibition and Angiotensin H Type 1 Receptor Blockade on Cardiac Remodeling After Myocardial Infarction in the Rat", Circulation, 1994, Vol. 89, pp. 2273-2282! in rats. In rat heart two days post-MI it has also been shown that both the left and right ventricles become more sensitive to treatment with AII resulting in reduced mechanical performance and that this negative effect can be blocked by co-administration of losartan ›See Capasso, J. M., et al., "Alterations in ANG II Responsiveness in Left and Right Myocardium after Infarction-induced Heart Failure in Rats", Am. J. Physiol., 1993, Vol. 264(33) pp. H2056-H2067!. Also in the rat, AII AT.sub.1 receptor binding density in infarcted heart was recently shown to increase significantly as early as 3 days post-MI ›See Sun, Y., et al., "Angiotensin II Receptor Binding Following Myocardial Infarction in the Rat", Cardiovascular Research, 1994; Vol. 28. pp. 1623-1628!. These recent experimental observations may have clinical implications as to the usefulness of losartan in the treatment of infarction induced heart failure. The importance of using a physiological preparation for the study of AII receptor antagonism should be emphasized because it has recently been shown that donor tissue from rat atria experiences an almost complete loss of AT.sub.2 receptors during isolation and culturing while the expression of AT.sub.1 receptors in cultured ventricular cells may be up-regulated by the culture conditions ›See Feolde, E., et al., "Angiotensin II Receptor Subtypes and Biological Responses in the Rat Heart", J. Mol. Cell. Cardiol., 1993, Vol. 25, pp. 1359-1367!. On the other hand, use of in vivo experimental models of myocardial ischemia to study the cardiac renin-angiotensin system (RAS) may give results in which it is difficult to differentiate the influence of the local cardiac RAS from circulating AII effects ›See de Graeff, P. A., et. al., "The Cardiac Renin-Angiotensin System in Different Ischemic Syndromes of the Heart. In: Lindpaintner, K. and Ganten, D., eds. "The Cardiac-Renin Angiotensin System, Armonk, N.Y.: Futura Publishing Co., Inc., 1994, pp. 201-231!. In the present investigation the role of AII in the development of myocardial dysfunction during ischemia and reperfusion, is probed in a physiologically relevant isolated working rat heart model ›See Cohen, S. M., et. al., "Simultaneous 31-P Nuclear Magnetic Resonance Spectroscopy and Mechanical Function in Working Heart Models Affected by Drugs", Drug Dev. Res., 1989, Vol. 18, pp. 305-325! using the AII AT.sub.1 receptor antagonist, losartan. The effects of oral pre-treatment with losartan are

Patents 93

compared with those of placebo treatment and with losartan treatment in vitro. Observations of myocardial function are correlated with measurement of high energy phosphate metabolism and intracellular pH (pH.sub.i) in the same isolated working rat hearts by continuous.sup.31 P NMR measurements before, during, and after ischemia. According to the present invention there is provided a method of acute treatment for enhancing functional recovery of the heart post-ischemia comprising the administration of a therapeutically effective amount of losartan, its active metabolite, EXP3174, or a pharmaceutically acceptable salt therefrom, to a patient or a patient's isolated heart in need of such treatment. Web site: http://www.delphion.com/details?pn=US05795904__ •

Method for reducing mortality with an angiotensin II antagonist Inventor(s): Beere; Polly A. (Lahaska, PA), Chang; Paul I. (Doylestown, PA), Pitt; Bertram (Ann Arbor, MI), Rucinska; Eva J. (Blue Bell, PA), Segal; Robert (Gwynedd Valley, PA), Sharma; Divakar (Hatfield, PA), Snavely; Duane B. (Chalfont, PA) Assignee(s): Merck & Co., Inc. (rahway, Nj) Patent Number: 6,201,002 Date filed: January 6, 1998 Abstract: Angiotensin II receptor antagonists are useful in reducing and preventing mortality and sudden cardiac death in symptomatic heart failure patients. Losartan potassium has been shown to reduce mortality and sudden cardiac death in this patient population. Additionally, losartan potassium has been shown to reduce the need for hospitalization of symptomatic heart failure patients. Excerpt(s): Angiotensin-converting-enzyme (ACE) inhibitors have been shown to reduce morbidity and mortality in patients with chronic heart failure and systolic left ventricular dysfunction as well as in patients post myocardial infarction. (See The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1997; 316: 1429-1435; The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293-302; The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685-691; Cohn J N, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303-310; Pfeffer MA, Braunwald E, Moye L A, et al. on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992; 327: 669-677; The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342: 812-828; Fonarow GC, Chelimsky-Fallick C, Warner Stevenson L, et al. Effect of direct vasodilation with hydralazine versus angiotensin-converting enzyme inhibition with captopril on mortality in advanced heart failure: the Hy-C trial. J Am Coll Cardiol 1992; 19: 842-850; Gruppo Italiano per lo Studio delia Sopravvivenza nell'infarto Miocardico. GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994; 343: 1115-1122; ISIS Collaborative Group OU. ISIS-4:

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Randomized study of oral isosorbide mononitrate in over 50,000 patients with suspected acute myocardial infarction. Circulation 1993; 89: 1394.) The benefits of ACE inhibitors have been attributed to blockade of angiotensin II production and/or to a decrease in the breakdown of bradykinin. (See Pitt B, Chang P, Timmermans P. Angiotensin II receptor antagonists in heart failure: Rationale and design of the Evaluation of Losartan in the Elderly (ELITE) Trial. Cardiovascular Drugs and Therapy 1995; 9: 693-700; and Gavras I. Bradykinin-mediated effects of ACE inhibition. Kidney Int 1992; 42:1020-1029.) Bradykinin has been shown to have beneficial effects associated with the release of nitric oxide and prostacyclin which may contribute to the hemodynamic effects of ACE inhibition. Bradykinin may, however, also be responsible for certain adverse effects associated with use of ACE inhibitors, such as cough, angioedema, renal dysfunction, and hypotension. (See Pitt B, Chang P, Timmermans P. Angiotensin II receptor antagonists in heart failure: Rationale and design of the Evaluation of Losartan in the Elderly (ELITE) Trial. Cardiovascular Drugs and Therapy 1995; 9: 693-700; Gavras I. Bradykinin-mediated effects of ACE inhibition. Kidney int 1992; 42: 1020-1029; Israili Z H, Hall W D. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992; 117: 234-242; Chalmers D, Dombey S L, Lawson D H. Post-marketing surveillance of captopril (for hypertension): a preliminary report. Br J Clin Pharmacol 1987; 24: 343-349; Lacourciere Y, Brunner H, Irwin R, et al. and the Losartan Cough Study Group. Effects of modulators of the renin-angiotensin-aldosterone system on cough. J Hypertension 1994; 12: 1387-1393.) These adverse effects may account in part for the fact that ACE inhibitors are used in less than 30 percent of patients with heart failure in spite of their proven clinical benefit. (See Stafford R S, Saglam D, Blumenthal D. Low rates of angiotensin-converting enzyme inhibitor use in congestive heart failure. Circulation 1996; 94: I-194(Abstract)). The Evaluation of Losartan In The Elderly (ELITE) Study was conducted to compare effects on renal function, morbidity/mortality, and tolerability of long-term treatment with losartan versus captopril, in older patients with symptomatic heart failure. A method for reducing mortality by administering to a symptomatic heart failure patient a therapeutically effective amount of an angiotensin II antagonist. A method for reducing sudden cardiac death by administering to a symptomatic heart failure patient a therapeutically effective amount of an angiotensin II antagonist. A method for reducing mortality and sudden cardiac death by administering to a symptomatic heart failure patient a therapeutically effective amount of an angiotensin II antagonist is disclosed. A method for preventing sudden cardiac death by administering to a symptomatic heart failure patient a therapeutically effective amount of an angiotensin II antagonist. A method for reducing hospitalization by administering to a symptomatic heart failure patient a therapeutically effective amount of an angiotensin 11 antagonist. Web site: http://www.delphion.com/details?pn=US06201002__ •

Method of modifying ovarian hormone-regulated AT1 receptor activity as treatment of incapacitating symptom(s) of P.M.S. Inventor(s): dePadova; Anathony S. (49 Dexter Dr., North, Basking Ridge, NJ 07920) Assignee(s): None Reported Patent Number: 5,464,854 Date filed: April 29, 1994

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Abstract: The method of treatment moderating, blocking and/or eliminating premenstrual syndrome embodies the intermittent administering of an AT1 antagonist to a female having menstrual cycles characterized predominately by during substantially the luteal phase inclusive of at least one and frequently by two or more affective and/or autonomic and/or somatic symptoms of substantially incapacitating severity(ies) proximately substantially prior to menses of a menstrual cycle. Losartan is an example of an AT1 inhibitor and is administered either orally or parenterally continuously to a female during her menstrual cycle's luteal phase. Excerpt(s): This invention is directed to a method of treatment for obviating and/or blocking premenstrual tension syndrome on an interim basis during the luteal phase of a menstrual cycle of a patient suffering from premenstrual syndrome characterized by a concurrent plurality of symptoms inclusive of affectlye and/or autonomic and/or somatic symptoms cumulatively of substantially incapacitating severity prior to the menses. United States Patent to Blankley, C. J., et. al., U.S. Pat. No. 5,246,943 granted Sep. 21, 1993 states in sections 3 line 40 that "excessive secretion of AVP (vasopressin, also known as antidiuretic hormone) as been linked to a number of disorders including excessive water retention associated with the female reproductive disorder known as premenstrual syndrome (PMS) (Janowski, et.al., Psychosomatic Medicine 35:143-154 (1973)". The authors claim that compounds which block angiotensin II subtype 2 (AT2) receptors induced AVP secretion are therefore, useful in treating the above disorders. The abovementioned article of Janowsky does not suggest nor even specifically mention AVP as a cause of PMS. Janowski, et. al. describes an increase in the retention of sodium (Na) with a subsequent retention of water. Janowski, et. al. correlated the similarity of their findings to the physiologically known effects of aldosterone. In fact, a rise in body sodium would cause a decrease in AVP secretion. Ganong, W. F., in his textbook of physiology (1987) clearly states on Page 607, "the amount of sodium in the ECF (extracellular fluid) is the most important determinant of ECF volume. rise in ECF volume inhibits vasopressin (AVP) secretion. Volume stimuli override the osmotic regulation of vasopressin secretion." More importantly, is the fact that no correlation exists between circulating levels or changes in circulating levels of AVP aldosterone or any other hormone and the appearance of the symptoms of PMS. (Reid, R. L.: Premenstrual Syndrome: Current Problems in Obstetrics, Gynecology and Fertility, February, Vol. VIII, No. 2, 1985). Additionally when an AT2 receptor antagonist (PD123319) was administered to dogs, it had no effect on circulating vasopressin levels. (Keiser, J. A., et. al., Renal Hemodynamic and Excretory Responses to PD123319 and Losartan Nonpeptide AT1 and AT2 Subtype Specific Angiotension II ligands, J. Pharmacol. Exp. Ther., September 1992; 263(3): 1154-60. In addition, there are no differences in any of the measured hormonal changes between PMS and non-PMS patient. In addition, Blankley, et. al. in section 2, line 51 declare that their invention refers specifically to agents that block the angiotension II subtype 2 (AT2) receptors found in the central nervous system of mammals and the compounds described are supposedly effective in blocking only the binding of angiotension II (Ang II) at AT2 receptors. They claim that various disorders including neurologic, psychiatric, neuroendocrine, neurodegenerative and neuroimmunological disorders including addiction, anxiety, depression, epilepsy, hyperactivity, memory, pain, psychosis, regulation of autonomic functions and sleep are included in their patent only when regulated by AT2 receptors. A study evaluating the effects of blocking AT1 and AT2 receptors on sympathetic (autonomic) nervous system function and effects of intravenously administered norepenephrine (NE) showed that blocking the subtype 2 receptor (using PD123177) did not modify the effects of intravenous NE nor modify effects of sympathetic nervous system stimulation, thus showing that there are distinct

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differences in the effects of these different receptors in regulating antonomic functions and therefore, clearly separting the present invention from the prior art (Wong, P. C., et. al., Effect of Blocking Angiotension II Receptor Subtype on Rat Sympathetic Nerve Function, Hypertension, January 1992; 19(6PT2): 663-7). Web site: http://www.delphion.com/details?pn=US05464854__ •

Method of treatment for eiph in racing stock Inventor(s): Pantano; James A. (2459 Riverbend Rd., Allentown, PA 18103) Assignee(s): None Reported Patent Number: 5,550,127 Date filed: September 7, 1995 Abstract: The prevention and treatment of exercise-induced pulmonary hemorrhaging in non-human mammals is accomplished by the timely administration of effective amounts of vasodilators, including angiotensin converting enzyme inhibitors such as lisinopril, enalapril and captopril, and angiotensin II blocking vasodilators such as losartan potassium. Excerpt(s): This application is a U.S. continuation-in-part of International Application No. PCT/US94/04816, with an International Filing Date of May 11, 1994. The present invention is directed to a method for preventing and treating exercise-induced pulmonary hemorrhage (EIPH) in non-human mammals by the administration of vasodilators to affected or potentially affected animals. Of particular interest is the use of vasodilators from the class of angiotensin converting enzyme (ACE) inhibitors in the prevention or treatment of EIPH in racing animals such as horses, camels, dogs and the like. Exercise-induced pulmonary hemorrhage (EIPH) is a condition common to a large percentage of racing and maximally exercised animals, particularly horses, and is defined by the appearance of blood in the lungs of the animal following a strenuous exercise routine. Web site: http://www.delphion.com/details?pn=US05550127__

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Uterine fibroid treatment Inventor(s): Ahmed; Asif Syed (Birmingham, GB) Assignee(s): The University of Birmingham (birmingham, Gb) Patent Number: 5,981,470 Date filed: February 19, 1997 Abstract: The use of a) an angiotensin-converting enzyme (ACE) inhibitor such as Captopril or Enalapril, b) an angiotensin II-receptor antagonist such as Saralasin or Losartan, or c) a renin inhibitor, such as Remikiren or [N-(pyridyl-3-propionyl)phenylalanyl-histidyl-(3S,4S) ACHPA-isoleucylamino]-2-methyl-2-dihydroxy-1,3propane, for the manufacture of a medicament for the treatment of uterine fibroids is disclosed. The ACE inhibitor may be used concomitantly or sequentially with a gonadotropin-releasing hormone agonist such as Buserelin or Goserelin. Excerpt(s): This invention relates to uterine fibroid treatment. Cellular proliferation and differentiation in uterine tissue is considered to be regulated by ovarian steroids as

