CYCLOSPORINE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Cyclosporine: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00324-4 1. Cyclosporine-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on cyclosporine. 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 CYCLOSPORINE ......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Cyclosporine................................................................................ 14 E-Journals: PubMed Central ....................................................................................................... 70 The National Library of Medicine: PubMed ................................................................................ 72 CHAPTER 2. NUTRITION AND CYCLOSPORINE ............................................................................. 121 Overview.................................................................................................................................... 121 Finding Nutrition Studies on Cyclosporine .............................................................................. 121 Federal Resources on Nutrition ................................................................................................. 123 Additional Web Resources ......................................................................................................... 124 CHAPTER 3. ALTERNATIVE MEDICINE AND CYCLOSPORINE ....................................................... 127 Overview.................................................................................................................................... 127 National Center for Complementary and Alternative Medicine................................................ 127 Additional Web Resources ......................................................................................................... 140 General References ..................................................................................................................... 143 CHAPTER 4. DISSERTATIONS ON CYCLOSPORINE ......................................................................... 145 Overview.................................................................................................................................... 145 Dissertations on Cyclosporine ................................................................................................... 145 Keeping Current ........................................................................................................................ 146 CHAPTER 5. PATENTS ON CYCLOSPORINE .................................................................................... 147 Overview.................................................................................................................................... 147 Patents on Cyclosporine............................................................................................................. 147 Patent Applications on Cyclosporine......................................................................................... 170 Keeping Current ........................................................................................................................ 179 CHAPTER 6. BOOKS ON CYCLOSPORINE ....................................................................................... 181 Overview.................................................................................................................................... 181 Book Summaries: Federal Agencies............................................................................................ 181 The National Library of Medicine Book Index ........................................................................... 183 Chapters on Cyclosporine .......................................................................................................... 183 CHAPTER 7. PERIODICALS AND NEWS ON CYCLOSPORINE.......................................................... 185 Overview.................................................................................................................................... 185 News Services and Press Releases.............................................................................................. 185 Newsletters on Cyclosporine...................................................................................................... 187 Newsletter Articles .................................................................................................................... 188 Academic Periodicals covering Cyclosporine ............................................................................. 188 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 191 Overview.................................................................................................................................... 191 U.S. Pharmacopeia..................................................................................................................... 191 Commercial Databases ............................................................................................................... 192 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 197 Overview.................................................................................................................................... 197 NIH Guidelines.......................................................................................................................... 197 NIH Databases........................................................................................................................... 199 Other Commercial Databases..................................................................................................... 201 APPENDIX B. PATIENT RESOURCES ............................................................................................... 203 Overview.................................................................................................................................... 203 Patient Guideline Sources.......................................................................................................... 203 Finding Associations.................................................................................................................. 209 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 211
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Overview.................................................................................................................................... 211 Preparation................................................................................................................................. 211 Finding a Local Medical Library................................................................................................ 211 Medical Libraries in the U.S. and Canada ................................................................................. 211 ONLINE GLOSSARIES................................................................................................................ 217 Online Dictionary Directories ................................................................................................... 217 CYCLOSPORINE DICTIONARY............................................................................................... 219 INDEX .............................................................................................................................................. 311
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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 cyclosporine 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 cyclosporine, 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 cyclosporine, 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 cyclosporine. 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 cyclosporine, 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 cyclosporine. 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 CYCLOSPORINE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on cyclosporine.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and cyclosporine, 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 “cyclosporine” (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: •
Pharmacokinetics of Neoral Before and After Total Gastrectomy in a Renal Transplant Patient Source: Transplantation Proceedings. 34(3): 805-806. May 2002. Contact: Available from Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010. (212) 633-3730. Website: www.elsevier.com. Summary: Abundant information is available about improved gastrointestinal absorption of the newer form of cyclosporine CsA, Neoral, compared with the older formulation (Sandimmune). However, no studies have investigated the possibility that an abnormal gastrointestinal tract could influence the absorption of Neoral (N). Because N absorption and pharmacokinetics profiles after a gastrectomy (Gx) have not yet been described, this article presents a case of altered absorption of N in the early post-Gx
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period with an even more remarkable restoration of absorption at 1 year post-Gx. The 56 year old male patient underwent kidney transplantation 6 years previously and had a stable renal function. The authors performed a total Gx for early stomach cancer. The authors describe the patient's postoperative recovery and immunosuppressive regimen. The authors also provide recommendations for managing patients in this situation. 1 figure. 1 table. 5 references. •
Gingival Overgrowth in Cyclosporine A: Treated Multiple Sclerosis Patients Source: Journal of Periodontology. 65(8): 744-749. August 1994. Summary: Correlations have been reported between cyclosporine A (CsA) induced gingival overgrowth (OG) and plaque induced gingivitis, duration of CsA therapy, and blood and tissue drug levels. This article reports on a study that evaluated the relative importance of such factors using data from a 2 year, double blind study of CsA therapy in multiple sclerosis (MS) patients. Ninety subjects (40 taking CsA; 50 placebo) were evaluated for plaque, calculus, gingivitis, probing depths, attachment levels, and CsA levels in blood and saliva. OG was determined by a panel of 11 calibrated examiners from standardized clinical photographs taken at the end of the study. Four (17 percent) out of 23 CsA patients with CsA trough blood levels less than 400 ng per ml exhibited OG. In contrast, 10 (59 percent) out of 17 CsA patients with CsA trough blood levels greater than 400 ng per ml were affected with OG. The study did not reveal a relationship between plaque and OG or calculus and OG. This result may be explained by the generally poor oral hygiene of the participants in the present study, reflecting a lack of manual dexterity often observed with MS patients. 6 tables. 36 references. (AAM).
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Long-Term Treatment of Focal Segmental Glomerulosclerosis in Children with Cyclosporine Given as a Single Daily Dose Source: American Journal of Kidney Diseases. 38(4): 754-760. October 2001. Contact: Available from W.B. Saunders Company. Periodicals Department, 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (407) 345-4000. Summary: Cyclosporine (CsA) has been successfully used for treatment of children with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS) for the last decade. Response rates of 50 to 100 percent have been reported using twice daily dosing of 5 to 32 milligrams per kilogram of body weight per day. Treatment has been associated with a high incidence of side effects, including nephrotoxicity (damage to the kidneys), hypertension (high blood pressure), gingival hyperplasia (overgrowth of the gums), and hirsutism (unusual hair growth). This article reports on a study undertaken to determine whether once daily, low dose CsA could minimize side effects and still induce remission. The study included 21 children with biopsy proven FSGS and NS, each treated with CsA, 4.6 milligrams per kilogram per day (plus or minus 0.8 milligrams per kilogram per day), with no predetermined target trough blood levels. Eleven of the 21 children (52 percent) attained complete remission and 5 of 21 children (24 percent) attained partial remission, for a total response rate of 76 percent. Mean time to response was 2.8 months (plus or minus 0.8 months), and mean duration of therapy was 20.6 months (plus or minus 13.7 months). CsA dosage was tapered or stopped in 9 responders; 3 of these patients maintained remission at last followup 6 to 13 months later, and 6 patients relapsed at 1.5 to 18.7 months (mean 8.7 months). Five of these 6 patients responded again when CsA therapy was restarted or the dosage was increased. Twelve of 16 responders were still being administered CsA at last followup 11 to 60
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months (mean, 24.6 months) later. Five of 21 patients (24 percent) had no response to CsA during 2 to 27 months of therapy; 4 of these 5 patients developed end stage renal disease after CsA therapy was stopped. Side effects of CsA therapy were minimal: 1 patient each developed new onset hypertension or gingival hyperplasia, and no patient had hirsutism or nephrotoxicity. The authors conclude that single daily low dose CsA appears to be effective for the long term treatment of children with FSGS and NS, with fewer side effects than twice daily dosing. 2 figures. 2 tables. 32 references. •
Critical Review of Cyclosporine Therapy in Inflammatory Bowel Disease Source: Inflammatory Bowel Diseases. 1(1): 48-63. Spring 1995. Contact: Available from Raven Press, Ltd. 1185 Avenue of the Americas, New York, NY 10036. (800) 777-2836 or (212) 930-9500. Fax (212) 869-3495. Summary: Cyclosporine A (CsA) is a potent inhibitor of cell-mediated immunity; in this article, the author critically reviews the use of CsA in patients with Crohn's disease and ulcerative colitis (UC). Topics covered include the mechanism of action; pharmacology; results in Crohn's disease, in controlled studies, uncontrolled studies, and in patients with fistulous disease; results in UC, including controlled and uncontrolled studies in severe UC, the use in patients with UC associated with primary sclerosing cholangitis, and in refractory left-sided UC; results in the extra-intestinal manifestations of inflammatory bowel disease (IBD); the correlation of clinical response with cyclosporine blood concentrations and with dose; and cyclosporine toxicity. The author concludes that CsA must be used at relatively high (and potentially toxic) dosages to achieve efficacy in IBD. 3 figures. 7 tables. 138 references. (AA-M).