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fibroids appear in the reproductive years and regress after the menopause. Uterine fibroids are most commonly treated by surgery, usually by full or partial hysterectomy, although removal of individual fibroids (myomectomy) is also undertaken at rather greater risk on women who have not completed child bearing. As far as medical treatment is concerned, agonist analogues of LHRH (luteinizing hormone-releasing hormone) such as Buserilin (GnRH analogue) have been employed to suppress oestrogen-progesterone as fibroids are ovarian steroid dependent. Such medical treatments, however, suffer from a variety of side effects such as predisposition to osteopetrosis and are not recommended for long term use. It is an object of the present invention to provide an alternative medical treatment for uterine fibroids which, it is believed, may have potential for use in situations where the above-mentioned medical treatments are inadvisable. Web site: http://www.delphion.com/details?pn=US05981470__

Patent Applications on Losartan As of December 2000, U.S. patent applications are open to public viewing.10 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 losartan: •

Method of treatment Inventor(s): Brenner, Barry M.; (Weston, MA), Shahinfar, Shahnaz; (Newton Square, PA), Zhang, Zhongxin; (Blue Bell, PA) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20030073705 Date filed: May 10, 2002 Abstract: This disclosure relates to a method of preventing end stage renal disease using an angiotensin II antagonist in patients with impaired renal function. Angiotensin II antagonists such as candesartan cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, 2-butyl-4-chloro-1-[(2'-tetrazol-5-yl)biphenyl-4yl)methyl]imidazolecarbo- xylic acid and 3-(2'-(tetrazol-5-yl)-1,1'-biphen-4-yl)methyl5,7-dimethyl-- 2-ethyl-3H-imidazo[4,5-b]pyridine, or pharmaceutically acceptable salts thereof are useful. Excerpt(s): Angiotensin II (AII) is a potent vasoconstrictor. Its generation in the reninangiotensin cascade results from the enzymatic action of renin on a blood plasma, 2globulin, angiotensinogen, to produce angiotensin I (AI). AI is then converted by angiotensin converting enzyme (ACE) to the octapeptide hormone, AII. AII has been implicated as a causitive agent in hypertension. Therefore, ACE inhibitiors, which inhibit the production of AII, and AII receptor antagonists, which inhibit the function of AII, are useful in the treatment of hypertension. The efficacy of these compounds in the treatment of heart failure is also being studied. Pals, et al., Circulation Research, 29, 673 (1971) describe the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone AII to yield an (octa)peptide that blocks the effects of AII on the blood pressure of pithed rats. This analog, [Sar1, Ala8]

10

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

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AII, initially called "P-113" and subsequently "Saralasin," was found to be one of the most potent competitive antagonists of the actions of AII, although, like most of the socalled peptide-AII-antagonists, it also possesses agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating AII (Pals et al., Circulation Research, 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B. V., p. 246 (1984)). However, due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AII. Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are severely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard. Some known non-peptide antihypertensive agents act by inhibiting an enzyme, called angiotensin converting enzyme (ACE), which is responsible for conversion of angiotensin I to AII. Captopril and enalapril are commercially available ACE inhibitors (ACEI's). Based on experimental and clinical evidence, about 40% of hypertensive patients are non-responsive to treatment with ACEI's. But when a diuretic such as furosemide or hydrochlorothiazide is given together with a CEI, the blood pressure of the majority of hypertensive patients is effectively normalized. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of treatment using a gastric retained losartan dosage Inventor(s): Cumming, K. Iain; (Dublin, IE), Devane, John; (Athlone, IE), Gusler, Gloria M.; (Cupertino, CA), Hou, Sui Yuen Eddie; (Foster City, CA) Correspondence: Cooley Godward, Llp; 3000 EL Camino Real; 5 Palo Alto Square; Palo Alto; CA; 94306; US Patent Application Number: 20030158244 Date filed: October 25, 2002 Abstract: A method of treatment for hypertension and other disease states is described, which comprises the delivery of losartan in a gastric retained dosage form. Excerpt(s): The present invention relates to the use of losartan in a gastric retained dosage form. More specifically, the invention relates to the use of such dosage form to treat hypertension and other disease states. Losartan was the first orally active angiotensin II receptor antagonist (McIntyre, et al., Pharmacol. Ther. 74(2):181-194 (1997); Siegel, Journal of Hypertension 11(3):S19-S22 (1993)). At present, losartan is marketed as losartan potassium (C.sub.22H.sub.22ClKN.sub.6O), which is chemically described as 2-butyl-4-chloro-1[p-(o-1H-tetrazol-5-yl- phenyl) benzyl]imidazole-5methanol monopotassium salt. Losartan potassium is administered to treat hypertension and is commercially available in 25 mg, 50 mg and 100 mg tablet dosage forms. Dosage regimens are typically 25 mg to 100 mg either once- or twice-daily. The effects of losartan potassium are observed at 24 hours for both the 50 mg and the 100 mg dosages, but not for the 25 mg dosage (McIntyre, et al., supra). McIntyre also observes that there is an approximately 30% blockade of the diastolic pressure response to angiotensin II at 24 hours after dosing. Further, the peak:trough blood pressure ratio (5-6 hours after dosing: 24 hours after dosing) was found to be 60% for a 50 mg dosage and 72% for a 100 mg dosage.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Process for the synthesis of a known tetrazol derivative Inventor(s): Bagdy, Judit Nagyne; (Budapest, HU), Ballo, Ildiko; (Budapest, HU), Czibula, Laszlo; (Budapest, HU), Farkas, Jen?ouml;me; (Budapest, HU), Fischer, Janos; (Budapest, HU), Hegedus, Istvan; (Budapest, HU), Juhasz, Ida Deutschne; (Budapest, HU), Kreidl, Janos; (Budapest, HU), Nemes, Andras; (Budapest, HU), Petenyi, Endrene; (Budapest, HU), Werkne Papp, Eva; (Budapest, HU) Correspondence: The Firm OF Karl F Ross; 5676 Riverdale Avenue; PO Box 900; Riverdale (bronx); NY; 10471-0900; US Patent Application Number: 20030078435 Date filed: July 24, 2002 Abstract: The invention relates to a process for the synthesis of losartan potassium of formula (I), chemical name: 2-n-butyl-4-chloro-1-[(2'-(tetrazol-5-yl)-- 1,1'biphenyl-4-yl)methyl]-imidazol-5-methanol potassium, starting from 2-n-butyl-4-chloro-1-[(2'-(2triphenylmetyl-2H-tetrazol-5-yl)-1,1'-biphen- yl-4-yl)-methyl]-1H-imidazol-4-methanol of formula (III). According to the process the compound of formula (III) is reacted in an alcohol of formula (VI),--wherein the meaning of R is C.sub.1-C.sub.4 straight chain alkyl group--with 0.1-1 equivalent of potassium hydroxide. The final product of formula (I) is isolated after crystallizing out by changing the solvent to an aprotic or weakly protic solvent (I). Excerpt(s): In the examples of the above patent applications the detritylation was carried out either with aqueous hydrochloric acid or with aqueous sulfuric acid in the presence of tetrahydrofuran or acetonitrile. The total yield of losartan potassium was 72 or 80% from the acidic compound of formula (II), which was isolated after complicated operations. The disadvantages of this process are that the transformation can be carried out only in two steps, the cleavage of the trityl group proceeds by strong, corrosive mineral acid--hydrochloric acid or sulfuric acid--solution and the desired losartan potassium was isolated after addition of aqueous potassium hydroxide with complicated operations: azeotropic distillation, in low yield. It is known, that during the synthesis of other biphenyltetrazolyl compounds, for example according to U.S. Pat. No. 5,281,603, the trityl protecting group was cleaved by catalytic amount of acid in organic solvents. According to an other known procedure, for example the one described in the U.S. Pat. No. 5,281,604, the trityl group of a tetrazolyl-quinazolinone derivative is cleaved by refluxing in a mixture of methanol and tetrahydrofuran for 18 hours. The purified acidic tetrazol derivative was obtained after concentration of the reaction mixture by complicated column chromatography in low yield. From this tetrazol derivative the desired salts can be formed by known procedures. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Processes for preparing losartan and losartan an potassium Inventor(s): Dolitzky, Ben-Zion; (Petach Tiqva, IL) Correspondence: Kenyon & Kenyon; 1500 K Street, N.W., Suite 700; Washington; DC; 20005; US Patent Application Number: 20040034077 Date filed: April 29, 2003 Abstract: Losartan is prepared by acid catalyzed cleavage of a triarylmethyl group from a triarylmethyl-substituted losartan derivative in a diluent comprising liquid ketone. The reaction mixture is basified and liquid ketone is evaporated from the mixture leaving a residue from which a triarylmethyl alcohol and losartan are each obtained in high yield and high purity. In addition, losartan potassium is prepared by a process that is more convenient that those previously known in the art in which losartan is contacted with potassium ions in substantially pure liquid alcohol and losartan potassium is precipitated from the alcohol. Excerpt(s): This application claims the benefit under 35 U.S.C.sctn.119(e) of provisional application Serial No. 60/376,322, filed Apr. 29, 2002 which is incorporated herein by reference. The present invention relates to therapeutic agents that inhibit angiotensin II binding to AT.sub.1 receptors and, more particularly, to a process for preparing the AT.sub.1 receptor antagonist losartan. Activation of AT.sub.1 receptors in the outer membrane of vascular smooth muscle cells of the heart and arteries causes those tissues to constrict. Blocking of vasoconstriction mediated by AT.sub.1 receptors has been found to be beneficial to patients with hypertension. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of an angiotensin II receptor antagonist for the preparation of drugs to increase the survival rate of renal transplant patients Inventor(s): Remuzzi, Giuseppe; (Bergamo, IT) Correspondence: Browdy And Neimark, P.L.L.C.; Sutie 300; 624 Ninth Street, N.W.; Washington; DC; 20001-5303; US Patent Application Number: 20020115702 Date filed: February 19, 2002 Abstract: The present invention relates to the use, for the preparation of drugs to increase the survival rate of transplant patients, including renal and heart transplant patients, of a therapeutically effective amount of an angiotension II receptor antagonist compound, such as the class of substituted imidazoles represented by formula (I) and in particular by losartan potassium, 2-butyl-4-chloro-[(2'-tetrazol-5-yl)biphenyl-4-il]methyl]-5-(hydroxymethyl)imidazole potassium salt. Excerpt(s): This invention relates to the use of an angiotensin II receptor antagonist, such as substituted imidazole compounds, for the treatment of Post-transplant hypertension. The invention also relates to use of an angiotensin II receptor antagonist, such as substituted imidazole compounds, for the preparation of drugs to increase the survival rate of transplant patients, including renal transplant patients. The invention also relates to a method of using an angiotensin II receptor antagonist, such as substituted for increasing the survival rate of transplant patients, including renal transplant patients. Substituted imidazoles of formula I are known to inhibit the action of the octapeptide

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hormone angiotensin II (AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma.alpha.2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causitive agent, for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds disclosed in this application inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. The present application discloses a method for the improvement of insulin sensitivity by administering an angiotensin II receptor antagonist, such as a substituted imidazole of formula I, to a species of mammal with hypertension due to angiotensin II. Administration of an angiotensin II receptor antagonist, such as a substituted imidazole of formula I, with a diuretic, such as furosemide or hydrochlorothiazide; either as a stepwise combined therapy (diuretic first) or as a physical mixture, enhances the antihypertensive effect of the compound, while also improving the insulin sensitivity of the patient. wherein R1 is hydrogen, nitro or amino; R2 is phenyl, furyl or thienyl optionally substituted by halogen, lower alkyl, lower alkoxy or di-lower alkylamino; R3 is hydrogen or lower alkyl and X is halogen; and their physiologically acceptable salts. These compounds have diuretic and hypotensive actions. 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 losartan, 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 “losartan” (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 losartan. You can also use this procedure to view pending patent applications concerning losartan. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 5. PERIODICALS AND NEWS ON LOSARTAN Overview In this chapter, we suggest a number of news sources and present various periodicals that cover losartan.