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Cyclosporine Hits Autoimmune Ills Source: Medical World News. September 1991. p. 57. Summary: Cyclosporine, a drug well known for its beneficial immunosuppressive effects in transplantation, shows promise as a weapon against a host of autoimmune diseases, including inflammatory bowel disease. This brief article reviews the new uses of cyclosporine. The author also discusses the potential side effect of kidney damage and how it can be avoided in patients on cyclosporine.
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Long-Term Safety of Cyclosporine in Renal Transplant Recipients: Worldwide Experience Source: Transplantation Proceedings. 25(4 Supplement 3): 17-19. August 1993. Summary: During the past decade, cyclosporine (Sandimmune) has become established as the central component of immunosuppressant therapy in patients undergoing organ transplantation. This article reviews the efficacy and safety of cyclosporine during longterm treatment. Topics covered include data on the efficacy of cyclosporine, as demonstrated by the findings of the Collaborative Transplant Study (CTS); the safety of long-term cyclosporine treatment as studied in an open trial involved 56 centers in 17 countries (4584 renal transplant recipients); adverse events with multiple-drug regimens; and the effect of cyclosporine dose on graft survival. 1 figure. 1 table. 14 references.
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Cyclosporine for Thrombotic Thrombocytopenic Purpura (editorial) Source: Annals of Internal Medicine. 118(12): 987-988. June 15, 1993.
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Summary: In this letter to the editor, the authors describe a 64-year-old man in whom thrombotic thrombocytopenic purpura (TTP) was controlled by cyclosporine after plasmapheresis failed. The patient was in full clinical and hematologic remission for 9 months on cyclosporine. Cyclosporine alone appears to have induced a remission in this patient. It also was effective when the patient experienced a subsequent relapse. The authors conclude that, in contrast to other immunosuppressive therapy, cyclosporine has fewer side effects and may prove to be a useful alternative therapy for patients with chronic TTP. 1 figure. •
Approaching the Therapeutic Window for Cyclosporine in Kidney Transplantation: A Prospective Study Source: JASN. Journal of the American Society of Nephrology. 12(4): 828-833. April 2001. Contact: Available from Lippincott Williams and Wilkins. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-6423. Summary: Neoral (a type of cyclosporine) dosing is traditionally based on cyclosporine (CyA) trough levels. Previous studies have shown that the 4 hour area under the curve (AUC4) for Neoral in the early posttransplantation period had a better correlation to acute rejection (AR) and CyA nephrotoxicity (harm or toxicity to the kidney) compared with CyA trough levels. This article describes a prospective study undertaken to assess the feasibility, safety, and efficacy of dosing Neoral solely by the AUC4 monitoring, regardless of CyA trough levels, in the first 3 months after kidney transplantation. The study included 59 kidney transplant recipients who received Neoral based triple immunosuppression. AUC4 was measured on days 3, 5, 7, 10, and 14; and weeks 3, 4, 6, and 8, then monthly. No patients had CyA nephrotoxicity while AUC4 was in the target range. Four patients had reversible CyA neprotoxicity with AUC levels greater than the target level. In analysis, higher early AUC4 was the only significant variable associated with lower serum (blood) creatinine at 3 months. The authors conclude that Neoral dose monitoring by AUC4 is a potentially valuable tool for optimizing Neoral immunosuppression. 4 figures. 2 tables. 22 references.
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Renal Function Following Conversion from Sandimmune to Neoral in Stable Renal Transplant Recipients Source: Journal of Transplant Coordination. 7(2): 78-81. June 1997. Contact: Available from InnoVision Communications. 101 Columbia, Aliso Viejo, CA 92656. (800) 899-1712 ext. 532 or (714) 362-2050 ext. 532. Fax (714) 362-2022. E-mail:
[email protected]. Summary: Neoral is a microemulsion formulation of cyclosporine that is absorbed from the gastrointestinal tract with less variability than the original Sandimmune formulation. However, conversion of stable renal transplant patients from Sandimmune to Neoral may pose a risk of shortterm nephrotoxicity. This article reports on a study in which serial serum creatinine concentrations were measured in 141 kidney and simultaneous kidney pancreas transplant recipients who were converted from Sandimmune to Neoral on a 1 to 1 dosing basis and followed for up to 11 months. Following conversion, the cyclosporine dose was reduced in 74 percent of patients with a mean dose reduction of 22.6 percent for the entire cohort. Serum creatinine concentrations transiently increased to more than 30 percent above baseline in 48 percent of patients and remained more than 30 percent above baseline in 16 percent of patients. Multivariate analyses suggested that acute rejection, maintenance steroid therapy, young age, Sandimmune dose prior to conversion, and an increment in trough
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cyclosporine levels after conversion were positive predictors of renal insufficiency following conversion. The authors conclude that lower doses of Neoral should be considered at the time of conversion in order to minimize nephrotoxicity. 3 tables. 9 references. (AA-M). •
Cyclosporine A-Related Hemolytic Uremic Syndrome After Living Renal Transplantation: Case Report Source: Transplantation Proceedings. 34(2): 569-571. March 2002. Contact: Available from Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010. (212) 633-3730. Website: www.elsevier.com. Summary: One of the early complications of renal (kidney) transplantation is thrombotic microangiopathy (TMA), characterized by hemolytic uremic syndrome (HUS), and thrombotic thrombocytopenic purpura (TTP). This article reports a case of cyclosporine A related HUS after a kidney transplantation from a living donor. The clinical symptoms of HUS are thrombocytopenia, microangiopathic anemia, and acute renal failure (ARF). Renal biopsy is useful for establishing the diagnosis. The most common triggering factor is calcineurin antagonist such as cyclosporine A (CsA) or tacrolimus, but posttransplant HUS may also be caused by an acute vascular rejection episode, sepsis, viral infection, and other immunosuppressive drugs such as monoclonal antiCD3 thymocyte globulin (OKT3). The case report features a 26 year old woman who underwent a renal transplantation, from a kidney donated by her 51 year old mother. The diagnosis of CsA-induced HUS was made on the fifth postoperative day. After treatment, including discontinuation of the CsA, on the 12th day after transplantation, renal function began to improve progressively. On the 29th day, the patient was discharged from the hospital. CsA has never been reintroduced to this patient's regimen, but approximately 2 months after discharge FK 506 (tacrolimus) was added to immunosuppression and no relapse of HUS occurred. At 11 months posttransplant, the function of the transplanted kidney is satisfactory and the patient feels well. 14 references.
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Is It Time To Shelve Cyclosporine? Source: Medical World News. 31(15): 21. September 1990. Summary: The superpotent immunosuppressant FK-506 continues to yield good results amid proponents' claims that the drug may revolutionize transplantation. This brief article discusses FK-506 and compares its benefits and side effects with those of cyclosporine. The author reports that most of the clinical experience in the United States with FK-506 has been with liver transplants. In contrast to cyclosporine, the newer drug has less kidney toxicity, and apparently causes no hypertension in most patients. The author notes that surgeons continue to improve success rates with cyclosporine as they experiment with various regimens aimed at lowering toxicity and infection rates. However, many surgeons predict that FK-506 will replace cyclosporine in two or three years.