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

Losartan/hydrochlorothiazide better than hydrochlorothiazide in ambulatory HTN Source: Reuters Industry Breifing Date: December 26, 2003

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Losartan may reduce sudden cardiac death risk in diabetics Source: Reuters Industry Breifing Date: August 21, 2003

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Losartan reduces microalbuminuria in normotensive patients with diabetes Source: Reuters Industry Breifing Date: July 22, 2003

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DASH diet enhances blood pressure lowering effects of losartan Source: Reuters Medical News Date: June 13, 2003

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Benefit of losartan in diabetic renal disease unaffected by ACE polymorphisms Source: Reuters Industry Breifing Date: May 12, 2003

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FDA panel backs stroke-prevention indication for losartan Source: Reuters Medical News Date: January 07, 2003

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FDA panel backs cardio survival indication for Merck's Cozaar Source: Reuters Industry Breifing Date: January 06, 2003

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US FDA staffer backs new use for Merck's Cozaar Source: Reuters Industry Breifing Date: January 03, 2003

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Losartan improves nocturnal blood-pressure dip in stroke survivors Source: Reuters Industry Breifing Date: November 26, 2002

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Merck's Cozaar approved in UK for renal protection Source: Reuters Industry Breifing Date: November 13, 2002

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Losartan approved in UK for renal protection Source: Reuters Medical News Date: November 13, 2002

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Losartan may prevent diabetic retinopathy Source: Reuters Industry Breifing Date: November 01, 2002

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Losartan superior to atenolol in isolated systolic hypertension with LV hypertrophy Source: Reuters Industry Breifing Date: September 24, 2002

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Lisinopril but not losartan improves myocardial perfusion in hypertensive heart disease Source: Reuters Medical News Date: September 20, 2002

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Losartan does not improve mortality rate over captopril after complicated acute MI Source: Reuters Industry Breifing Date: September 03, 2002

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British health bodies told to balance benefits of losartan against costs Source: Reuters Industry Breifing Date: June 28, 2002

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Losartan reduces sympathetic nerve activity in animal hypertension model Source: Reuters Industry Breifing Date: June 21, 2002

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FDA panel backs Merck's Cozaar for treatment of kidney disease in type 2 diabetics Source: Reuters Industry Breifing Date: April 12, 2002

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FDA advisors back losartan for kidney disease in type 2 diabetes Source: Reuters Medical News Date: April 12, 2002

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FDA staff reviewer backs new use of Merck's Cozaar Source: Reuters Industry Breifing Date: April 11, 2002

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Losartan reduces cardiovascular morbidity, mortality more than atenolol Source: Reuters Industry Breifing Date: March 20, 2002

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Losartan-enalapril combination relieves IgA nephropathy-related proteinuria Source: Reuters Industry Breifing Date: August 01, 2001

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Losartan improves sexual function in hypertensive men with erectile dysfunction Source: Reuters Industry Breifing Date: May 02, 2001

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Long-term losartan use lowers blood pressure and improves cardiac function Source: Reuters Industry Breifing Date: October 20, 2000

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Indomethacin blunts the antihypertensive effects of captopril and losartan Source: Reuters Industry Breifing Date: October 06, 2000

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Losartan reduces atherosclerosis in monkeys Source: Reuters Medical News Date: April 04, 2000

•

Impaired cognitive function improved with losartan Source: Reuters Medical News Date: December 07, 1999

•

Losartan confers no survival advantage over captopril among patients with CHF Source: Reuters Medical News Date: November 12, 1999

•

Irbesartan a more potent angiotensin II antagonist than valsartan, losartan Source: Reuters Medical News Date: October 27, 1999

•

Aspirin does not affect efficacy of enalapril or losartan Source: Reuters Medical News Date: September 15, 1999

•

Losartan improves exercise tolerance in patients with diastolic dysfunction Source: Reuters Medical News Date: May 07, 1999

•

More patients with essential hypertension respond to valsartan than losartan Source: Reuters Medical News Date: May 06, 1999

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•

Losartan does not increase bronchial responsiveness in asthma Source: Reuters Medical News Date: October 21, 1998

•

[] - Merck Says Losartan Prescribed 25,000 Times Per Week Source: Reuters Medical News Date: December 15, 1995

•

Losartan And Atenolol Equally Effective Therapy For Mild To Moderate Essential Hypertension Source: Reuters Medical News Date: June 09, 1995 The NIH

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

Academic Periodicals covering Losartan Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to losartan. In addition to these sources, you can search for articles covering losartan 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 6. 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 losartan. 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 losartan. 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 losartan: Losartan •

Systemic - U.S. Brands: Cozaar http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202767.html

Losartan and Hydrochlorothiazide •

Systemic - U.S. Brands: Hyzaar http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203639.html

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

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

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APPENDICES

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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

•

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

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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/

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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 “losartan” (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 4178 0 187 0 7 4372

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 “losartan” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

14

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

15

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

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Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

19 Adapted 20

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on losartan 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 losartan. 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 losartan. 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 “losartan”:

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Diabetes http://www.nlm.nih.gov/medlineplus/diabetes.html Diabetic Kidney Problems http://www.nlm.nih.gov/medlineplus/diabetickidneyproblems.html Heart Failure http://www.nlm.nih.gov/medlineplus/heartfailure.html Kidney Diseases http://www.nlm.nih.gov/medlineplus/kidneydiseases.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 National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search this site located at http://www.guideline.gov/ by using the keyword “losartan” (or synonyms). The following was recently posted: •

A guideline for the management of heart failure Source: National Heart Foundation of New Zealand - Disease Specific Society; 1996 (revised 2001 Dec); 30 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3309&nbr=2535&a mp;string=losartan

•

ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evalua Source: American College of Cardiology Foundation - Medical Specialty Society; 1995 November 1 (revised 2001 Dec); 56 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3114&nbr=2340&a mp;string=losartan

•

Congestive heart failure in adults Source: Institute for Clinical Systems Improvement - Private Nonprofit Organization; 1997 October (revised 2002 Jan); 71 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3165&nbr=2391&a mp;string=losartan

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•

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Diagnosis and management of hypertension in the primary care setting Source: Department of Defense - Federal Government Agency [U.S.]; 1999 May; Various pagings http://www.guideline.gov/summary/summary.aspx?doc_id=2579&nbr=1805&a mp;string=losartan

•

Diagnosis and treatment of heart failure due to left ventricular systolic dysfunction. A national clinical guideline Source: Scottish Intercollegiate Guidelines Network - National Government Agency [Non-U.S.]; 1999 February; 68 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2906&nbr=2132&a mp;string=losartan

•

Essential hypertension Source: University of Michigan Health System - Academic Institution; 1997 (revised 2002 Aug); 14 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3539&nbr=2765&a mp;string=losartan

•

Glomerulonephritis Source: National Committee on Renal Care (Singapore); 2001 October; 132 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2971&nbr=2197&a mp;string=losartan

•

Guidelines for the diagnosis and treatment of chronic heart failure Source: European Society of Cardiology - Medical Specialty Society; 2001 September; 34 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2976&nbr=2202&a mp;string=losartan

•

Heart failure Source: American Medical Directors Association - Professional Association; 1996 (revised 2002); 18 pages http://www.guideline.gov/summary/summary.aspx?doc_id=3303&nbr=2529&a mp;string=losartan

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Heart Failure Society of America guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction: pharmacological approaches Source: Heart Failure Society of America, Inc - Disease Specific Society; 1999 December; 36 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2736&nbr=1962&a mp;string=losartan

•

The management of diabetes mellitus in the primary care setting Source: Department of Defense - Federal Government Agency [U.S.]; 1999 December; 147 pages http://www.guideline.gov/summary/summary.aspx?doc_id=2583&nbr=1809&a mp;string=losartan 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 losartan. 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

•

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

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to losartan. By consulting all of associations listed in

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this chapter, you will have nearly exhausted all sources for patient associations concerned with losartan. 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 losartan. 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 “losartan” (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 “losartan”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “losartan” (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 “losartan” (or a synonym) into the search box, and click “Submit Query.”

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125

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

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

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

•

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/

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

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

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

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

•

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

23

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

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•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

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

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

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

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

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

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

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

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

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

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

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

•

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

•

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

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

•

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

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

•

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

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

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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

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

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

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

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

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

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

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

•

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

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

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

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

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

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

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

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

•

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

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

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

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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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

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

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

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

•

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

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

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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

•

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

•

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

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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

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

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

•

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

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

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

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

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

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

•

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

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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LOSARTAN DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. Abdomen: That portion of the body that lies between the thorax and the pelvis. [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] 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] 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] Actin: Essential component of the cell skeleton. [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] 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] Adenocarcinoma: A malignant epithelial tumor with a glandular organization. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Administration, Oral: The giving of drugs, chemicals, or other substances by mouth. [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]

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Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenergic beta-Antagonists: Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic betaantagonists are used for treatment of hypertension, cardiac arrythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. [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] Aerosol: A solution of a drug which can be atomized into a fine mist for inhalation therapy. [EU]

Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Ageusia: Complete or severe loss of the subjective sense of taste, frequently accompanied by olfaction disorders. [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] 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]

Dictionary 135

Albuminuria: More than normal amounts of a protein called albumin in the urine. Albuminuria may be a sign of kidney disease. [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] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allograft: An organ or tissue transplant between two humans. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [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] 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] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amlodipine: 2-((2-Aminoethoxy)methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5pyridinedicarboxylic acid 3-ethyl 5-methyl ester. A long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of angina pectoris and hypertension. [NIH] Amputation: Surgery to remove part or all of a limb or appendage. [NIH] Amyloid: A general term for a variety of different proteins that accumulate as extracellular fibrils of 7-10 nm and have common structural features, including a beta-pleated sheet conformation and the ability to bind such dyes as Congo red and thioflavine (Kandel,

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Schwartz, and Jessel, Principles of Neural Science, 3rd ed). [NIH] Amyloidosis: A group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] 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] Analysis of Variance: A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable. [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] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] 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] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Anginal: Pertaining to or characteristic of angina. [EU] Angioedema: A vascular reaction involving the deep dermis or subcutaneous or submucal tissues, representing localized edema caused by dilatation and increased permeability of the capillaries, and characterized by development of giant wheals. [EU] Angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor. [NIH] Angioneurotic: Denoting a neuropathy affecting the vascular system; see angioedema. [EU] Angioneurotic Edema: Recurring attacks of transient edema suddenly appearing in areas of the skin or mucous membranes and occasionally of the viscera, often associated with dermatographism, urticaria, erythema, and purpura. [NIH] Angiotensin converting enzyme inhibitor: A drug used to decrease pressure inside blood vessels. [NIH] Angiotensin I: The decapeptide precursor of angiotensin II, generated by the action of renin on angiotensinogen. It has limited pharmacologic activity. [NIH]

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Angiotensin-Converting Enzyme Inhibitors: A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. [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] 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] Antiarrhythmic: An agent that prevents or alleviates cardiac arrhythmia. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] 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] Antidiuretic: Suppressing the rate of urine formation. [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]

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Antihypertensive Agents: Drugs used in the treatment of acute or chronic hypertension regardless of pharmacological mechanism. Among the antihypertensive agents are diuretics (especially diuretics, thiazide), adrenergic beta-antagonists, adrenergic alpha-antagonists, angiotensin-converting enzyme inhibitors, calcium channel blockers, ganglionic blockers, and vasodilator agents. [NIH] Anti-inflammatory: Having to do with reducing inflammation. [NIH] 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] Antitussive: An agent that relieves or prevents cough. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Anxiety: Persistent feeling of dread, apprehension, and impending disaster. [NIH] Anxiolytic: An anxiolytic or antianxiety agent. [EU] Aorta: The main trunk of the systemic arteries. [NIH] Apheresis: Components plateletpheresis. [NIH]

being

separated

out,

as

leukapheresis,

plasmapheresis,

Apnea: A transient absence of spontaneous respiration. [NIH] Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] 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] Aromatic: Having a spicy odour. [EU] Arrhythmia: Any variation from the normal rhythm or rate of the heart beat. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH]

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Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Aspartate: A synthetic amino acid. [NIH] Aspergillosis: Infections with fungi of the genus Aspergillus. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Atenolol: A cardioselective beta-adrenergic blocker possessing properties and potency similar to propranolol, but without a negative inotropic effect. [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] Attenuation: Reduction of transmitted sound energy or its electrical equivalent. [NIH] Autacoids: A chemically diverse group of substances produced by various tissues in the body that cause slow contraction of smooth muscle; they have other intense but varied pharmacologic activities. [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] Azoxymethane: A potent carcinogen and neurotoxic compound. It is particularly effective in inducing colon carcinomas. [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] Bacterial Infections: Infections by bacteria, general or unspecified. [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] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] 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] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

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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 blocker: A drug used to slow the heart rate and reduce pressure inside blood vessels. It also can regulate heart rhythm. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biological 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 cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biophysics: The science of physical phenomena and processes in living organisms. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] 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] 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

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heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] 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] 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] 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] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Breeding: The science or art of changing the constitution of a population of plants or animals through sexual reproduction. [NIH] 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] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Buspirone: An anxiolytic agent and a serotonin receptor agonist belonging to the azaspirodecanedione class of compounds. Its structure is unrelated to those of the benzodiazepines, but it has an efficacy comparable to diazepam. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] 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 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]

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Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools. Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms. [NIH] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] 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] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Permeability: Property of blood capillary walls that allows for the selective exchange of substances. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (tight junctions) which may limit large molecule movement. [NIH] Capsaicin: Cytotoxic alkaloid from various species of Capsicum (pepper, paprika), of the Solanaceae. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Captopril: A potent and specific inhibitor of peptidyl-dipeptidase A. It blocks the conversion of angiotensin I to angiotensin II, a vasoconstrictor and important regulator of arterial blood pressure. Captopril acts to suppress the renin-angiotensin system and inhibits pressure responses to exogenous angiotensin. [NIH] Carbohydrates: The largest class of organic compounds, including starches, glycogens, cellulose, gums, and simple sugars. Carbohydrates are composed of carbon, hydrogen, and oxygen in a ratio of Cn(H2O)n. [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] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Cardiac: Having to do with the heart. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often

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of obscure or unknown etiology. [EU] Cardiopulmonary: Having to do with the heart and lungs. [NIH] Cardioselective: Having greater activity on heart tissue than on other tissue. [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] 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] 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] Catecholamines: A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. [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] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell 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 Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Aqueduct: Narrow channel in the mesencephalon that connects the third and fourth ventricles. [NIH]

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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] 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] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] 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] 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] Chemotherapy: Treatment with anticancer drugs. [NIH] Chest Pain: Pressure, burning, or numbness in the chest. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chromaffin System: The cells of the body which stain with chromium salts. They occur along the sympathetic nerves, in the adrenal gland, and in various other organs. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic Obstructive Pulmonary Disease: Collective term for chronic bronchitis and emphysema. [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] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH]

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Circadian: Repeated more or less daily, i. e. on a 23- to 25-hour cycle. [NIH] Circulatory system: The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system. [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 calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH] Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Clot Retraction: Retraction of a clot resulting from contraction of platelet pseudopods attached to fibrin strands that is dependent on the contractile protein thrombosthenin. Used as a measure of platelet function. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] 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]

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Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] 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] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confounding: Extraneous variables resulting in outcome effects that obscure or exaggerate the "true" effect of an intervention. [NIH] Congestive heart failure: Weakness of the heart muscle that leads to a buildup of fluid in body tissues. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] 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

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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] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constrict: Tighten; narrow. [NIH] Constriction: The act of constricting. [NIH] Constriction, Pathologic: The condition of an anatomical structure's being constricted beyond normal dimensions. [NIH] 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] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [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 Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary Circulation: The circulation of blood through the coronary vessels of the heart. [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] Corpus: The body of the uterus. [NIH] Corpus Callosum: Broad plate of dense myelinated fibers that reciprocally interconnect regions of the cortex in all lobes with corresponding regions of the opposite hemisphere. The corpus callosum is located deep in the longitudinal fissure. [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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internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [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] Cost Savings: Reductions in all or any portion of the costs of providing goods or services. Savings may be incurred by the provider or the consumer. [NIH] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclosporine: A drug used to help reduce the risk of rejection of organ and bone marrow transplants by the body. It is also used in clinical trials to make cancer cells more sensitive to anticancer drugs. [NIH] Cyst: A sac or capsule filled with fluid. [NIH] 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] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH]

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Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delusions: A false belief regarding the self or persons or objects outside the self that persists despite the facts, and is not considered tenable by one's associates. [NIH] 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] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] 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] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [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 Insipidus: A metabolic disorder due to disorders in the production or release of vasopressin. It is characterized by the chronic excretion of large amounts of low specific gravity urine and great thirst. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [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] Diaphragm: The musculofibrous partition that separates the thoracic cavity from the abdominal cavity. Contraction of the diaphragm increases the volume of the thoracic cavity aiding inspiration. [NIH] Diastole: Period of relaxation of the heart, especially the ventricles. [NIH] Diastolic: Of or pertaining to the diastole. [EU]

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Diastolic pressure: The lowest pressure to which blood pressure falls between contractions of the ventricles. [NIH] Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [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] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] 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] Distal: Remote; farther from any point of reference; opposed to proximal. In dentistry, used to designate a position on the dental arch farther from the median line of the jaw. [EU] Diuresis: Increased excretion of urine. [EU] Diuretics, Thiazide: Diuretics characterized as analogs of 1,2,4-benzothiadiazine-1,1dioxide. All have a common mechanism of action and differ primarily in the dose required to produce a given effect. They act directly on the kidney to increase the excretion of sodium chloride and water and also increase excretion of potassium ions. [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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Dorsal: 1. Pertaining to the back or to any dorsum. 2. Denoting a position more toward the back surface than some other object of reference; same as posterior in human anatomy; superior in the anatomy of quadrupeds. [EU] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dose-dependent: Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose dependent. [NIH] Double-blind: Pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment knows which treatment any particular subject is receiving. [EU] Double-blinded: A clinical trial in which neither the medical staff nor the person knows which of several possible therapies the person is receiving. [NIH] Drinking Behavior: Behaviors associated with the ingesting of water and other liquids; includes rhythmic patterns of drinking (time intervals - onset and duration), frequency and satiety. [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] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [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] 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] Dysgeusia: A condition characterized by alterations of the sense of taste which may range from mild to severe, including gross distortions of taste quality. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Ectopic: Pertaining to or characterized by ectopia. [EU] 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 produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Ejection fraction: A measure of ventricular contractility, equal to normally 65 8 per cent; lower values indicate ventricular dysfunction. [EU]

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Elastin: The protein that gives flexibility to tissues. [NIH] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] 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] 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] Emphysema: A pathological accumulation of air in tissues or organs. [NIH] Enalapril: An angiotensin-converting enzyme inhibitor that is used to treat hypertension. [NIH]

Endocrine Glands: Ductless glands that secrete substances which are released directly into the circulation and which influence metabolism and other body functions. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endometrium: The layer of tissue that lines the uterus. [NIH] Endorphins: One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxins: Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. [NIH] 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]

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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] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme 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] Ependyma: A thin membrane that lines the ventricles of the brain and the central canal of the spinal cord. [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] 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] Erection: The condition of being made rigid and elevated; as erectile tissue when filled with blood. [EU] 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] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Estrogens: A class of sex hormones associated with the development and maintenance of secondary female sex characteristics and control of the cyclical changes in the reproductive cycle. They are also required for pregnancy maintenance and have an anabolic effect on protein metabolism and water retention. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of

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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] Excrete: To get rid of waste from the body. [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] 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 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] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [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]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Felodipine: A dihydropyridine calcium antagonist with positive inotropic effects. It lowers blood pressure by reducing peripheral vascular resistance through a highly selective action on smooth muscle in arteriolar resistance vessels. [NIH] 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] Fertilizers: Substances or mixtures that are added to the soil to supply nutrients or to make available nutrients already present in the soil, in order to increase plant growth and productivity. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH]

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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] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibroid: A benign smooth muscle tumor, usually in the uterus or gastrointestinal tract. Also called leiomyoma. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Ficoll: A sucrose polymer of high molecular weight. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Flatus: Gas passed through the rectum. [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] Foetoplacental: Pertaining to the fetus and placenta. [EU] Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fosinopril: A phosphinic acid-containing angiotensin-converting enzyme inhibitor that is effective in the treatment of hypertension. It is a prodrug that is converted to its active metabolite fosinoprilat. [NIH] Fourth Ventricle: An irregularly shaped cavity in the rhombencephalon, between the medulla oblongata, the pons, and the isthmus in front, and the cerebellum behind. It is continuous with the central canal of the cord below and with the cerebral aqueduct above, and through its lateral and median apertures it communicates with the subarachnoid space. [NIH]

Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Furosemide: A sulfamyl saluretic and diuretic. It has a fast onset and short duration of action and is used in edema and chronic renal insufficiency. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglionic Blockers: Agents having as their major action the interruption of neural transmission at nicotinic receptors on postganglionic autonomic neurons. Because their actions are so broad, including blocking of sympathetic and parasympathetic systems, their therapeutic use has been largely supplanted by more specific drugs. They may still be used in the control of blood pressure in patients with acute dissecting aortic aneurysm and for the induction of hypotension in surgery. [NIH]

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Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gastric: Having to do with the stomach. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] 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] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH] Glomeruli: Plural of glomerulus. [NIH] Glomerulonephritis: Glomerular disease characterized by an inflammatory reaction, with leukocyte infiltration and cellular proliferation of the glomeruli, or that appears to be the result of immune glomerular injury. [NIH] Glomerulosclerosis: Scarring of the glomeruli. It may result from diabetes mellitus (diabetic glomerulosclerosis) or from deposits in parts of the glomerulus (focal segmental glomerulosclerosis). The most common signs of glomerulosclerosis are proteinuria and kidney failure. [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] 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

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than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glucuronides: Glycosides of glucuronic acid formed by the reaction of uridine diphosphate glucuronic acid with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and bilirubin metabolism to a more water-soluble compound that can be eliminated in the urine and bile. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

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] Gonadal: Pertaining to a gonad. [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]

Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] 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] 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] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU]

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Haemodialysis: The removal of certain elements from the blood by virtue of the difference in the rates of their diffusion through a semipermeable membrane, e.g., by means of a haemodialyzer. [EU] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [NIH] 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] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemorrhaging: A copious discharge of blood from the blood vessels. [NIH] Hepatic: Refers to the liver. [NIH] Hepatotoxicity: How much damage a medicine or other substance does to the liver. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterodimers: Zippered pair of nonidentical proteins. [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]

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]

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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] Humoral: Of, relating to, proceeding from, or involving a bodily humour - now often used of endocrine factors as opposed to neural or somatic. [EU] Humour: 1. A normal functioning fluid or semifluid of the body (as the blood, lymph or bile) especially of vertebrates. 2. A secretion that is itself an excitant of activity (as certain hormones). [EU] Hydralazine: A direct-acting vasodilator that is used as an antihypertensive agent. [NIH] Hydrochloric Acid: A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. Gastric acid is the hydrochloric acid component of gastric juice. [NIH] Hydrochlorothiazide: A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. [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] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydronephrosis: Abnormal enlargement of a kidney, which may be caused by blockage of the ureter (such as by a kidney stone) or chronic kidney disease that prevents urine from draining into the bladder. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [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] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycemia: Abnormally high blood sugar. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hyperthyroidism: Excessive functional activity of the thyroid gland. [NIH] Hypertrophic cardiomyopathy: Heart muscle disease that leads to thickening of the heart walls, interfering with the heart's ability to fill with and pump blood. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to

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an increase in the number of cells. [NIH] Hyperuricaemia: Excess of uric acid or urates in the blood; it is a prerequisite for the development or gout and may lead to renal disease. Called also uricacidaemia and, formerly, lithemia. [EU] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypotension: Abnormally low blood pressure. [NIH] 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] Hysterectomy: Excision of the uterus. [NIH] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Immunoglobulins: Glycoproteins present in the blood (antibodies) and in other tissue. They are classified by structure and activity into five classes (IgA, IgD, IgE, IgG, IgM). [NIH] Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunology: The study of the body's immune system. [NIH] Immunophilin: A drug for the treatment of Parkinson's disease. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] Impotence: The inability to perform sexual intercourse. [NIH] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In Situ Hybridization: A technique that localizes specific nucleic acid sequences within

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intact chromosomes, eukaryotic cells, or bacterial cells through the use of specific nucleic acid-labeled probes. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Indapamide: A sulfamyl diuretic with about 16x the effect of furosemide. It has also been shown to be an effective antihypertensive agent in the clinic. [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indomethacin: A non-steroidal anti-inflammatory agent (NSAID) that inhibits the enzyme cyclooxygenase necessary for the formation of prostaglandins and other autacoids. It also inhibits the motility of polymorphonuclear leukocytes. [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]

Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] 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] 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]

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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] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] 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] Intracellular: Inside a cell. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravascular: Within a vessel or vessels. [EU] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ionization: 1. Any process by which a neutral atom gains or loses electrons, thus acquiring a net charge, as the dissociation of a substance in solution into ions or ion production by the passage of radioactive particles. 2. Iontophoresis. [EU] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] 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] Itraconazole: An antifungal agent that has been used in the treatment of histoplasmosis, blastomycosis, cryptococcal meningitis, and aspergillosis. [NIH] Kallidin: A decapeptide bradykinin homolog produced by the action of tissue and glandular kallikreins on low-molecular-weight kininogen. It is a smooth-muscle stimulant and hypotensive agent that functions through vasodilatation. [NIH] 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]

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Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] 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] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Lateral Ventricles: Cavity in each of the cerebral hemispheres derived from the cavity of the embryonic neural tube. They are separated from each other by the septum pellucidum, and each communicates with the third ventricle by the foramen of Monro, through which also the choroid plexuses of the lateral ventricles become continuous with that of the third ventricle. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Leiomyoma: A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissues, probably arising from the smooth muscle of small blood vessels in these tissues. [NIH] Leukapheresis: The preparation of leukocyte concentrates with the return of red cells and leukocyte-poor plasma to the donor. [NIH] Leukemia: Cancer of blood-forming tissue. [NIH] Leukemic Infiltration: A pathologic change in leukemia in which leukemic cells permeate various organs at any stage of the disease. All types of leukemia show various degrees of

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infiltration, depending upon the type of leukemia. The degree of infiltration may vary from site to site. The liver and spleen are common sites of infiltration, the greatest appearing in myelocytic leukemia, but infiltration is seen also in the granulocytic and lymphocytic types. The kidney is also a common site and of the gastrointestinal system, the stomach and ileum are commonly involved. In lymphocytic leukemia the skin is often infiltrated. The central nervous system too is a common site. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukopenia: A condition in which the number of leukocytes (white blood cells) in the blood is reduced. [NIH] Leukostasis: Abnormal intravascular leukocyte aggregation and clumping often seen in leukemia patients. The brain and lungs are the two most commonly affected organs. This acute syndrome requires aggressive cytoreductive modalities including chemotherapy and/or leukophoresis. It is differentiated from leukemic infiltration which is a neoplastic process where leukemic cells invade organs. [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Levorphanol: A narcotic analgesic that may be habit-forming. It is nearly as effective orally as by injection. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Ligaments: Shiny, flexible bands of fibrous tissue connecting together articular extremities of bones. They are pliant, tough, and inextensile. [NIH] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkages: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipid: Fat. [NIH] 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] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lisinopril: An orally active angiotensin-converting enzyme inhibitor that has been used in the treatment of hypertension and congestive heart failure. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH]

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Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lumbar: Pertaining to the loins, the part of the back between the thorax and the pelvis. [EU] Luteal Phase: The period of the menstrual cycle that begins with ovulation and ends with menstruation. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] 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] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Malondialdehyde: The dialdehyde of malonic acid. [NIH] Manic: Affected with mania. [EU] Manic-depressive psychosis: One of a group of psychotic reactions, fundamentally marked by severe mood swings and a tendency to remission and recurrence. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Staff: Professional medical personnel who provide care to patients in an organized facility, institution or agency. [NIH]

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Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Medullary: Pertaining to the marrow or to any medulla; resembling marrow. [EU] Melanin: The substance that gives the skin its color. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into 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] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental: 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] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [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] 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] Metolazone: A potent, long acting diuretic useful in chronic renal disease. It also tends to lower blood pressure and increase potassium loss. [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] Microorganism: An organism that can be seen only through a microscope. Microorganisms

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include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Middle Cerebral Artery: The largest and most complex of the cerebral arteries. Branches of the middle cerebral artery supply the insular region, motor and premotor areas, and large regions of the association cortex. [NIH] Mineralocorticoid: 1. Any of the group of C21 corticosteroids, principally aldosterone, predominantly involved in the regulation of electrolyte and water balance through their effect on ion transport in epithelial cells of the renal tubules, resulting in retention of sodium and loss of potassium; some also possess varying degrees of glucocorticoid activity. Their secretion is regulated principally by plasma volume, serum potassium concentration and angiotensin II, and to a lesser extent by anterior pituitary ACTH. 2. Of, pertaining to, having the properties of, or resembling a mineralocorticoid. [EU] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monocrotaline: A pyrrolizidine alkaloid and a toxic plant constituent that poisons livestock and humans through the ingestion of contaminated grains and other foods. The alkaloid causes pulmonary artery hypertension, right ventricular hypertrophy, and pathological changes in the pulmonary vasculature. Significant attenuation of the cardiopulmonary changes are noted after oral magnesium treatment. [NIH] Monocyte: A type of white blood cell. [NIH] Monophosphate: So called second messenger for neurotransmitters and hormones. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Morphine: The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. [NIH] Morphology: The science of the form and structure of organisms (plants, animals, and other forms of life). [NIH] Motility: The ability to move spontaneously. [EU] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

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Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscle relaxant: An agent that specifically aids in reducing muscle tension, as those acting at the polysynaptic neurons of motor nerves (e.g. meprobamate) or at the myoneural junction (curare and related compounds). [EU] Muscle Spindles: Mechanoreceptors found between skeletal muscle fibers. Muscle spindles are arranged in parallel with muscle fibers and respond to the passive stretch of the muscle, but cease to discharge if the muscle contracts isotonically, thus signaling muscle length. The muscle spindles are the receptors responsible for the stretch or myotactic reflex. [NIH] Mutagenesis, Site-Directed: Mutagenesis where the mutation is caused by in vitro induction directed at a specific site in a DNA molecule. The most common method involves use of a chemically synthesized oligonucleotide mutant which can hybridize with the DNA target molecule. The resulting mismatch-carrying DNA duplex may then be transfected into a bacterial cell line and the mutant strands recovered. [NIH] Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [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] Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [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] 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] Natriuresis: The excretion of abnormal amounts of sodium in the urine. [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] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU]