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Efficacy and Safety of Cyclosporine in Renal-Transplant Recipients (letters) Source: New England Journal of Medicine. 331(26): 1777-1778. December 29, 1994. Summary: These three letters to the editor of the New England Journal of Medicine comment on a study reported in the August 11, 1994, issue of the same journal. The study investigated the long-term efficacy and safety of cyclosporine in renal-transplant
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recipients. The author of the first letter expresses concern over methodology used in the study, particularly the inclusion in the results of a percentage of patients who had actually stopped taking cyclosporine. The author wishes to know when (in the study) these patients stopped taking cyclosporine and what happened to their renal function thereafter. The second letter expresses concern over the researchers' conclusion that graft failure is usually due to chronic rejection and not to cyclosporine-induced nephropathy. The writer stresses that, in the absence of biopsy specimens, it is impossible to discern whether graft failure is due to cyclosporine-induced nephrotoxicity, chronic rejection, or both. He maintains that the crucial question is why kidney-transplant recipients should be different and not have progressive chronic nephropathy when other patients treated with low-dose cyclosporine do. The third letter is a response by the authors of the study. The researchers state that they do not think the lack of kidney-biopsy specimens diminishes their conclusions about the safety of cyclosporine. They conclude that, while some cyclosporine-treated recipients of heart or liver transplants have had progression to end-stage renal failure, most have impaired by stable renal function. 5 references. •
Retrospective Analysis of Late Renal Graft Function: Correlation with Mean Cyclosporine Levels and Lack of Evidence for Chronic Cyclosporine Toxicity Source: Transplantation Proceedings. 23(1): 1018-1019. February 1991. Contact: Available from Appleton and Lange. P.O. Box 86, Congers, NY 10920-0086. (203) 406-4623. Summary: This article briefly reports on a retrospective analysis performed on all patients transplanted at the University of Florida with better than 6 months of followup who had received their standard triple drug protocol of cyclosporine (CyA), azathioprine and prednisone. A total of 359 patients were included in the study. The authors suggest that their results support the hypothesis that the current tendency to lower CyA doses and levels as a function of time may lead to decreased renal function, perhaps as a result of chronic or ongoing rejection due to inadequate immunosuppression. In addition, they found no evidence that high CyA levels resulted in decreased renal function. 1 figure.
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Cyclosporine Causes Gout in Kidney Transplant Patients Source: Research Resources Reporter. 14(3): 1-4. March 1990. Contact: Available from Superintendent of Documents. U.S. Government Printing Office, Washington, DC 20402. (202) 783-3238 (for charge orders). Summary: This article describes research demonstrating the increased incidence of gout in kidney transplant patients receiving cyclosporine for immunosuppression. The prevalence and cause of hyperuricemia and gout was studied in two group of patients: one treated with cyclosporine and prednisone (A) and the other treated with prednisone and azathioprine (B). Uric acid clearance was lower in patients in group A. The data suggest that hyperuricemia and gout develop as a result of the diminished uric acid clearance. The researchers also found that patients taking cyclosporin frequently develop hypertension.
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Understanding Cyclosporine (Neoral, Sandimmune, Gengraf) Source: Stadtlanders Lifetimes. Issue 3: 30-31. 2000.
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Contact: Available from Stadtlanders Lifetimes. Stadtlanders Pharmacy, 600 Penn Center Boulevard, Pittsburgh, PA 15235-5810. E-mail:
[email protected]. Summary: This article offers kidney transplant recipients an overview of the use of cyclosporine (Neoral, Sandimmune, Gengraf are the brand names of this drug). Cyclosporine prevents rejection of the donated organ by blocking an important signal that activates T cells, which are the major cells involved in organ rejection. Most of the recent research being conducted with cyclosporine involves its use with the newer immunosuppressive medications. For example, the combination of cyclosporine with mycophenolate and steroids has led to a reduction in acute rejection by up to 10 percent over cyclosporine in combination with azathioprine and steroids in studies of kidney transplant recipients. The combination also decreases the severity of the rejection episodes that are experienced. Another area of research involves determining the best method to monitor cyclosporine blood concentrations, a necessity due to the narrow range between where cyclosporine is effective in decreasing rejection and the point where side effects increase. The article describes some of the side effects of cyclosporine and how those side effects can be prevented or reduced. Side effects can include kidney damage, problems with the nervous system, increased blood pressure, increased cholesterol levels, hair growth, and overgrowth of the gums around the teeth (gingival enlargement). The article concludes with a brief discussion of the recent approval of generic cyclosporine, including cautions for switching between drug products. 1 figure. •
Reversion of Gingival Hyperplasia in a Heart Transplant Patient Upon Interruption of Cyclosporine Therapy Source: SCD. Special Care in Dentistry. 16(1): 18-21. January-February 1996. Summary: This article presents a case of reversion of gingival hyperplasia in a heart transplant patient upon interruption of cyclosporine therapy. A heart transplant patient undergoing a combined cyclosporine and prednisone treatment was monitored during the 18 months following transplantation. Complete oral and dental examinations were performed on a set schedule; data collected included gingival hyperplasia secondary to cyclosporine use, and clinical and periodontal variables. Cyclosporine treatment was replaced by azathioprine treatment in month 10 because the patient was experiencing nephrotoxicity. Between months 9 and 18, gingival hyperplasia regressed by 26.5 percent due to reductions in the fibrous connective tissue mass, fibroblasts, and inflammatory infiltration. A control group included 13 heart transplant patients subject to equivalent conditions except for discontinuance of cyclosporine treatment. Seven of these patients had developed hyperplasia by month 9. Results provide further evidence for the causal relationship between cyclosporine therapy and gingival hyperplasia and suggest that this side-effect is reversible. 7 figures. 7 references. (AA-M).
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Elective Cyclosporine Withdrawal After Renal Transplantation: A Meta-Analysis Source: JAMA. Journal of American Medical Association. 269(3): 395-400. January 20, 1993. Summary: This article reports on a research review project designed to determine whether it is safe to electively discontinue cyclosporine therapy after renal transplantation. Using MEDLine and bibliographies from recent publications, the authors reviewed controlled trials assessing the rate of acute rejection, graft loss, and mortality after elective cyclosporine withdrawal. The authors reviewed a total of 13 randomized and 10 nonrandomized trials. Results show that although there is an increased incidence of acute rejection following elective cyclosporine withdrawal, it
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does not affect short-term graft or patient survival after renal transplantation. 3 figures. 1 table. 81 references. (AA-M). •
Dyslipidemia in Renal Transplant Recipients Treated with a Sirolimus and Cyclosporine-Based Immunosuppressive Regimen: Incidence, Risk Factors, Progression, and Prognosis Source: Transplantation. 76(2): 375-382. July 2003. Summary: This article reports on a retrospective study that compared the incidence, severity, and predisposing factors for dyslipidemia among renal (kidney) transplant patients treated for up to 6 years. The study protocol compared a cyclosporine based immunosuppressive regimen without (n = 118) or with (n = 280) ascending exposures to sirolimus. Hypercholesterolemia (elevated levels of cholesterol in the blood) was observed in 46 percent to 80 percent and hypertriglyceridemia (elevated levels of triglycerides in the blood) in 43 percent to 78 percent of sirolimus-treated patients during the first 6 posttransplantation months. The mean peak serum lipid levels among patients in the sirolimus group were significantly higher than those in the nonsirolimus group. The lipid values, which were persistently elevated during the first posttransplantation year, decreased slowly thereafter but remained significantly higher than the pretransplantation levels beyond 4 years after transplantation. The authors conclude that the dyslipidemia associated with sirolimus therapy, albeit persistent, does not seem to represent a major risk factor for the early emergence of cardiovascular complications. 3 figures. 3 tables. 30 references.
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FK-506 Shows Similar Graft Survival Rate to Cyclosporine but Fewer Side Effects: Pitt Transplant Team Source: Nephrology News and Issues. 5(11): 42-43, 46. November 1991. Summary: This article reports on a study at the University of Pittsburgh that investigated kidney graft survival rates for patients treated with either FK-506 or cyclosporine. Kidney transplant patients placed on the experimental anti-rejection drug FK-506 post-transplant were able to cut back on the use of steroids and antihypertension medication earlier than cyclosporine users, and had lower cholesterol levels. The researchers also used the drug to treat patients with nephrotic syndrome and glomerulopathy and have been able to better define the groups of patients most likely to benefit from FK-506.
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Cyclosporine in Recent Onset Type I Diabetes Mellitus: Effects on Islet B Cell Function Source: Journal of Diabetes and Its Complications. 6(2): 77-88. April-June 1992. Summary: This article reports on a study designed to confirm the immunological basis of insulin-dependent diabetes mellitus (IDDM) and to determine if immune intervention alters the course of the disease. The researchers studied the use of cyclosporine in a 1year, randomized, double-masked, placebo-controlled trial in 23 subjects enrolled within 6 weeks of diagnosis. Subjects included 12 males and 11 females, ages 9-38 years. The results demonstrate relative preservation of pancreatic islet beta cell function in response to a physiological meal stimulus in subjects treated with cyclosporine. The authors note that the small number of subjects precludes drawing any conclusion about the frequency of periods of freedom from insulin therapy in response to cyclosporine. Yet the results support the hypothesis that IDDM has an immune mechanism involved in its pathogenesis. 10 figures. 1 table. 45 references. (AA-M).