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Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [NIH] Nephron: A tiny part of the kidneys. Each kidney is made up of about 1 million nephrons, which are the working units of the kidneys, removing wastes and extra fluids from the blood. [NIH] Nephropathy: Disease of the kidneys. [EU] Nephrosis: Descriptive histopathologic term for renal disease without an inflammatory 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] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurologic: Having to do with nerves or the nervous system. [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] Neurosecretory Systems: A system of neurons that has the specialized function to produce and secrete hormones, and that constitutes, in whole or in part, an endocrine organ or system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [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] Neutrophil: A type of white blood cell. [NIH] Nicardipine: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl) methyl 2(methyl(phenylmethyl)amino)-3,5-pyridinecarboxylic acid ethyl ester. A potent calcium channel blockader with marked vasodilator action. It has antihypertensive properties and is effective in the treatment of angina and coronary spasms without showing cardiodepressant effects. It has also been used in the treatment of asthma and enhances the action of specific antineoplastic agents. [NIH]

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Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful antianginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] 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]

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] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Normotensive: 1. Characterized by normal tone, tension, or pressure, as by normal blood pressure. 2. A person with normal blood pressure. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Odour: A volatile emanation that is perceived by the sense of smell. [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]

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]

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Olfaction: Function of the olfactory apparatus to perceive and discriminate between the molecules that reach it, in gas form from an external environment, directly or indirectly via the nose. [NIH] Olfaction Disorders: Loss of or impaired ability to smell. This may be caused by olfactory nerve diseases; paranasal sinus diseases; viral respiratory tract infections; craniocerebral trauma; smoking; and other conditions. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Opiate: A remedy containing or derived from opium; also any drug that induces sleep. [EU] Opium: The air-dried exudate from the unripe seed capsule of the opium poppy, Papaver somniferum, or its variant, P. album. It contains a number of alkaloids, but only a few morphine, codeine, and papaverine - have clinical significance. Opium has been used as an analgesic, antitussive, antidiarrheal, and antispasmodic. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [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] Osmosis: Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. [NIH] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteopetrosis: Excessive formation of dense trabecular bone leading to pathological fractures, osteitis, splenomegaly with infarct, anemia, and extramedullary hemopoiesis. [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] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [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

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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 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 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] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxytocin: A nonapeptide posterior pituitary hormone that causes uterine contractions and stimulates lactation. [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] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Partial remission: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial response. [NIH] Partial response: A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. [NIH] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH]

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Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] 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] Perindopril: An angiotensin-converting enzyme inhibitor. It is used in patients with hypertension and heart failure. [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] 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] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [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] Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of actions and effects of drugs with their chemical structure; also, such effects on the actions of a particular drug or drugs. [EU] 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] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer

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phenotype, characteristic of yeasts. [NIH] 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] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Photoreceptor: Receptor capable of being activated by light stimuli, as a rod or cone cell of the eye. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigments: Any normal or abnormal coloring matter in plants, animals, or micro-organisms. [NIH]

Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placebos: Any dummy medication or treatment. Although placebos originally were medicinal preparations having no specific pharmacological activity against a targeted condition, the concept has been extended to include treatments or procedures, especially those administered to control groups in clinical trials in order to provide baseline measurements for the experimental protocol. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of

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organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] 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] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Plateletpheresis: The preparation of platelet concentrates with the return of red cells and platelet-poor plasma to the donor. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Pneumonia: Inflammation of the lungs. [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]

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Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Portal Pressure: The venous pressure measured in the portal vein. [NIH] Portal Vein: A short thick vein formed by union of the superior mesenteric vein and the splenic vein. [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] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium hydroxide: A toxic and highly corrosive chemical used to make soap, in bleaching, and as a paint remover. It is used in small amounts as a food additive and in the preparatrion of some drugs. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Prazosin: A selective adrenergic alpha-1 antagonist used in the treatment of heart failure, hypertension, pheochromocytoma, Raynaud's syndrome, prostatic hypertrophy, and urinary retention. [NIH] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] 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 Maintenance: Physiological mechanisms that sustain the state of pregnancy. [NIH]

Premenstrual: Occurring before menstruation. [EU] 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] Presynaptic: Situated proximal to a synapse, or occurring before the synapse is crossed. [EU]

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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] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Probe: An instrument used in exploring cavities, or in the detection and dilatation of strictures, or in demonstrating the potency of channels; an elongated instrument for exploring or sounding body cavities. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Prone: Having the front portion of the body downwards. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Propranolol: A widely used non-cardioselective beta-adrenergic antagonist. Propranolol is used in the treatment or prevention of many disorders including acute myocardial infarction, arrhythmias, angina pectoris, hypertension, hypertensive emergencies, hyperthyroidism, migraine, pheochromocytoma, menopause, and anxiety. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some

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cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19hydroxy derivatives are found in many organs and tissues. [NIH] Prostaglandins D: Physiologically active prostaglandins found in many tissues and organs. They show pressor activity, are mediators of inflammation, and have potential antithrombotic effects. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] 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 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 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] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] 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] Proteome: The protein complement of an organism coded for by its genome. [NIH] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] 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] Psychosis: A mental disorder characterized by gross impairment in reality testing as

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evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of his behaviour; the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g. manic-depressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. [EU] 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] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [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] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radioactive: Giving off radiation. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Ramipril: A long-acting angiotensin-converting enzyme inhibitor. It is a prodrug that is transformed in the liver to its active metabolite ramiprilat. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Reality Testing: The individual's objective evaluation of the external world and the ability to differentiate adequately between it and the internal world; considered to be a primary ego

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function. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] 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] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Reflex: An involuntary movement or exercise of function in a part, excited in response to a stimulus applied to the periphery and transmitted to the brain or spinal cord. [NIH] Refractory: Not readily yielding to treatment. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Remission: A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although there still may be cancer in the body. [NIH] Renal amyloidosis: A disease of unknown etiology characterized by the abnormal deposition of amyloid, a translucent homogenous glycoprotein, in various organs and tissues of the body. [NIH] Renal Artery: A branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal Plasma Flow: The amount of plasma that perfuses the kidneys per unit time, approximately 10% greater than effective renal plasma flow (renal plasma flow, effective). It should be differentiated from the renal blood flow (RBF) which refers to the total volume of blood flowing through the renal vasculature, while the renal plasma flow refers to the rate of plasma flow (RPF). [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] Renin-Angiotensin System: A system consisting of renin, angiotensin-converting enzyme, and angiotensin II. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. The converting enzyme contained in the lung acts on angiotensin I in the plasma converting it to angiotensin II, the most powerful directly pressor substance known. It causes contraction of the arteriolar smooth muscle and has other indirect actions mediated through the adrenal cortex. [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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Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Response rate: The percentage of patients whose cancer shrinks or disappears after treatment. [NIH] 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 Neovascularization: Formation of new blood vessels originating from the retinal veins and extending along the inner (vitreal) surface of the retina. [NIH] Retinal Vein: Central retinal vein and its tributaries. It runs a short course within the optic nerve and then leaves and empties into the superior ophthalmic vein or cavernous sinus. [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] Rheumatoid: Resembling rheumatism. [EU] 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] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Risk patient: Patient who is at risk, because of his/her behaviour or because of the type of person he/she is. [EU] 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

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dilutions. [NIH] Saralasin: 1-(N-Methylglycine)-5-L-valine-8-L-alanineangiotensin II. An octapeptide analog of angiotensin II (bovine) with amino acids 1 and 8 replaced with sarcosine and alanine, respectively. It is a highly specific competitive inhibitor of angiotensin II. [NIH] Sarcosine: Methylamino-acetic acid. [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] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Segmental: Describing or pertaining to a structure which is repeated in similar form in successive segments of an organism, or which is undergoing segmentation. [NIH] Segmentation: The process by which muscles in the intestines move food and wastes through the body. [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] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Sequence Homology: The degree of similarity between sequences. Studies of amino acid and nucleotide sequences provide useful information about the genetic relatedness of certain species. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an

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ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] 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] 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 intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Smooth Muscle Tumor: A tumor composed of smooth muscle tissue, as opposed to leiomyoma, a tumor derived from smooth muscle. [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] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [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] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH]

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Sperm: The fecundating fluid of the male. [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] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Splenomegaly: Enlargement of the spleen. [NIH] Stabilization: The creation of a stable state. [EU] 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] Stenosis: Narrowing or stricture of a duct or canal. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stricture: The abnormal narrowing of a body opening. Also called stenosis. [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] Subcutaneous: Beneath the skin. [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] 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] Sudden cardiac death: Cardiac arrest caused by an irregular heartbeat. [NIH] Sulfuric acid: A strong acid that, when concentrated is extemely corrosive to the skin and

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mucous membranes. It is used in making fertilizers, dyes, electroplating, and industrial explosives. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Superoxide Dismutase: An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [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] Suspensions: Colloids with liquid continuous phase and solid dispersed phase; the term is used loosely also for solid-in-gas (aerosol) and other colloidal systems; water-insoluble drugs may be given as suspensions. [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] 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] Systemic: Affecting the entire 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] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] 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] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH]

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Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thoracic: Having to do with the chest. [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] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] 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] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] 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] Tone: 1. The normal degree of vigour and tension; in muscle, the resistance to passive elongation or stretch; tonus. 2. A particular quality of sound or of voice. 3. To make permanent, or to change, the colour of silver stain by chemical treatment, usually with a heavy metal. [EU] Tonic: 1. Producing and restoring the normal tone. 2. Characterized by continuous tension. 3. A term formerly used for a class of medicinal preparations believed to have the power of restoring normal tone to tissue. [EU]

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Tonus: A state of slight tension usually present in muscles even when they are not undergoing active contraction. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicokinetics: Study of the absorption, distribution, metabolism, and excretion of test substances. [NIH] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] 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] 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] 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] 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] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureter: One of a pair of thick-walled tubes that transports urine from the kidney pelvis to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

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Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary Retention: Inability to urinate. The etiology of this disorder includes obstructive, neurogenic, pharmacologic, and psychogenic causes. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [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] Uterine Contraction: Contraction of the uterine muscle. [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] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] 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] Vasopressor: 1. Stimulating contraction of the muscular tissue of the capillaries and arteries. 2. An agent that stimulates contraction of the muscular tissue of the capillaries and arteries. [EU]

Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venter: Belly. [NIH] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] 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 Dysfunction: A condition in which the ventricles of the heart exhibit a

Dictionary 189

decreased functionality. [NIH] Ventricular Function: The hemodynamic and electrophysiological action of the ventricles. [NIH]

Ventricular Remodeling: The geometric and structural changes that the ventricle undergoes, usually following myocardial infarction. It comprises expansion of the infarct and dilatation of the healthy ventricle segments. While most prevalent in the left ventricle, it can also occur in the right ventricle. [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] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

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] 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] Zidovudine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIVinduced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form,

190

Losartan

usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

191

INDEX A Abdomen, 133, 141, 162, 164, 173, 184, 186 Abdominal, 133, 149, 166, 172, 173, 176, 180 Abortion, 133, 170 Acceptor, 133, 164, 172 Acetylcholine, 133, 144, 169, 170 Actin, 133, 168 Acute renal, 31, 36, 68, 133 Adaptability, 133, 143 Adaptation, 133, 175 Adduct, 23, 133 Adenocarcinoma, 23, 133 Adenosine, 133, 141, 174 Administration, Oral, 90, 98, 133 Adolescence, 22, 133 Adrenal Cortex, 133, 135, 148, 170, 177, 180 Adrenal Glands, 134, 136, 180 Adrenergic, 17, 28, 134, 138, 139, 150, 153, 176, 177 Adrenergic beta-Antagonists, 134, 138 Adverse Effect, 94, 134, 174, 182 Aerobic, 134, 154, 167 Aerosol, 134, 185 Afferent, 10, 134 Affinity, 24, 71, 134, 149, 164, 183 Age of Onset, 18, 134, 187 Ageusia, 68, 134 Agonist, 19, 24, 96, 97, 134, 141, 150 Airway, 134, 183 Alanine, 21, 90, 97, 134, 182 Albumin, 4, 15, 25, 31, 77, 134, 135, 175 Albuminuria, 13, 135 Aldosterone, 8, 15, 21, 36, 58, 66, 74, 81, 94, 95, 135, 167 Alertness, 135, 141 Algorithms, 135, 140 Alimentary, 135, 172 Alkaline, 135, 142 Alkaloid, 135, 142, 167 Allergen, 135, 149 Allograft, 8, 36, 135 Alpha-1, 135, 176 Alternative medicine, 106, 135 Amino Acid Sequence, 135, 137 Amino Acid Substitution, 28, 135

Amlodipine, 33, 35, 39, 40, 41, 44, 54, 60, 67, 73, 135 Amputation, 5, 135 Amyloid, 135, 180 Amyloidosis, 45, 136 Anabolic, 136, 150, 153 Anaesthesia, 136, 161 Analgesic, 28, 136, 145, 164, 167, 171 Analog, 90, 97, 136, 149, 182 Analysis of Variance, 15, 136 Anaphylatoxins, 136, 146 Anatomical, 136, 139, 144, 147, 150, 160 Anemia, 5, 136, 171, 189 Aneurysm, 136, 155, 188 Angina, 5, 30, 77, 134, 135, 136, 162, 169, 170, 177 Angina Pectoris, 30, 77, 134, 135, 136, 177 Anginal, 136, 170 Angioedema, 94, 136 Angiogenesis, 12, 136 Angioneurotic, 94, 136 Angioneurotic Edema, 94, 136 Angiotensin converting enzyme inhibitor, 8, 15, 45, 49, 96, 136 Angiotensin I, 5, 7, 9, 26, 33, 34, 46, 74, 75, 80, 90, 92, 93, 94, 97, 101, 136 Angiotensin-Converting Enzyme Inhibitors, 69, 77, 137, 138 Angiotensinogen, 12, 90, 97, 101, 136, 137, 180 Animal model, 18, 23, 30, 137 Anions, 134, 137, 162, 185 Antagonism, 9, 19, 22, 26, 72, 92, 137, 141 Antiarrhythmic, 72, 137 Antibacterial, 21, 137 Antibiotic, 137, 173 Antibodies, 70, 137, 158, 160, 165, 175 Antibody, 134, 137, 146, 158, 160, 161, 165, 183 Anticoagulant, 137, 178 Anticonvulsant, 137, 174 Antidiuretic, 95, 137 Antifungal, 137, 162 Antigen, 134, 137, 146, 158, 159, 160, 161, 165 Antigen-Antibody Complex, 137, 146

192

Losartan

Antihypertensive, 3, 4, 15, 31, 32, 34, 35, 37, 38, 39, 41, 60, 63, 76, 77, 80, 90, 91, 98, 101, 105, 137, 138, 159, 161, 169 Antihypertensive Agents, 4, 90, 98, 138 Anti-inflammatory, 138, 148, 156, 161, 176 Antineoplastic, 138, 148, 169 Antineoplastic Agents, 138, 169 Antioxidant, 138, 172 Antitussive, 138, 149, 171 Antiviral, 138, 173 Anuria, 68, 138, 163 Anus, 138, 141, 145 Anxiety, 95, 134, 138, 177 Anxiolytic, 138, 141 Aorta, 24, 138, 180, 188 Apheresis, 46, 77, 138 Apnea, 138 Apolipoproteins, 138, 164 Apoptosis, 23, 138 Aqueous, 99, 138, 139, 148, 159 Arachidonic Acid, 20, 138, 164, 177 Arginine, 20, 136, 138, 170 Aromatic, 23, 138, 142, 174 Arrhythmia, 137, 138, 189 Arterial, 10, 44, 90, 98, 138, 142, 144, 159, 170, 178, 185 Arteries, 6, 34, 46, 53, 54, 82, 100, 138, 139, 141, 144, 147, 165, 166, 168, 179, 186, 188 Arteriolar, 139, 141, 154, 180 Arterioles, 139, 141, 142, 168 Artery, 6, 24, 25, 41, 66, 136, 138, 139, 147, 152, 167, 179, 180 Aspartate, 139, 149 Aspergillosis, 139, 162 Asymptomatic, 93, 139 Atenolol, 16, 37, 39, 41, 46, 47, 55, 59, 66, 69, 104, 105, 106, 139 Atrial, 41, 46, 139 Atrium, 139, 188 Attenuation, 23, 139, 167 Autacoids, 139, 161 Autonomic, 26, 95, 133, 139, 155, 170, 173, 185 Autonomic Nervous System, 139, 173, 185 Azoxymethane, 23, 139 B Bacteria, 21, 137, 139, 146, 152, 166, 167, 187 Bacterial Infections, 21, 139 Bacteriophage, 139, 187 Base, 28, 139, 149, 162, 163 Basement Membrane, 139, 154

Benign, 139, 155, 158, 163 Benzodiazepines, 140, 141 Beta blocker, 4, 140 Bilateral, 36, 140 Bile, 140, 155, 157, 159, 164, 184 Bilirubin, 134, 140, 157 Binding Sites, 24, 28, 140 Biochemical, 6, 29, 36, 63, 140, 163, 173, 182 Biological therapy, 140, 157 Biophysics, 29, 140 Biopsy, 8, 13, 25, 27, 140, 173 Biotechnology, 30, 106, 115, 140 Biotransformation, 23, 36, 140 Bladder, 140, 146, 159, 178, 187, 188 Blastomycosis, 140, 162 Blood Coagulation, 140, 142, 186 Blood Glucose, 140, 158, 162 Blood Platelets, 140, 182, 186 Body Fluids, 141, 151, 183 Bone Marrow, 141, 148, 153, 157, 183, 189 Bowel, 141, 150, 162, 173, 184 Bowel Movement, 141, 150, 184 Bradykinin, 11, 69, 94, 141, 162, 170, 175 Branch, 129, 141, 152, 172, 179, 180, 183, 185 Breakdown, 94, 141, 150, 156, 171 Breeding, 29, 141 Bronchi, 141, 153 Bronchial, 106, 141 Bronchitis, 141, 144 Buspirone, 14, 141 C Caffeine, 14, 141 Calcineurin, 27, 141 Calcium, 3, 40, 53, 54, 135, 138, 141, 142, 146, 154, 169, 170, 183, 189 Calcium channel blocker, 53, 54, 135, 138, 142, 189 Calcium Channel Blockers, 138, 142 Calculi, 142, 157 Calmodulin, 141, 142 Capillary, 7, 12, 61, 141, 142, 156, 189 Capillary Permeability, 141, 142 Capsaicin, 11, 142 Capsules, 142, 151, 156 Captopril, 9, 13, 36, 40, 46, 49, 50, 55, 65, 70, 74, 75, 77, 80, 81, 90, 93, 96, 98, 104, 105, 142 Carbohydrates, 142, 143 Carboxy, 142 Carboxylic Acids, 21, 142

Index 193

Carcinogen, 23, 133, 139, 142 Carcinogenic, 23, 142, 161, 184 Cardiac, 5, 10, 18, 19, 29, 37, 38, 42, 43, 92, 93, 94, 105, 134, 137, 141, 142, 153, 168, 184 Cardiomyopathy, 85, 142 Cardiopulmonary, 143, 167 Cardioselective, 139, 143, 177 Cardiovascular disease, 6, 57, 58, 59, 76, 143 Carotene, 143, 181 Carrier Proteins, 143, 175 Case report, 68, 143, 145 Catecholamines, 28, 143, 150 Cations, 143, 162 Caudal, 143, 150, 160, 176 Cell Death, 9, 82, 138, 143 Cell Differentiation, 143, 183 Cell Division, 139, 143, 157, 167, 174 Cell membrane, 13, 142, 143, 149, 162, 174 Cell proliferation, 19, 80, 143, 183 Cell Survival, 143, 157 Central Nervous System, 10, 95, 133, 134, 139, 141, 143, 155, 157, 158, 164, 167, 182 Cerebral, 5, 6, 143, 144, 153, 155, 163, 167, 186 Cerebral Aqueduct, 143, 155, 186 Cerebral Arteries, 6, 144, 167 Cerebral Cortex, 144 Cerebrovascular, 142, 143, 144 Cerebrum, 143, 144 Character, 90, 98, 136, 144, 149 Chemoprevention, 14, 23, 144 Chemotactic Factors, 144, 146 Chemotherapy, 144, 164 Chest Pain, 85, 144 Chin, 144, 166 Cholesterol, 33, 140, 144, 147, 159, 164, 165, 184 Cholesterol Esters, 144, 164 Cholinergic, 81, 144 Chromaffin System, 144, 152 Chromatin, 138, 144 Chromosome, 6, 144, 146, 164 Chronic Disease, 12, 144 Chronic Obstructive Pulmonary Disease, 12, 144 Chronic renal, 48, 144, 155, 166 Chylomicrons, 144, 164 Circadian, 76, 145 Circulatory system, 145, 152 Cirrhosis, 50, 64, 66, 74, 145

CIS, 145, 181 Clinical study, 145, 147 Clinical trial, 5, 6, 7, 8, 20, 27, 33, 85, 86, 115, 145, 147, 148, 151, 167, 174, 178, 179 Cloning, 10, 29, 140, 145 Clot Retraction, 145, 175 Coagulation, 39, 140, 145, 175, 186 Codeine, 145, 149, 171 Cofactor, 145, 178, 186 Collagen, 44, 135, 139, 145, 155, 175, 177 Collapse, 141, 145, 183 Colloidal, 134, 145, 185 Colon, 23, 139, 145, 146, 163 Colorectal, 23, 145, 146 Colorectal Cancer, 23, 146 Combination Therapy, 4, 15, 22, 69, 146 Complement, 12, 136, 146, 156, 175 Compliance, 25, 146 Computational Biology, 115, 146 Cones, 146, 181 Confounding, 9, 146 Congestive heart failure, 51, 72, 93, 120, 146, 164 Conjugated, 28, 146, 148 Conjugation, 140, 146 Connective Tissue, 141, 145, 147, 149, 155 Consciousness, 136, 147, 150 Constrict, 100, 147 Constriction, 147, 162, 188 Constriction, Pathologic, 147, 188 Continuous infusion, 29, 147 Contractility, 137, 147, 151 Contraindications, ii, 147 Control group, 15, 147, 174, 177 Controlled clinical trial, 4, 147 Controlled study, 8, 25, 41, 147 Coronary, 5, 25, 34, 54, 80, 82, 136, 143, 147, 166, 168, 169, 170 Coronary Arteriosclerosis, 147, 168 Coronary Circulation, 136, 147, 170 Coronary heart disease, 143, 147 Coronary Thrombosis, 147, 166, 168 Corpus, 147, 177, 186, 189 Corpus Callosum, 147, 186 Corpus Luteum, 147, 177 Cortex, 147, 148, 167 Cortical, 8, 12, 148, 154, 182 Corticosteroid, 148, 176 Cortisol, 14, 134, 148 Cortisone, 148, 176 Cost Savings, 5, 148 Creatinine, 4, 6, 15, 24, 77, 148, 163

194

Losartan

Cultured cells, 23, 148 Curative, 148, 185 Cyclic, 20, 141, 142, 148, 157, 170, 177 Cyclosporine, 82, 148 Cyst, 22, 148 Cytochrome, 14, 23, 36, 56, 62, 148 Cytoplasm, 138, 143, 148, 152, 157 Cytoskeleton, 29, 148 Cytotoxic, 142, 148, 183 D Degenerative, 149, 181 Deletion, 56, 68, 138, 149 Delusions, 149, 179 Dendrites, 149, 169 Density, 11, 13, 24, 76, 92, 149, 164, 171 Depolarization, 149, 183 Dermis, 136, 149, 187 Desensitization, 19, 24, 149 Deuterium, 149, 159 Dextromethorphan, 14, 149 Diabetes Insipidus, 149, 159 Diabetes Mellitus, 25, 122, 149, 156, 157, 158 Diabetic Retinopathy, 7, 25, 104, 149, 174 Diagnostic procedure, 89, 106, 149 Dialysate, 70, 149 Dialyzer, 149, 158 Diaphragm, 13, 149 Diastole, 149 Diastolic, 37, 98, 105, 149, 150, 159 Diastolic pressure, 98, 150, 159 Diencephalon, 150, 160, 186 Digestion, 135, 140, 141, 150, 162, 164, 184, 188 Digestive system, 87, 150 Dihydrotestosterone, 150, 180 Dihydroxy, 96, 135, 150 Dilatation, 133, 136, 150, 177, 188, 189 Dilatation, Pathologic, 150, 188 Dilated cardiomyopathy, 80, 150 Dilation, 141, 150, 188 Dilator, 150, 170 Dimethyl, 97, 150, 169 Direct, iii, 24, 26, 92, 93, 109, 150, 159, 180, 185 Disposition, 14, 36, 62, 69, 150 Dissociation, 134, 150, 162 Distal, 150, 178 Diuresis, 141, 150 Diuretics, Thiazide, 138, 150 Dopamine, 150, 169, 174 Dorsal, 151, 176

Dosage Forms, 71, 98, 151 Dose-dependent, 43, 151, 189 Double-blind, 4, 14, 25, 32, 35, 41, 43, 48, 60, 65, 80, 151 Double-blinded, 25, 151 Drinking Behavior, 42, 151 Drive, ii, vi, 11, 19, 22, 27, 79, 151, 162 Drug Interactions, 49, 110, 151 Drug Tolerance, 151, 186 Duct, 151, 181, 184 Dyes, 135, 151, 185 Dysgeusia, 68, 151 Dysplasia, 9, 151 E Ectopic, 9, 151 Edema, 136, 149, 151, 155, 159, 169 Effector, 133, 146, 151 Ejection fraction, 93, 151 Elastin, 145, 152 Electrocoagulation, 145, 152 Electrolyte, 20, 27, 135, 148, 152, 163, 167, 176, 183 Electrophysiological, 152, 189 Electroplating, 152, 185 Elementary Particles, 152, 165, 178 Embolus, 152, 161 Embryo, 133, 143, 152, 161, 170 Emphysema, 144, 152 Endocrine Glands, 152 Endocrine System, 29, 152, 169 Endogenous, 14, 90, 97, 150, 152, 153, 157, 171 Endometrium, 152, 166 Endorphins, 152, 169 Endothelial cell, 7, 24, 152, 186 Endothelium, 152, 170, 175 Endothelium-derived, 152, 170 Endotoxins, 146, 152 End-stage renal, 15, 22, 34, 59, 63, 144, 152 Enhancers, 14, 153 Enkephalins, 153, 169 Environmental Health, 114, 116, 153 Enzymatic, 90, 97, 135, 142, 143, 146, 153, 155, 181 Enzyme Inhibitors, 153, 175 Ependyma, 153, 186 Epidermis, 149, 153, 179 Epinephrine, 134, 150, 153, 169, 170, 187 Epithelial, 12, 13, 23, 133, 153, 167 Epithelial Cells, 23, 153, 167 Epithelium, 29, 139, 152, 153 Erectile, 105, 153

Index 195

Erection, 153 Erythema, 136, 153, 188 Erythrocytes, 136, 141, 153 Erythropoietin, 61, 69, 73, 81, 153 Esophagus, 150, 153, 184 Estrogens, 28, 153, 157 Eukaryotic Cells, 153, 161, 171 Excitation, 10, 153, 169 Excitatory, 11, 26, 154, 157 Excrete, 4, 138, 154, 163 Exercise Test, 37, 154 Exercise Tolerance, 52, 105, 154 Exhaustion, 137, 154 Exogenous, 140, 142, 152, 154, 157, 187 Extracellular, 22, 95, 135, 147, 154, 155, 183 Extracellular Matrix, 22, 147, 154, 155 Extracellular Space, 154 Extraction, 42, 154 F Family Planning, 115, 154 Fat, 138, 141, 143, 147, 148, 152, 154, 164 Fatigue, 85, 154, 158 Fatty acids, 134, 142, 154, 177, 186 Felodipine, 65, 69, 154 Femoral, 12, 154 Femur, 154 Fertilizers, 154, 185 Fetus, 133, 153, 154, 155, 174, 188 Fibrin, 140, 145, 154, 155, 175, 186 Fibrinogen, 56, 154, 155, 175, 186 Fibrinolysis, 39, 59, 155 Fibroblasts, 28, 155 Fibroid, 96, 155, 163 Fibrosis, 11, 18, 59, 155 Ficoll, 13, 155 Filtration, 13, 22, 155, 163 Flatus, 155, 156 Fluorescence, 19, 155 Foetoplacental, 155, 170 Fold, 155, 166 Forearm, 78, 141, 155 Fosinopril, 73, 155 Fourth Ventricle, 143, 155, 186 Fructose, 26, 155, 162 Furosemide, 77, 90, 98, 101, 155, 161 G Gallbladder, 133, 150, 155 Ganglia, 133, 155, 169, 173, 185 Ganglionic Blockers, 138, 155 Gas, 12, 20, 61, 155, 156, 159, 170, 171, 184, 185 Gastric, 98, 151, 156, 159