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Stability of Renal Allograft Glomerular Filtration Rate Associated with Long-Term Use of Cyclosporine A Source: Transplantation. 55(5): 1014-1017. May 1993. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (800) 638-6423; in Maryland (800) 638-4007. Summary: This article reports on a study in which the renal allograft glomerular filtration rates (GFR) were measured at 4-month intervals for up to 1 year in 43 patients treated with cyclosporine A (CsA). Study patients were divided into cohorts based on time (years) after transplantation at study entry (0-1, 1-2, 2-3, and greater than 3) and entry GFR levels (20-29, 30-39, 40-49, and greater than 50). The results are consistent with retrospective population studies of aggregate serum creatinine levels, indicating that long-term CsA use is not uniformly associated with accelerated loss of renal allograft function consequent to a progressive, toxic nephropathy. The data also suggest that neither absolute GFR level nor time after transplantation represent indications for routine dose reduction or conversion to azathioprine. 1 figure. 5 tables. 23 references.
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Long-Term Improvement in Renal Function with Sirolimus After Early Cyclosporine Withdrawal in Renal Transplant Recipients: 2-Year Results of the Rapamune Maintenance Regimen Study Source: Transplantation. 76(2): 364-370. July 2003. Summary: This article reports on a study that evaluated early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA steroid (ST) regimen. Within 48 hours after transplantation, 525 primary (90 percent) or secondary (10 percent) renal (kidney) allograft recipients with cadaveric (89 percent) or living (11 percent) donors received 2 milligrams of SRL, CsA, and ST. Those eligible (n = 430) were randomly assigned at 3 months to remain on triple drug therapy or to have CsA withdrawn. At 24 months, there were no statistically significant differences in patient survival, graft survival, acute rejection, or discontinuations. Serum creatinine level (a measure of kidney function) was significantly better in patients who had CsA withdrawn. Similarly, systolic blood pressure was lower in patients who had CsA withdrawn. High density lipoprotein (HDL) cholesterol was significantly higher in the SRL-ST group, whereas total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were not significantly different. The authors conclude that data at 2 years confirm that early CsA withdrawal followed by an SRL-ST maintenance regimen results in long-term improvement in both renal function and blood pressure, without increased risk of graft loss or late acute rejection. 4 figures. 5 tables. 16 references.
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Chronic Cyclosporine Nephropathy in Renal Transplantation Source: Transplantation Proceedings. 28(4): 2100-2103. August 1996. Summary: This article reviews chronic cyclosporine (CyA) nephropathy in the context of chronic renal allograft failure. Topics include the renal effects of CyA, chronic CyA nephropathy in renal transplantation, the pathophysiology of chronic CyA nephropathy, and management considerations. The authors question whether the toxic effects of CyA could coexist with those produced by chronic rejection or, alternatively, inadequate doses of CyA might actually contribute to progressive graft failure. 29 references.
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Neoral Use in the Renal Transplant Recipient Source: Transplantation Proceedings. 32(Supplement 3A): 10S-19S. 2000. Contact: Available from Appleton and Lange. P.O. Box 86, Congers, NY 10920-0086. (203) 406-4623. Summary: This article reviews recent developments that have contributed to improvements in clinical outcomes with cyclosporine (CyA, trade name Neoral) based immunosuppression and provides the clinician with an update on strategies and tools for the optimization of CyA immunosuppression in the renal transplant patient. The author focuses on management strategies to optimize Neoral therapy in new renal patients; management strategies to optimize Neoral therapy in the maintenance patient; and the basis of Neoral therapy as the core immunosuppressant therapy with the newer adjunct agents. The major additions to therapeutic choices in renal transplantation, such as mycophenolate mofetil, sirolimus (rapamycin), and the anti IL 2 receptor drugs have all been tested as adjunct agents with CyA as the core immunosuppressant. The author reviews the critical role of CyA in these studies and in selected studies that document CyA dosage reductions or withdrawal and the consequences to the transplant recipient. CyA formulation influences clinical outcomes, particularly with respect to acute rejection, as confirmed by several multicenter studies. The CyA microemulsion formulation reduces pharmacokinetic variability and its consequent impact on outcomes over the long term. An advanced therapeutic drug monitoring strategy can improve the effectiveness and safety of immunosuppression in both new and maintenance renal transplant patients. There are potential risks resulting from CyA withdrawal strategies. The author concludes that Neoral is an indispensable part of combination protocols in renal transplantation. 5 figures. 6 tables. 56 references.
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Alternative to Cyclosporine Scores on Reduced Toxicity Source: Medical World News. September 1991. p. 56. Summary: This brief news article provides an update on the use of FK506, a new immunosuppressive agent being used as an antirejection drug in transplantation and in treating autoimmune diseases. Investigators hope that FK506 will prove either more efficient or less toxic than other immunosuppressants, including cyclosporine. Other research efforts are testing the use of FK506 in treating insulin-dependent diabetes mellitus and less-common autoimmune diseases, including nephrotic syndrome, uveitis, and pyoderma gangrenosum. A majority of patients treated with the new drug had some toxicity, primarily increased creatinine levels that normalized when the dosages were reduced. 1 figure.
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Study Finds IV Cyclosporine To Be Effective in Steroid-Resistant Ulcerative Colitis Source: IBD Chronicle. 1(1): 1-2. May 1993. Contact: Available from Medical Information Services P.O. Box 1384, Ansonia Station, New York, NY 10023. Summary: This newsletter article reports on conferences and research related to inflammatory bowel disease. The article describes a study that found intravenous (IV) cyclosporine effective in steroid-resistant ulcerative colitis. In a double-blind study of 16 patients who had failed 10 days of therapy with parenteral steroids, 14 (88 percent) of those given cyclosporine (4 mg/kg/day) responded favorably, with a mean response time of 7.1 days. The intravenous route was chosen because oral cyclosporine is associated with erratic absorption and erratic blood levels in patients with bowel disease
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and diarrhea. The final section of the article explains how this research study confirms an earlier, pilot study of intravenous cyclosporine. •
Human Papillomavirus in a Patient with Severe Gingival Overgrowth Associated with Cyclosporine Therapy: A Case Report Source: Journal of Periodontology. 67(5): 528-531. May 1996. Summary: This report relates a case of severe gingival overgrowth in a 31-year-old female who had received cyclosporine therapy in conjunction with a kidney transplant. Because of the severe gingival overgrowth, the authors analyzed a biopsy, which was positive for human papillomavirus. The case was treated and followed for 18 months. Several reports indicate that local factors and inflammation influence the severity of the cyclosporine-induced gingival overgrowth. Immunosuppressive therapy, notably in renal allograft recipients, has also been associated with high rates of extensive human papillomavirus infections. The authors caution physicians to use the lowest dose of immunosuppressant consistent with the desired clinical result. They also recommend the use of biopsy in patients undergoing cyclosporine therapy and with severe gingival overgrowth in order to help determine appropriate diagnosis and treatment. 6 figures. 23 references. (AA-M).
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Use of Cytotoxic Agents and Cyclosporine in the Treatment of Autoimmune Disease. Part 2: Inflammatory Bowel Disease, Systemic Vasculitis, and Therapeutic Toxicity Source: Annals of Internal Medicine. 129(1): 49-58. July 1, 1998. Summary: When cytotoxic (cell-damaging) agents were introduced, their ability to disrupt nucleic acid and protein synthesis led to their effective use for the treatment of neoplastic disease (cancer). It then became apparent that these agents also suppress the immune system. This usually unwelcome effect was subsequently studied and beneficially directed toward treating non-neoplastic diseases in which autoimmune mechanisms play a role. This article discusses the use of cytotoxic agents and cyclosporine in the treatment of inflammatory bowel disease (IBD) and systemic vasculitis, and reviews the toxic effects of these agents. The authors caution that because these medications can cause treatment-induced illness or even death, it is imperative to weigh the benefits and risks of cytotoxic therapy when treating a non-neoplastic disease. The authors review research studies that investigated the use of these drugs. Drugs used for IBD include azathioprine and 6-mercaptopurine, methotrexate, and cyclosporine. These drugs are frequently used in combination with other agents and require careful monitoring. The authors stress that the optimal use of various drug combinations requires not only a knowledge of appropriate indications and dosage but also a thorough assessment of patient expectations and quality of life, a careful weighing of the various risks of medical and surgical therapies, the judicious use of other supportive measures, and extensive patient education. The section on toxicity discusses cyclophosphamide, chlorambucil, methotrexate, azathioprine, 6-mercaptopurine, and cyclosporine. The authors caution that infection is still an important cause of illness and death that is largely related to the nonspecific actions of these agents on the immune response. 3 tables. 75 references.
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Use of Cytotoxic Agents and Cyclosporine in the Treatment of Autoimmune Disease. Part 1: Rheumatologic and Renal Diseases Source: Annals of Internal Medicine. 128(12, Part 1): 1021-1028. June 15, 1998.