Gastrin, 156, 159 Gastrointestinal, 141, 153, 155, 156, 163, 164, 182, 184 Gastrointestinal tract, 155, 156, 163, 164, 182 Gene, 6, 9, 13, 17, 18, 23, 140, 156, 175 Gene Expression, 9, 156 Genetic Engineering, 140, 145, 156 Genetics, 27, 29, 146, 156 Genotype, 18, 28, 56, 63, 68, 156, 173 Ginseng, 14, 156 Gland, 133, 144, 148, 156, 159, 172, 174, 178, 182, 184, 186 Glomerular, 8, 13, 20, 22, 25, 27, 31, 35, 156, 162, 163, 180 Glomerular Filtration Rate, 8, 25, 27, 156, 163 Glomeruli, 13, 22, 54, 156 Glomerulonephritis, 31, 67, 121, 156 Glomerulosclerosis, 19, 22, 27, 48, 156 Glomerulus, 23, 156 Glucocorticoid, 156, 167, 176 Glucose, 26, 140, 149, 156, 158, 161, 181 Glucose Intolerance, 149, 156 Glucuronic Acid, 28, 157 Glucuronides, 157 Glutamate, 149, 157 Glutamic Acid, 157, 169, 177 Glycine, 135, 157, 169 Glycoprotein, 14, 153, 155, 157, 180, 186 Gonadal, 157, 184 Gonadotropin, 96, 157 Gout, 39, 157, 160 Governing Board, 157, 176 Gp120, 157, 173 Graft, 8, 157, 160, 168 Graft-versus-host disease, 157, 168 Granulocytes, 157, 183, 189 Growth, 7, 9, 22, 44, 133, 136, 137, 138, 143, 154, 157, 165, 168, 171, 174, 186, 187, 188 Growth factors, 23, 157 Guanylate Cyclase, 157, 170 H Habitual, 144, 157 Haemodialysis, 73, 158 Haptens, 134, 158 Headache, 141, 158, 176 Heart attack, 143, 158 Heartbeat, 158, 184 Heme, 140, 148, 158 Hemodialysis, 42, 61, 73, 149, 158, 163 Hemodynamics, 66, 67, 73, 158

196

Losartan

Hemoglobin, 5, 136, 153, 158 Hemorrhage, 96, 152, 158, 179, 184, 189 Hemorrhaging, 96, 158 Hepatic, 28, 51, 59, 134, 158 Hepatotoxicity, 60, 158 Heredity, 156, 158 Heterodimers, 22, 158 Heterogeneity, 134, 158 Homeostasis, 29, 74, 158 Homologous, 24, 158, 185 Hormonal, 57, 81, 95, 148, 158 Hormone, 90, 94, 95, 96, 97, 101, 135, 148, 153, 156, 158, 159, 161, 172, 177, 182, 185, 186 Humoral, 11, 46, 50, 159 Humour, 159 Hydralazine, 93, 159 Hydrochloric Acid, 99, 159 Hydrochlorothiazide, 32, 34, 39, 52, 63, 69, 71, 72, 76, 90, 98, 101, 103, 110, 159 Hydrogen, 101, 133, 139, 142, 149, 159, 164, 167, 172, 178, 185 Hydrogen Peroxide, 159, 164, 185 Hydrolysis, 140, 159, 162, 174, 178 Hydronephrosis, 12, 159 Hydrophobic, 28, 159, 164 Hydroxylysine, 145, 159 Hydroxyproline, 135, 145, 159 Hypercholesterolemia, 28, 159 Hyperglycemia, 17, 159 Hypersensitivity, 135, 149, 159, 164 Hyperthyroidism, 159, 177 Hypertrophic cardiomyopathy, 18, 85, 159 Hypertrophy, 16, 18, 19, 21, 26, 31, 34, 36, 38, 41, 46, 47, 49, 65, 66, 67, 77, 85, 104, 159, 167, 176 Hyperuricaemia, 39, 160 Hyperuricemia, 39, 70, 157, 160 Hypoglycemia, 57, 160 Hypoplasia, 9, 160 Hypotension, 49, 94, 155, 160 Hypotensive, 52, 101, 160, 162 Hypothalamus, 139, 150, 160, 174, 186 Hysterectomy, 97, 160 I Id, 82, 120, 121, 122, 128, 130, 160 Idiopathic, 19, 31, 160 Imidazole, 91, 98, 100, 160 Immune system, 140, 160, 164, 165, 173, 189 Immunity, 134, 160 Immunoglobulins, 160, 175

Immunohistochemistry, 12, 160 Immunologic, 144, 160, 189 Immunology, 134, 160 Immunophilin, 141, 160 Immunosuppressive, 48, 141, 156, 160, 185 Immunotherapy, 140, 149, 160 Impairment, 13, 63, 67, 160, 166, 178 Implantation, 160, 170 Impotence, 153, 160 In situ, 10, 12, 97, 160 In Situ Hybridization, 10, 12, 160 In vitro, 7, 12, 24, 28, 58, 93, 161, 168, 185, 186 In vivo, 7, 12, 23, 24, 28, 54, 92, 161, 171, 185, 186 Indapamide, 35, 74, 161 Indicative, 161, 172, 188 Indomethacin, 20, 51, 105, 161 Induction, 9, 23, 155, 161, 168 Infarction, 5, 46, 74, 75, 80, 92, 93, 161, 180 Infection, 140, 144, 161, 165, 169, 173, 188, 189 Infiltration, 12, 156, 161, 164 Inflammation, 11, 134, 138, 141, 155, 161, 164, 166, 175, 178, 181 Infusion, 6, 26, 28, 161 Ingestion, 161, 166, 167 Initiation, 23, 36, 161 Inotropic, 139, 150, 154, 161 Insecticides, 161, 189 Insight, 7, 19, 161 Insomnia, 161, 176 Insulin, 26, 73, 101, 161, 162, 187 Insulin-dependent diabetes mellitus, 161, 162 Intermittent, 95, 162, 173 Internal Medicine, 5, 13, 15, 36, 44, 47, 48, 51, 52, 67, 68, 80, 81, 82, 162, 169 Interstitial, 8, 12, 154, 162, 180 Intestine, 28, 141, 146, 162, 163 Intracellular, 12, 19, 93, 141, 142, 161, 162, 170, 176, 177, 182 Intramuscular, 162, 172 Intravascular, 162, 164 Intravenous, 17, 63, 95, 161, 162, 172 Intrinsic, 8, 12, 54, 134, 139, 162 Inulin, 156, 162 Involuntary, 162, 168, 180 Ion Transport, 29, 162, 167 Ionization, 61, 162 Ions, 100, 139, 142, 150, 152, 159, 162 Ischemia, 92, 162, 180

Index 197

Isosorbide, 93, 162 Isosorbide Dinitrate, 93, 162 Itraconazole, 49, 162 K Kallidin, 141, 162 Kb, 114, 162 Kidney Disease, 3, 4, 21, 27, 38, 54, 62, 87, 105, 114, 120, 135, 159, 163 Kidney Failure, 19, 25, 152, 156, 163 Kidney Failure, Acute, 163 Kidney Failure, Chronic, 163 Kidney stone, 159, 163, 188 Kinetic, 163 L Labile, 146, 163 Lactation, 163, 170, 172 Large Intestine, 146, 150, 162, 163, 180, 183 Latent, 163, 176 Lateral Ventricles, 163, 186 Lectin, 9, 163 Leiomyoma, 155, 163, 183 Leukapheresis, 138, 163 Leukemia, 163, 164 Leukemic Infiltration, 163, 164 Leukocytes, 141, 144, 157, 161, 164 Leukopenia, 164, 189 Leukostasis, 7, 164 Leukotrienes, 138, 164 Levorphanol, 149, 164 Library Services, 128, 164 Ligaments, 147, 164 Ligands, 22, 95, 164 Ligation, 12, 164 Linkages, 158, 164, 189 Lipid, 138, 142, 161, 164, 172 Lipid Peroxidation, 164, 172 Lipophilic, 20, 164 Lipoprotein, 15, 164, 165 Lisinopril, 24, 35, 43, 93, 96, 104, 164 Lobe, 20, 164 Localization, 28, 160, 165 Localized, 136, 161, 165, 174, 182, 188 Low-density lipoprotein, 56, 164, 165 Lumbar, 26, 165 Luteal Phase, 95, 165 Lymph, 145, 152, 159, 165 Lymphocyte, 76, 137, 165 Lymphoid, 137, 165 M Macrophage, 12, 165 Magnetic Resonance Imaging, 165

Magnetic Resonance Spectroscopy, 12, 92, 165 Malignant, 133, 138, 165 Malnutrition, 134, 165 Malondialdehyde, 73, 165 Manic, 165, 179 Manic-depressive psychosis, 165, 179 Manifest, 90, 98, 165 Mediate, 6, 7, 26, 28, 150, 165 Mediator, 11, 165, 182 Medical Staff, 151, 165 Medicament, 96, 166 MEDLINE, 115, 166 Medullary, 149, 166 Melanin, 166, 174, 187 Membrane, 100, 143, 146, 149, 153, 157, 158, 166, 171, 174, 176, 181, 183 Memory, 20, 80, 81, 95, 166 Meninges, 143, 166 Meningitis, 162, 166 Menopause, 97, 166, 170, 177 Menstrual Cycle, 95, 165, 166, 170, 176, 177 Menstruation, 165, 166, 176 Mental, iv, 5, 14, 87, 114, 116, 144, 150, 154, 166, 178, 179, 187 Mental Disorders, 87, 166, 178, 179 Mental Health, iv, 5, 87, 114, 116, 166, 179 Mesenteric, 24, 166, 176 Mesentery, 166, 173 Metabolic disorder, 149, 157, 166 Metabolite, 33, 36, 52, 61, 62, 63, 64, 70, 81, 91, 93, 140, 150, 155, 166, 177, 179 Methanol, 91, 98, 99, 166 Methionine, 150, 166 Metolazone, 43, 166 MI, 51, 92, 93, 104, 131, 166 Microbe, 166, 187 Microorganism, 145, 166, 189 Microscopy, 9, 29, 139, 167 Middle Cerebral Artery, 6, 167 Mineralocorticoid, 15, 167 Mitochondria, 167, 171 Mitosis, 138, 167 Modeling, 19, 167 Modification, 19, 135, 156, 167, 179, 189 Monitor, 10, 148, 167, 170 Monocrotaline, 80, 167 Monocyte, 46, 167 Monophosphate, 20, 167 Monotherapy, 31, 167 Morphine, 28, 145, 167, 168, 171

198

Losartan

Morphology, 12, 167 Motility, 161, 167, 182 Multicenter study, 27, 167 Muscle Fibers, 168 Muscle relaxant, 168, 174 Muscle Spindles, 168, 174 Mutagenesis, Site-Directed, 19, 168 Mycophenolate mofetil, 82, 168 Myocardial infarction, 5, 39, 43, 46, 49, 65, 74, 75, 80, 92, 93, 147, 166, 168, 177, 189 Myocardial Ischemia, 85, 92, 136, 168 Myocardium, 92, 136, 166, 168 Myosin, 52, 141, 168 N Narcotic, 164, 167, 168 Natriuresis, 137, 168 Nausea, 151, 168, 176, 187 NCI, 1, 86, 113, 145, 168 Need, 3, 21, 25, 93, 123, 134, 144, 168, 186 Neoplastic, 164, 168 Nephrology, 27, 31, 32, 33, 35, 44, 48, 54, 56, 62, 67, 69, 71, 72, 76, 81, 82, 169 Nephron, 13, 34, 40, 48, 61, 156, 169 Nephrosis, 169 Nephrotic, 19, 27, 62, 169 Nephrotic Syndrome, 19, 169 Nerve, 26, 96, 104, 134, 144, 149, 165, 169, 171, 176, 181, 184, 187 Nervous System, 10, 95, 134, 139, 143, 165, 169, 173, 185 Neural, 10, 20, 26, 134, 136, 155, 159, 163, 169 Neuroendocrine, 20, 95, 169 Neurologic, 95, 169 Neuronal, 10, 169 Neurons, 10, 20, 149, 154, 155, 168, 169, 185 Neuropathy, 136, 169 Neurosecretory Systems, 152, 169 Neurotoxic, 139, 169 Neurotoxicity, 20, 149, 169 Neurotransmitter, 20, 133, 135, 141, 150, 157, 169, 170, 182, 184 Neutrophil, 9, 169 Nicardipine, 53, 78, 169 Nifedipine, 7, 170 Nitric Oxide, 9, 11, 17, 20, 24, 29, 73, 81, 94, 170 Nitroglycerin, 72, 162, 170 Norepinephrine, 134, 150, 169, 170 Normotensive, 6, 25, 44, 45, 47, 104, 170 Nuclear, 22, 92, 146, 153, 170

Nuclei, 20, 26, 147, 156, 165, 167, 170, 178 Nucleic acid, 160, 170, 189 Nucleus, 26, 138, 139, 144, 148, 149, 152, 153, 170, 178, 184 O Odour, 138, 170 Oestrogen, 97, 170 Ointments, 151, 170 Olfaction, 134, 171 Olfaction Disorders, 134, 171 Oliguria, 163, 171 Opacity, 149, 171 Opiate, 167, 171 Opium, 167, 171 Opsin, 171, 181 Optic Disk, 149, 171 Organ Culture, 171, 186 Organelles, 29, 148, 171, 175 Osmosis, 171 Osmotic, 20, 95, 134, 162, 171 Osteopetrosis, 97, 171 Osteoporosis, 170, 171 Ovary, 147, 170, 171 Overexpress, 9, 171 Ovulation, 165, 171 Ovum, 147, 171, 177 Oxidants, 7, 171 Oxidation, 54, 56, 62, 69, 133, 138, 140, 148, 164, 171, 172 Oxidation-Reduction, 140, 171, 172 Oxidative Stress, 9, 28, 172 Oxygen Consumption, 72, 154, 172, 181 Oxytocin, 20, 172 P Palliative, 170, 172, 185 Pancreas, 133, 150, 161, 172 Parenteral, 90, 98, 172 Paroxysmal, 136, 172 Partial remission, 27, 172, 180 Partial response, 172 Patch, 172, 187 Pathogenesis, 8, 10, 69, 172 Pathologic, 138, 140, 147, 159, 163, 172 Pathologic Processes, 138, 172 Pathologies, 26, 172 Pathophysiology, 94, 172 Pelvis, 133, 163, 165, 173, 187, 188 Penicillin, 21, 137, 173, 188 Peptide, 9, 42, 90, 97, 135, 173, 178 Peptide T, 97, 173 Percutaneous, 25, 173 Perfusion, 104, 173