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Contact: Available from American College of Physicians. American Society of Internal Medicine. 190 North Independence Mall West, Philadelphia, PA 19106-1572. Website: www.acponline.org. Summary: When cytotoxic agents were initially introduced, their ability to disrupt nucleic acid and protein synthesis led to their effective use for the treatment of neoplastic disease (including cancer). During the course of this use, however, it became apparent that these agents also suppress the immune system. This usually unwelcome effect was subsequently studied and beneficially directed toward the treatment of nonneoplastic diseases in which autoimmune mechanisms were considered important to pathogenesis. As a result of these investigations, cytotoxic agents and, more recently, cyclosporine have emerged to become an important part of the therapeutic regimen for many autoimmune diseases. Nonetheless, these medications may still cause treatment induced illness or even death. This article is the first in a two part Clinical Staff Conference that reviews data on the efficacy and toxicity of cytotoxic drugs and cyclosporine in selected autoimmune diseases. This article examines how these agents have been used to treat rheumatologic and renal diseases. Renal diseases discussed include minimal change nephropathy (lipoid nephrosis, Nil disease), Goodpasture disease, renal vasculitis, membranous nephropathy, and lupus nephritis. 2 tables. 70 references. •
Cyclosporine in the Treatment of Idiopathic Nephrosis (editorial review) Source: Journal of the American Society of Nephrology. 5(4): 1049-1056. October 1994. Contact: Available from Williams and Wilkins. 428 East Preston Street, Baltimore, MD 21202-3993. (800) 638-6423. Summary: Within the past decade, there have been numerous reports on the use of cyclosporine in idiopathic nephrosis. In this review article, the results of both uncontrolled and controlled studies of the therapeutic effects of cyclosporine in steroidsensitive/dependent idiopathic nephrosis are analyzed. Cyclosporine is efficient in up to 80 percent of these patients; most patients, however, relapse when the drug is withdrawn, thus necessitating prolonged treatments. The main worrisome side effect of cyclosporine is chronic nephrotoxicity. Followup studies including pretreatment and posttreatment renal biopsies show a lack of correlation between structural damage and renal function, suggesting that a histologic examination of the renal parenchyma is the only reliable way of evaluating chronic cyclosporine nephrotoxicity. 2 tables. 71 references.
Federally Funded Research on Cyclosporine The U.S. Government supports a variety of research studies relating to cyclosporine. 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.
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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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 cyclosporine. 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 cyclosporine. The following is typical of the type of information found when searching the CRISP database for cyclosporine: •
Project Title: A NEW CLASS OF DRUG CARRIERS FOR TREATMENT OF MS Principal Investigator & Institution: Kosak, Kenneth M.; Kk Biomed 825 N 300 W, Ste C320 Salt Lake City, Ut 84120 Timing: Fiscal Year 2002; Project Start 15-APR-2001; Project End 31-MAR-2004 Summary: (adapted from applicant's abstract): A patented, new class of drug carriers comprised of polymerized cyclodextrin (polyCD) will be synthesized and characterized for the treatment of MS. The carrier will provide a macromolecular delivery system through entrapment of the drug without conjugation. This can reduce side effects and increase bioavailability of drug. The carrier is designed to biodegrade arid release drug within the cell. The expected advantages are: (1) It will allow the use of drugs designed solely for efficacy without conjugation requirements. (2) It will allow the use of drugs designed solely for efficacy without regard for solubility. (3) Unconjugated drugs can be delivered as macromolecules and released within the T cell. (4) Drugs can be targeted by coupling the carrier to biorecognition molecules. These are advantages not currently available for treatment of MS. Two carriers will be synthesized and compared for efficacy. One will have mitoxantrone and the other cyclosporin an entrapped within it. The drug-loaded carriers will be purified by gel chromatography. The carrying capacity, stability, release activity, and T cell inhibition in vitro of each drug-loaded carrier will be characterized. PROPOSED COMMERCIAL APPLICATION: Polymerized cyclodextrin drug carriers can expand long-term treatment options for MS. Other markets include cancer treatment as well as treatment for many infectious diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AAV TYPE 1 AND 5 VECTORS FOR GENE DELIVERY IN THE KIDNEY Principal Investigator & Institution: Agarwal, Anupam; Associate Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2006 Summary: (provided by applicant): The goals of this pilot proposal (PA-01-127, Pilot and Feasibility Program related to the Kidney) are to explore the ability of the different serotypes of recombinant adeno-associated viral (rAAV) vectors to enhance the efficacy of gene delivery to the kidney, particularly the intra-renal vasculature. While kidney transplantation remains the treatment of choice for end stage renal disease, chronic vascular injury secondary to transplant rejection, cyclosporine toxicity, hypertension and recurrence of disease all contribute to graft loss, necessitating return to dialysis or re-transplantation. Specific approaches that target "protective" genes into the kidney and more importantly the intra-renal vasculature would be highly beneficial in prolonging graft survival. However, most of the previous studies in this area of investigation have demonstrated limited success due to the transient nature of transgene expression and the development of adverse host immune responses. The hypothesis of this application
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is that the efficacy of gene delivery to the vasculature and the kidney is enhanced by the use of recombinant adeno-associated viral (rAA V) serotype 1 and 5 vectors. This hypothesis will be tested by (1) exploring the efficacy of gene delivery to the vasculature and the kidney using rAAV serotype 1 and 5 vectors in comparison to rAAV type 2, the prototypic serotype used in most gene therapy studies to date, and (2) evaluating the role of a protective gene (heme oxygenase-1, HO-1) in chronic transplant rejection using the ideal rAAV serotype. In preliminary studies, we have observed that in comparison to rAAV2, rAAV1 and rAAV5 demonstrate markedly higher transduction efficiencies at lower levels of multiplicity of infection in human vascular endothelial and smooth muscle cells. Initial studies will be performed using reporter genes, followed by transduction using rAAV vectors containing a protective gene, HO-1. The effects of rAAV-mediated HO-1 gene delivery will be evaluated in a rat aortic allograft model of chronic vascular rejection, followed by studies in a rat model of renal transplantation. These studies have important therapeutic implications in limiting vascular injury that occurs not only in renal transplantation but also in native kidney diseases secondary to diabetes and other renal diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AZOLE-RESISTANT CANDIDA IN MARROW TRANSPLANT PATIENTS Principal Investigator & Institution: Marr, Kieren A.; Assistant Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOMARKER OF NEUROPROTECTANT EFFICACY Principal Investigator & Institution: Gabbita, Somasundar P.; Phase 2 Discovery, Inc. 3130 Highland Ave, 3Rd Fl Cincinnati, Oh 452192374 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JAN-2003 Summary: (provided by applicant): The objective of this Phase I feasibility study is to develop a sensitive biomarker for quantifying neuroprotectant drug efficacy in a rat model of traumatic brain injury (TBI). Currently, no widely accepted biochemical marker that quantifies neuronal injury in rat TBI models is available. We have previously shown that during axonal degeneration in humans, the brain cytoskeletal protein MAP-tau is cleaved. Our laboratory has developed a sensitive ELISA that specifically measures cleaved MAP-tau (C-tau) in human CSF following head injury. Using this ELISA, we have shown that brain C-tau levels increase in rats after sustaining cortical impact-induced TBI. By measuring lesion volumes, Scheff et al have previously demonstrated that cyclosporin A administration following TBI significantly ameliorates cortical damage in the cortical impact rat model. We hypothesize that C-tau is a reliable biomarker of TBI-induced neuronal injury in rats. We will test this hypothesis by determining if C-tau levels demonstrate a time-dependent increase after TBI and if a known neuroprotectant intervention, cyclosporin A, exerts expected effects on C-tau levels. Our Specific Aims are: Specific Aim 1: Determine whether TBI results in a timedependent increase in brain levels of C-tau. C-tau levels will be quantified by ELISA in TBI-affected and control brain regions and also in sham operated animals. Specific Aim 2: Determine if C-tau levels reliably quantify the effect of a known neuroprotectant intervention on TBI. The neuroprotective effect of cyclosporin A will be examined by
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administering either vehicle or cyclosporin A. C-tau levels will be quantified by ELISA at the time of maximum TBI-induced C-tau elevation determined in Specific Aim 1. Ctau levels will be compared as a function of neuroprotectant treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BLOOD AND MARROW TRANSPLANT CLINICAL RESEARCH NETWORK Principal Investigator & Institution: Appelbaum, Frederick R.; Director; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 05-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The objective of this grant application is to become one of the core clinical centers in the proposed Blood and Marrow Transplant Clinical Research Network. There are a number of features of the Fred Hutchinson Cancer Research Center (FECRC) Marrow Transplant Program that make it an attractive candidate for inclusion in the Network. First, we have maintained a large, stable transplant program for several decades transplanting between 450 and 550 patients per year with excellent clinical outcomes. Thus, we have access to a relatively large number of patients. Second, our group includes a large number of investigators focused on the general topic of transplantation. This group is supported by seven P0ls and 23 R0ls, and last year published 142 papers on the topic. Thus, our inclusion will help assure a source of possible studies for future testing in the Transplant Network. Third, our program is deeply committed to cooperative clinical research. For example, last year 231 of 451 patients transplanted in Seattle (51%) were entered onto multi-institutional trials. Finally, the FHCRC provides an outstanding environment in which to conduct the sorts of studies described, with state-of-the-art clinical and laboratory facilities. The proposed Blood and Marrow Transplant Clinical Research Network has the potential to facilitate studies leading to substantial improvements in the outcome of transplantation. Inclusion of the Fred Hutchinson Cancer Research Center in this network should help it achieve this goal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BROAD SPECTRUM MDR MODULATION IN AML Principal Investigator & Institution: Baer, Maria R.; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2003; Project Start 10-FEB-2003; Project End 31-JAN-2005 Summary: (provided by applicant): Multidrug resistance (MDR) is a major cause of treatment failure in acute myeloid leukemia (AML). MDR is frequently associated with energy-dependent drug efflux, and efflux may be blocked by competitive inhibition with non-cytotoxic substrates, termed MDR modulators. Pharmacological modulation of MDRis effective in laboratory models, but clinical application has been disappointing. Trials of pharmacological modulation of MDR in AML have targeted P-glycoprotein (Pgp), the best-characterized MDR-associated transport protein, but additional transport proteins, including muitidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP), are also likely to contribute to the clinical MDR phenotype. Pharmacological MDR modulation also promotes apoptosis independently of drug efflux, but this effect remains largely unexplored. The overall goal of this proposal is to develop clinical MDR modulation approaches in AML which take into account both the multiple efflux proteins expressed in AML cells and the drug efflux-independent effects of modulators. This requires determining the relevance of expression and function of
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MRP-1 and BCRP, in addition to Pgp, in AML and the spectrum of activity of available clinically applicable modulators. The studies will utilize the existing Cancer and Leukemia Group B (CALGB) repository of pre-treatment samples from patients > 60 years old with AML occurring de novo and following antecedent myelodysplastic syndromes, a population with a high incidence of clinical MDR, treated on a single protocol, CALGB9720. The specific aims are: 1. To determine the incidence and clinical significance of Pgp, MRP-1 and BCRP expression and function in an AML patient population with a high incidence of clinical drug resistance; 2. To compare the effects of diverse available clinically applicable modulators, including PSC-833, cyclosporine A, Biricodar (VX-710), VX-853, the fumitremorgin C analogue KO143, and the novel taxane-derived agents IDN5109 and tRA96023, on drug retention in AML cells that have been characterized with respect to Pgp, MRP-1 and BCRP expression and function; 3. To compare the drug transport-independent effects of PSC-833, cyclosporineA, biricodar, VX-853, KO143, IDN5109 and tRA96023, onAML cell survival, measured by the apoptotic response. The study is expected to provide essential information for the design of future clinical trials of broad-spectrum MDR modulation in AML and other malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: C. NEOFORMANS INFECTION IN ORGAN TRANSPLANT RECIPIENTS Principal Investigator & Institution: Singh, Nina; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): Organ transplant recipients have emerged as a leading and growing group of immunocompromised patients at risk for cryptococcosis. The immunosuppressive agents employed in transplant recipients have antifungal in vitro against C. neoformans. Existing data suggest that the spectrum, type, or presentation of cryptococcosis might be altered by the antifungal effects of primary immunosuppressive drugs [Husain 00]. Whether cryptococcal isolates in transplant recipients represent immunosuppressive drug resistant mutants is not known. The impact of gene mutations conferring immunosuppressive drug resistance, serotype, or other virulence factors of C. neoformans on tissue tropism and outcome in transplant recipients has not been elucidated. Finally, it is not known whether C. neoformans in transplant recipient represents reactivation of a latent infection or a new acquisition. The primary objectives of the study are: To determine if there are differences in clinical manifestations and outcome of cryptococcosis in transplant recipients receiving tacrolimus, cyclosporine, or rapamycin, and to assess whether cerebrospinal fluid levels of immunosuppressive agents correlate with central nervous system infection. 2.To determine if C. neoformans isolates in transplant recipients represent breakthrough infections with immunosuppressive agent resistant mutants and to compare the clinical manifestations, response to therapy, and outcome of mutant versus non-mutant cryptococcal isolates. 3. To determine whether the following characteristics of C. neoformans correlate with clinical manifestations and outcome: capsule formation, serotype, melanin synthesis, thermal susceptibility, urease, and phospholipase production. 4. To determine if C. neoformans represents reactivation of a latently harbored infection or a new acquisition and to discern if certain Western blot band patterns are more likely to reactivate than others. This study merges the molecular strategy of investigating the infecting strains of the fungus with clinical outcome. Knowledge regarding mutations has not only pathophysiologic, but potentially
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profound therapeutic, implications for the management of C. neoformans. The virulence factors identified may serve as molecular targets for novel therapeutic modalities. Finally, the data regarding reactivation or primary infection has implications relevant for the prevention of C. neoformans infection in transplant recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CALCINEURIN INHIBITION: LUNG REPERFUSION INJURY Principal Investigator & Institution: Mulligan, Michael S.; Associate Professor of Surgery; Surgery; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Approximately 25 percent of lung transplant recipients and 15 percent of patients treated for chronic pulmonary embolic disease will develop post- operative lung ischemia reperfusion injury (IRI). Treatment is conservative and this problem continues to account for significant morbidity and mortality. Requirements for several proinflammatory mediators have been characterized. However, antagonism of a single mediator rarely produces dramatic protection. Clinical treatment with directed antibodies is likely therefore to be expensive, impractical and marginally effective. More effective interventions would block several mediators at once, potentially by acting at the transcriptional level. Inhibition of calcineurin mediated activation of NF-kB can reduce expression of a variety of proinflammatory mediators. Since cyclosporin (CSA) and tacrolimus (TAC) are calcineurin inhibitors that are already available clinically, it would be desirable to examine their effects in experimental lung IRI. CSA and TAC reduce IRI in other tissues and can consistently reduce NF-kB activation both in vitro and in vivo. In preliminary studies, we have reliably established an animal model of lung IRI and shown that NF-kB activation follows lung IRI and that activation is associated with the appearance of a number of inflammatory cytokines and chemokines. Our hypothesis, therefore, is that calcineurin mediates NF-kB activation with lung IRI which results in transcriptional upregulation of critical pro-inflammatory mediators and the ultimate development of tissue injury. We will address this hypothesis systematically beginning with interventional studies in vivo and proceed to mechanistic analysis both in vivo and in vitro. We will pursue three related aims: Aim 1: To determine whether calcineurin inhibition is protective against the development of lung IRI. We will accomplish this using our animal model. Aim 2: To determine whether calcineurin inhibition results in transcriptional down-regulation of mediators involved in lung IRI through an NFkBdependent mechanism. We will measure protection offered by CSA/TAC and assess associated changes in cytokine production and NFkB in nuclear protein. Aim 3: To define the cellular sources of critical mediators of lung IRI and their dependence on calcineurin driven transcription and cell-cell interactions. We will accomplish this by culturing alveolar macrophages , type II pneumocytes and pulmonary artery endothelial cells (individually and in combination) and subject them to hypoxia and reoxygenation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PATHWAYS
CARDIAC
HYPERTROPHIC
INTRACELLULAR
SIGNALING
Principal Investigator & Institution: Molkentin, Jeffery D.; Associate Professor; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2002; Project Start 09-AUG-1999; Project End 31-JUL-2003