Index 199

Perindopril, 35, 56, 173 Peripheral Nervous System, 153, 169, 173, 184 Peritoneal, 75, 149, 173 Peritoneal Cavity, 173 Peritoneal Dialysis, 75, 149, 173 Peritoneum, 166, 173 Phagocyte, 171, 173 Pharmaceutical Solutions, 151, 173 Pharmacodynamics, 39, 45, 75, 173 Pharmacokinetic, 63, 173 Pharmacologic, 136, 139, 173, 187, 188 Phenotype, 18, 173 Phenyl, 98, 101, 174 Phenylalanine, 174, 187 Phenytoin, 49, 174 Phospholipases, 174, 183 Phospholipids, 154, 164, 174 Phosphorus, 142, 174 Photocoagulation, 145, 174 Photoreceptor, 174, 181 Physiologic, 134, 162, 166, 174, 177, 180 Physiology, 17, 19, 29, 73, 95, 133, 152, 169, 174 Pigments, 143, 174, 175, 181 Pilot study, 40, 41, 43, 70, 80, 174 Pituitary Gland, 20, 148, 174 Placebos, 14, 174 Placenta, 155, 174, 177 Plants, 135, 141, 156, 162, 163, 167, 170, 174, 181, 187 Plasma cells, 137, 175 Plasma protein, 52, 134, 175 Plasmapheresis, 138, 175 Plasmin, 22, 175 Plasminogen, 22, 56, 175 Plasminogen Activators, 175 Plasticity, 20, 175 Plastids, 171, 175 Platelet Activation, 54, 58, 175, 183 Platelet Aggregation, 136, 170, 175, 186 Plateletpheresis, 138, 175 Platelets, 170, 175, 186 Pneumonia, 147, 175 Polymorphic, 28, 175 Polymorphism, 69, 175 Polyposis, 146, 176 Portal Pressure, 66, 176 Portal Vein, 176 Posterior, 20, 151, 172, 176 Postsynaptic, 176, 183

Potassium, 15, 31, 50, 52, 59, 65, 69, 73, 83, 91, 93, 96, 98, 99, 100, 135, 150, 159, 166, 167, 176 Potassium hydroxide, 99, 176 Potentiates, 4, 32, 176 Potentiation, 176, 183 Practice Guidelines, 116, 120, 176 Prazosin, 28, 176 Precursor, 136, 137, 138, 150, 151, 152, 153, 170, 174, 175, 176, 177, 187, 188 Predisposition, 97, 176 Prednisolone, 31, 176 Prednisone, 27, 176 Pregnancy Maintenance, 153, 176 Premenstrual, 95, 176 Premenstrual Syndrome, 95, 176 Presynaptic, 169, 176 Prevalence, 4, 26, 177 Primary endpoint, 25, 177 Probe, 14, 177 Prodrug, 155, 177, 179 Progesterone, 97, 177, 184 Progression, 3, 7, 8, 15, 17, 21, 22, 25, 27, 42, 62, 65, 137, 177 Progressive, 5, 19, 65, 143, 144, 145, 151, 157, 163, 175, 177, 180 Proline, 145, 159, 177 Prone, 54, 177 Proportional, 5, 177 Propranolol, 64, 66, 139, 177 Prospective study, 14, 15, 177 Prostaglandin, 20, 137, 177, 186 Prostaglandins A, 11, 161, 177, 178 Prostaglandins D, 178 Prostate, 170, 178 Protease, 21, 146, 178 Protein C, 13, 134, 135, 138, 139, 164, 178 Protein Kinases, 29, 178 Protein S, 28, 30, 140, 178 Protein Subunits, 30, 178 Proteins, 13, 19, 21, 28, 135, 137, 138, 143, 144, 145, 146, 158, 167, 173, 175, 178, 182, 186 Proteinuria, 4, 8, 15, 16, 19, 21, 25, 27, 36, 38, 44, 45, 48, 55, 56, 62, 105, 156, 169, 178 Proteolytic, 135, 146, 155, 175, 178 Proteome, 19, 178 Protocol, 174, 178 Protons, 159, 165, 178, 179 Proximal, 12, 29, 150, 176, 178 Psychiatric, 95, 166, 178

200

Losartan

Psychiatry, 178 Psychic, 166, 178, 182 Psychosis, 95, 178 Public Health, 21, 116, 179 Public Policy, 115, 179 Pulmonary, 80, 96, 140, 154, 163, 164, 167, 179, 188 Pulmonary Artery, 140, 167, 179, 188 Pulmonary Edema, 163, 179 Pulmonary hypertension, 80, 179 Pulse, 41, 44, 167, 179 Purpura, 51, 70, 136, 179 Q Quality of Life, 25, 65, 179 R Radiation, 136, 152, 155, 179, 189 Radioactive, 159, 160, 162, 170, 179 Radiological, 173, 179 Ramipril, 7, 15, 17, 93, 179 Randomized, 3, 4, 8, 13, 14, 25, 27, 32, 35, 41, 44, 47, 48, 56, 66, 80, 94, 151, 179 Randomized clinical trial, 35, 44, 179 Reagent, 159, 179 Reality Testing, 178, 179 Rectum, 138, 141, 145, 146, 150, 155, 156, 163, 178, 180 Recurrence, 144, 165, 180 Reductase, 14, 180 Refer, 1, 146, 152, 165, 179, 180, 187 Reflex, 10, 168, 180 Refractory, 27, 152, 180 Regimen, 73, 151, 180 Remission, 165, 180 Renal amyloidosis, 56, 180 Renal Artery, 36, 42, 180 Renal failure, 12, 21, 65, 180 Renal Plasma Flow, 22, 180 Renin-Angiotensin System, 6, 13, 16, 17, 26, 29, 92, 137, 142, 180 Reperfusion, 92, 180 Reperfusion Injury, 180 Respiration, 138, 167, 181 Response rate, 19, 181 Retina, 146, 149, 181 Retinal, 7, 149, 171, 181 Retinal Neovascularization, 7, 181 Retinal Vein, 181 Retinol, 181 Retinopathy, 7, 149, 181 Rheumatoid, 172, 181 Rhodopsin, 19, 171, 181 Risk factor, 5, 18, 20, 177, 181

Risk patient, 46, 181 S Salivary, 150, 181 Salivary glands, 150, 181 Saphenous, 53, 181 Saphenous Vein, 53, 181 Saponins, 181, 184 Saralasin, 90, 96, 98, 182 Sarcosine, 90, 97, 182 Scleroderma, 49, 182 Screening, 145, 182 Secretion, 17, 20, 95, 148, 159, 162, 163, 167, 182, 188 Segmental, 19, 27, 48, 156, 182 Segmentation, 182 Seizures, 172, 174, 182 Sella, 174, 182 Sequence Homology, 173, 182 Serotonin, 141, 169, 182, 187 Serum, 4, 6, 15, 24, 39, 47, 134, 136, 146, 157, 163, 165, 167, 182 Sex Characteristics, 133, 153, 170, 182, 185 Shock, 80, 182 Side effect, 97, 109, 134, 140, 160, 182, 187 Signal Transduction, 6, 19, 141, 182 Skeletal, 12, 52, 168, 183 Skeleton, 133, 154, 177, 183 Sleep apnea, 39, 183 Small intestine, 144, 159, 162, 183 Smooth muscle, 59, 100, 136, 139, 141, 142, 154, 155, 163, 167, 170, 180, 183, 184 Smooth Muscle Tumor, 155, 183 Social Environment, 179, 183 Sodium, 4, 17, 26, 32, 50, 61, 74, 80, 81, 95, 135, 150, 157, 159, 167, 168, 183 Solid tumor, 136, 183 Solvent, 99, 166, 171, 173, 183 Soma, 183 Somatic, 95, 133, 159, 167, 173, 183 Specialist, 123, 150, 183 Species, 7, 8, 92, 101, 142, 153, 167, 182, 183, 184, 187, 189 Specificity, 70, 134, 183 Sperm, 144, 184 Spinal cord, 143, 144, 153, 166, 169, 173, 180, 184, 185 Spleen, 136, 164, 184 Splenomegaly, 171, 184 Stabilization, 174, 184 Stem Cells, 153, 157, 184 Stenosis, 36, 42, 184 Steroid, 22, 97, 148, 157, 170, 181, 184

Index 201

Stimulant, 141, 162, 184, 188 Stimulus, 147, 151, 153, 180, 184, 186 Stomach, 133, 150, 153, 156, 159, 164, 168, 173, 183, 184 Stool, 145, 163, 184 Strand, 21, 184 Stress, 8, 28, 139, 148, 168, 172, 176, 184, 188 Stricture, 184 Stroke, 5, 25, 45, 54, 59, 87, 104, 114, 143, 184 Subcutaneous, 53, 136, 151, 163, 172, 184 Subspecies, 183, 184 Substance P, 166, 182, 184 Substrate, 13, 18, 21, 28, 153, 184 Suction, 155, 184 Sudden cardiac death, 5, 18, 45, 61, 93, 94, 103, 184 Sulfuric acid, 99, 184 Superoxide, 9, 17, 185 Superoxide Dismutase, 17, 185 Suppression, 6, 10, 148, 185, 189 Survival Rate, 100, 185 Suspensions, 12, 185 Sympathetic Nervous System, 17, 95, 137, 139, 185 Symptomatic, 55, 57, 65, 81, 93, 94, 185 Synapse, 134, 176, 185, 187 Synaptic, 169, 183, 185 Systemic, 21, 26, 38, 42, 66, 69, 72, 110, 136, 138, 141, 153, 158, 161, 176, 182, 185 Systolic, 37, 40, 44, 47, 73, 93, 104, 121, 122, 159, 185 T Tacrolimus, 27, 185 Terminator, 185, 189 Testis, 170, 185 Testosterone, 180, 185 Therapeutics, 32, 33, 34, 40, 41, 42, 44, 49, 54, 56, 57, 63, 64, 75, 77, 80, 110, 185 Thigh, 154, 185 Third Ventricle, 26, 160, 163, 186 Thoracic, 11, 149, 186 Thorax, 133, 165, 186 Threonine, 173, 186 Threshold, 159, 186 Thrombin, 154, 155, 175, 178, 186 Thrombocytopenia, 52, 186 Thrombolytic, 175, 186 Thrombomodulin, 178, 186 Thrombosis, 178, 184, 186 Thromboxanes, 138, 186

Thrombus, 147, 161, 168, 175, 186 Thyroid, 159, 186, 187 Thyroxine, 134, 174, 186 Tissue, 29, 30, 92, 96, 134, 135, 136, 137, 139, 140, 141, 142, 143, 144, 145, 147, 149, 151, 152, 153, 154, 155, 157, 160, 161, 162, 163, 164, 165, 166, 168, 169, 173, 174, 175, 180, 181, 182, 183, 184, 186, 187, 188 Tissue Culture, 30, 186 Tolerance, 72, 77, 133, 157, 186 Tone, 10, 170, 186 Tonic, 11, 186 Tonus, 186, 187 Torsion, 161, 187 Toxic, iv, 147, 160, 166, 167, 169, 176, 187, 189 Toxicity, 58, 60, 151, 187 Toxicokinetics, 187 Toxicology, 40, 116, 187 Toxin, 186, 187 Transdermal, 93, 187 Transduction, 19, 182, 187 Transfection, 140, 187 Translation, 135, 187 Transmitter, 133, 150, 165, 170, 187 Transplantation, 9, 24, 31, 34, 35, 36, 41, 44, 55, 62, 67, 69, 71, 72, 76, 77, 81, 82, 144, 163, 187 Tryptophan, 145, 182, 187 Type 2 diabetes, 3, 4, 7, 26, 32, 42, 44, 56, 62, 105, 187 Tyrosine, 19, 143, 150, 187 U Unconscious, 160, 187 Uremia, 163, 180, 187 Ureter, 159, 187 Urethra, 178, 187, 188 Uric, 39, 45, 47, 62, 74, 157, 160, 188 Urinary, 12, 25, 54, 142, 171, 176, 188 Urinary Retention, 176, 188 Urinary tract, 12, 188 Urticaria, 136, 188 Uterine Contraction, 133, 172, 188 Uterus, 133, 147, 152, 155, 160, 163, 166, 177, 188 V Vacuoles, 171, 188 Valine, 182, 188 Vascular, 6, 7, 8, 24, 28, 47, 59, 72, 78, 100, 136, 142, 149, 152, 154, 161, 170, 174, 175, 186, 188

202

Losartan

Vasoactive, 9, 29, 188 Vasoconstriction, 9, 100, 153, 188 Vasodilation, 9, 93, 137, 188 Vasodilator, 6, 24, 69, 138, 141, 150, 159, 162, 169, 170, 188 Vasopressor, 101, 188 Vector, 187, 188 Vein, 136, 162, 170, 176, 181, 188 Venous, 42, 170, 176, 178, 188 Venter, 188 Ventral, 10, 160, 188 Ventricle, 46, 85, 163, 179, 185, 188, 189 Ventricular Dysfunction, 93, 151, 188 Ventricular Function, 93, 189 Ventricular Remodeling, 65, 92, 189 Venules, 141, 142, 189 Verapamil, 31, 64, 189 Veterinary Medicine, 115, 189 Viral, 20, 171, 187, 189

Virulence, 187, 189 Virus, 139, 153, 156, 157, 187, 189 Vitreous, 149, 181, 189 Vitreous Hemorrhage, 149, 189 Vitro, 28, 189 Vivo, 28, 53, 189 W White blood cell, 137, 164, 165, 167, 169, 175, 189 X Xenobiotics, 23, 189 Xenograft, 137, 189 X-ray, 155, 170, 189 Y Yeasts, 174, 189 Z Zidovudine, 28, 189 Zymogen, 178, 189

Index 203

204

Losartan

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