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Summary: (the applicant's description verbatim): In response to various forms of heart disease the myocardium undergoes hypertrophic growth to compensate for a loss in cardiac output. While this response is initially beneficial, it eventually leads to pathology and heart failure. Despite years of investigation, the molecular pathways that result in cardiac hypertrophy remain largely unknown. The transcription factor GATA4 has been shown to play an important role in regulating the hypertrophic response at the transcriptional level (Herzig, et al., 1997; Hasegawa, et al., 1997). To investigate the molecular mechanisms whereby GATA4 regulates the hypertrophic response, a yeast 2hybrid screen was performed which identified the transcription factor NF-AT3 (nuclear factor of activated T-cells). Studies in T-cells have demonstrated that NF-AT factors are sequestered in the cytoplasm until activated by the phosphatase calcineurin in response to stress or stimuli that increase intracellular calcium. Our recent results demonstrate that the myocardium also utilizes this stress-response signaling pathway. Transgenic mice expressing a constitutively active form of calcineurin or a constitutively nuclear NF-AT3 protein in the heart develop substantial hypertrophy resulting in heart failure. Furthermore, inhibition of endogenous calcineurin activity with the drug cyclosporin A prevents angiotensin II and adrenergic-mediated hypertrophy by effecting the transcription factor NF-AT3 and its ability to activate hypertrophic response genes. The goals of this study are: 1) To determine the extent to which calcineurin-mediated signaling is necessary for cardiac hypertrophy in multiple animal models using pharmacologic inhibitors. 2) To genetically inhibit calcineurin activity specifically in the hearts of transgenic mice. 3) To determine the down-stream consequences of calcineurin signaling in the myocardium and its effect on PKC and MAPK signaling pathways. Both transgenic and in vitro culture systems are proposed to elucidate a potentially novel cardiac response pathways. This novel pathways is predicted to regulate cardiac hypertrophy through any stimulus that increases intracellular calcium concentration (mechanical load, stretch, angiotensin II, etc.). The potential ramifications of the successful elucidation of this pathway are extensive given that cyclosporin A and FK506 are potent inhibitors of calcineurin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMICAL GENOMICS WITH NATURAL PRODUCTS ANALOG LIBRARIES Principal Investigator & Institution: Belshaw, Peter J.; Professor; Chemistry; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): The overall goals of the proposed research is to identify small molecule regulators of critical cellular processes in high-throughput screens of synthetic chemical libraries and to develop new methods to rapidly identify the cellular targets of active compounds from phenotypic screens. Chemical genomic approaches to identify the cellular functions of proteins have recently be shown to have great promise as a new tool for functional genomics and for the identification of new lead compounds and cellular targets for drug development. The proposed research aims to address two current deficiencies in the Chemical Genomic approach: modulating protein-protein interactions as targets of small molecules; identifying the cellular targets of bioactive small molecules identified in phenotype-directed screens. The specific aims of the proposed research are (1) Develop synthetic chemistry to achieve a versatile highyield, convergent solid-phase synthesis of the streptogramin B analogs. (2) Devise novel linkers for attachment of library members to solid phase synthesis resins such that linker cleavage generates an electrophilic reactive site (Michael acceptor) on each member of
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the library. (3) Synthesis and evaluation of a "target identification probe" (TIP) reagent to enable the rapid identification of the cellular targets of bioactive compounds from combinatorial libraries. (4) Identification of biologically active library members and determine the cellular targets of bioactive library members using target identification probe reagents. Our integrated approach to chemical genomics includes new methods for the synthesis of electrophilic libraries, novel biological assays and a novel method for target identification as a platform for biological discovery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIABETIC NEPHROPATHY Principal Investigator & Institution: Mauer, Michael S.; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: These continuation studies focus on large pancreas (PTx) and kidney (KTx) transplant populations of type 1 diabetic (D) patients (pts) in order to better understand diabetic nephropathy (DN), the leading cause of renal failure. Objectives are: (a) to determine whether PTx can more readily arrest or reverse the early vs. the more established lesions of DN; (b) to continue studies of renal structural-functional relationships in DN, with emphasis on the multifaceted pathologic DN lesions, including glomerular, vascular, interstitial lesions and glomerular-tubular connections; (c) to continue studies of DN natural history and the role of renal biopsy in predicting outcome; (d) to quantitate and understand the basis of atubular glomeruli (AG) in DN; (e) to elucidate glomerular (glom) epithelial cell abnormalities in DN; (f) to study the glom extracellular matrix abnormalities of DN; (g) to study the recurrence of DN in the KTx; (h) to study the molecular/genetic basis of DN and develop cellular markers of DN risk; (i) to determine the long-term (10-15 yr) structural consequences of cyclosporine (CSA) on the 'native kidneys of PTx recipients; and (j) to determine the shorter-term (5 yr) consequences of Prograf on the native kidneys of PTx recipients and compare these with those seen after 5 years of CSA treatment. Together, these studies will help to elucidate the pathogenesis and natural history of DN, unravel some of the molecular and genetic aspects of this disease, describe the dynamics of DN reversal in PTx pts, and recurrence in KTx pts and expand our knowledge of the nephrotoxic effects of calcinosis inhibitors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DIFFERENTIAL CYTOKINE SECRETION BY BASOPHILS Principal Investigator & Institution: Schroeder, John T.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2003 Summary: (Adapted from Investigator's abstract): This application examines the ability of human basophils to synthesize IL-4 and IL-13 utilizing a variety of agonists and contrasts conditions that modulate (augment or inhibit) production of each. The initial aim, and the one examined in greatest detail, examines the effects upon each cytokine by agonists that stimulate c-AMP, steroids, cyclosporin, FK506, and tyrosine kinase inhibitors. IL-13 protein and mRNA production will be examined, the former utilizing ultrapure basophil preparations and stimuli such as IL-3, ionomycin, and PMA. Flow cytometry will be used to determine intracellular cytokine expression. Primers acting through PKC such as IL-1b and TNFa will be tested as well as non-IgE dependent agonists such as C5a or FMLP, and IL-3-like growth factors such as GMCSF and IL-5.
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Cyclosporine
Perturbation of CD40L or CD32 (IgG receptor) will be tested for effects on IL-4/IL-13 secretion. The cells of atopic versus non-atopic subjects will be compared and correlation of levels of production of each cytokine with atopic symptoms sought. The kinetics of mRNA production versus protein accumulation will be compared, since preliminary data indicate that the synthesis of IL-4 precedes that of IL-13 but rates of up or down regulation at the mRNA level are unknown. Subpopulations of basophils secreting each cytokine will be sought or simultaneous or sequential production of IL-4 and/or IL-13 by single cells demonstrated. They will utilize flow cytometry with three color fluorescence, and monensin to inhibit protein secretion. Experiments in which IL-4 or IL-13 are added prior to stimulation will test whether each one can regulate the other. Drugs that inhibit apoptosis in B-cells by preventing NFkB activation will be tested for effects on IL-4 or IL-13 production as well as selected tyrosine kinase inhibitors. Aim 2 attempts to differentiate PKC isozymes in the regulation of IL-4 and IL-13 since phorbol esters examined thus far inhibit IL-4 synthesis, but seem to stimulate production of IL13. The effect of depletion of PKC by prolonged PMA stimulation on IL-3 and IgEstimulated IL-13 secretion will be examined. Calcium dependent versus calcium independent PKC inhibitors will be employed seeking differential effects. RT-PCR will be used for qualitative and semi-quantitative assessment of IL-4 and IL-13 mRNA levels. Finally, a recombinant human HRF will be tested for its ability to stimulate IL-13 secretion in IgE(+) versus IgE(-) cell donors. Direct stimulation and priming of other secretogogues by HRF will be examined. A variety of cytokine primers will be tested with HRF as agonist and IL-4 versus IL-13 secretion compared. The time of priming preincubation will be varied and any inhibitors of secretion sought. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOSING & SAFETY TRIALS USING CSA IN SEVERE HEAD INJURY Principal Investigator & Institution: Young, a B.; Johnston-Wright Chair of Surgery; Surgery; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2004 Summary: Head injury is a complex disease where the primary injury initiates a chemical cascade of central mediator release leading to secondary insults within the central nervous system and systemically. Morbidity and mortality rates remain high despite advances in guidelines for clinical management. Several potential mechanisms of secondary injury have been identified and therapeutic strategies for intervention have been tested in animal and human trials. Despite preliminary evidence of efficacy in small clinical trials, no drug has shown significant benefit when tested in larger well designed randomized investigations. Lack of pharmacokinetic data to guide dosing for specific pharmacodynamic endpoints is one of several possible reasons for failure of investigational drugs to demonstrate benefit. Recent evidence from animal research suggests a protective effect of Cyclosporin A (CsA) in neural trauma. CsA given to mice and rats following severe cortical contusion reduced neuronal injury by approximately 50%. CsA is a difficult drug to model and predict response. Our preliminary data from two TBI patients demonstrates a marked variability in serum trough concentrations of CsA. The systemic effects of head injury and the requirement for adequate delivery of drug to the injured brain mandate preliminary dose finding studies prior to progressing into clinical trials. In this pilot clinical trial, we will systematically define CsA pharmacokinetic and pharmacodynamic endpoints in a homogenous population of patients with traumatic brain injury. We will measure serum and cerebrospinal fluid (CSF) concentrations of drug and surrogate biochemical markers of secondary injury to identify potential pharmacodynamic endpoints useful in designing optimal drug dosing
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strategies. This dose-finding proposal will characterize the pharmacokinetic profile of CsA and provide preliminary safety data in patients with TBI. Information from this pilot study will be used to establish a dosing strategy for a future Phase 11 prospective randomized trial. We will test the hypothesis that clinically approved doses of CsA can be safely administered to patients with TBI and achieve measurable concentrations in the CSF and serum. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EGR-2/3 AND NAB2 IN T CELL ANERGY AND ACTIVATION Principal Investigator & Institution: Powell, Jonathan D.; Oncology Center; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): The ultimate outcome of T cell receptor engagement (TCR) is dictated not by the antigen but rather by the context in which the antigen is encountered. T cells that recognize antigen presented by activated APCs in the context of costimulation are activated, while T cells that recognize antigen presented by resting APCs are rendered tolerant. Our lab is interested in dissecting the pathways involved in TCR-induced tolerance vs. activation. This proposal will focus on the role of the transcription factors Egr-2 and Egr-3 in inducing T cell anergy as well as the co repressor/coactivator molecule NAB2 in facilitating TCR induced activation. Using T cell clones we will examine the regulation of Egr-2 and Egr-3 in anergic and non-anergic cells. We will inducibly over express Egr-2 and Egr-3 in order to demonstrate that these factors are the cyclosporin sensitive component of T cell anergy. In addition, we will utilize T cells from Egr-2 and Egr-3 knockout mice in order to determine the affect of these factors on T cell activation and tolerance induction. In order to determine the effect of these factors in vivo we will adoptively transfer TCR transgenic T cells from Egr knock out mice into animals which have a tumor expressing cognate antigen. Using this system we will assess the abilities of such cells to eradicate tumor as well as their susceptibility to tumor induced tolerance. NAB2, was originally discovered as a protein which binds to and can either co-repress or co-activate Egr mediated transcription. Indeed, we have generated preliminary data that NAB2 is upregulated by TCR engagement and that the over-expression of NAB2 leads to an increase in IL-2 promoter mediated transcription. In this proposal we will characterize the regulation of NAB2 in T cells as well as its effects on T cell activation and the induction of tolerance. Furthermore, we will assess the ability of T cells which over express NAB2 to eradicate tumor in vivo. Understanding the discreet pathways that lead to activation and tolerance should provide insight into devising specific clinical interventions. In the case of cancer immunotherapy, the goal is to inhibit tumor induced tolerance while at the same time enhance tumor specific T cell activation. On the other hand, in transplantation and autoimmunity, the objective is to inhibit T cell activation while at the same time promote TCR induced tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE MODIFIED T-CELLS FOR ENGRAFTMENT AND GVHD CONTROL Principal Investigator & Institution: Georges, George E.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-JUL-2004
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Cyclosporine
Summary: Dr. George Georges is strongly committed to a research career as a clinician scientist. His immediate career plans are to continue his research project under the mentorship of Dr. Rainer Storb at the Fred Hutchinson Cancer Research Center (FHCRC) to further develop the experience and skills using the dog model of transplantation to study T-cells and the control of graft versus host disease (GVHD). His long term career goals are to become an independent investigator in transplantation biology and carry out translational studies that will lead to improvements in the treatment of cancer and other diseases with stem cell transplantation. The FHCRC provides an outstanding environment for development of Dr. Georges' research career. The goal of this research project is to develop ex vivo expanded alloreactive cytotoxic Tlymphocytes (CTL) that can safely enhance engraftment of donor hematopoietic stem cells. The hypothesis to be tested is that addback of recipient-specific CTL can enhance engraftment without severe GVHD. The ex vivo transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene into CTL will make T-cells susceptible to elimination with the antiviral drug ganciclovir once engraftment is established but before onset of GVHD. This will be tested in two transplant models. The first is in major histocompatibility complex (MHC) haploidentical mismatched recipients of T-cell depleted stem cells following 920 cGy total body irradiation (TBI). We will ask if donor CTL can prevent graft rejection. After engraftment we will treat GVHD with ganciclovir. If successful, this could translate into universal donor availability for patients requiring hematopoietic stem cell transplantation. The second model is with MHC-matched littermates using a nonmyeloablative regimen. Following 200 cGy TBI before and 5 weeks of immunosuppression with mycophenolate mofetil and cyclosporine after marrow transplant, stable mixed hematopoietic donor-host chimerism is established. We will test if donor CTL specific for host minor histocompatibility antigens can convert mixed to complete donor chimerism. If successful this would make MHC-matched stem cell transplantation less toxic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC AND HORMONAL REGULATION OF HUMAN CYP3A Principal Investigator & Institution: Thummel, Kenneth E.; Professor; Pharmaceutics; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): The overall objective of this grant proposal is to identify the genetic and hormonal factors that define inter-individual differences in the expression of CYP3A in humans. We have directed our efforts to the study of CYP3A because of the central role that it has in the metabolic elimination of numerous drugs, including several with a narrow range of efficacious and nontoxic blood concentrations. We will test the hypothesis that "The steady-state level of CYP3A4 in the human small intestine is controlled primarily by 1,25-dihydroxy vitamin D3 signaling through the vitamin D receptor and the CYP3A4 PXR response element," with the following Specific Aims: Aim 1. Determine in healthy adults whether intestinal CYP3A4 phenotype covaries with CYP24 phenotype, a reporter for intestinal VDR-mediated transcriptional activation. We will also determine whether variability in intestinal CYP3A4 content is regulated by intestinal VDR mRNA content and plasma 1,25-D3 level. Aim 2. Demonstrate that acute 1,25-D3 treatment increases intestinal CYP3A23 transcription in the rat, and that 1,25-D3 replacement therapy can induce CYP3A4 transcription activity in patients with end stage renal disease. We will also test the hypothesis that "Inheritance of an A6981G mutation within intron-3 of the CYP3A5 gene controls the expression of hepatic and intestinal CYP3A5, and influence the oral bioavailability of
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some CYP3A drug substrates" with the following Specific Aims: Aim 3. Characterize and compare the CYP3A4- and CYP3A5-dependent intrinsic metabolic clearance for 10 different drugs using a heterologous expression system and CYP3A-phenotyped human liver and intestinal microsomes. In addition, we will determine in healthy Caucasian and African-American adults whether the CYP3A5*1 genotype successfully predicts, on average, a higher midazolam clearances than that for subjects with the homozygous CYP3A5*3 genotype. We will also demonstrate that for African-Americans, there is a CYP3A5*1 gene-dose effect for the accumulation of properly spliced mRNA and CYP3A5 protein in duodenal biopsy tissue and for in vivo midazolam clearance. Aim 4. Determine whether variability in the in vivo oral clearance of cyclosporine is determined, in part, by the CYP3A5 genotype. If the proposed hypotheses are validated, it may become possible to develop simple genotyping and phenotyping tests for individualizing therapy with narrow therapeutic index drugs, such as cyclosporine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENOMIC PROFILING OF CHILDHOOD DE NOVO AND RELAPSED AML Principal Investigator & Institution: Dahl, Gary V.; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (Provided by applicant): Acute myelogenous leukemia (AML) accounts for approximately 20 percent of cases of childhood leukemias. In contrast to lymphoblastic leukemias, the cure rate for childhood AML is still less than 50 percent. We propose to apply the powerful new technology of gene expression profiling to AML specimens from more than 600 children with de novo AML treated on the Pediatric Oncology Group (POG) Study #9421. Our hypothesis is that global gene expression profiles will provide new insights into genetic determinants of response to therapy and clinical behavior of childhood AML. The specific aims of this proposal are: (1) Gene expression profiling of childhood de novo AML specimens from patients enrolled in POG Study #9421. A total of 621 banked specimens are available. The microarrays for this project will contain 48,000 human genes. The profiles of gene expression of childhood AML will be compared to our existing databases including adult AML, lymphomas, and several types of carcinomas. In addition, gene expression clusters will be analyzed with reference to histopathological classification and cytogenetic abnormalities. It is likely that this approach will reveal clusters of genes which will re-define subclasses of childhood AML. (2) Prognostic significance of genes involved in drug resistance and apoptotic pathways. Modulation of drug resistance by high dose cyclosporine and high dose cytarabine were the two therapeutic questions addressed by #9421, resulting in 4 study cohorts. Although early in follow-up, there is a trend to increased survival with high dose cyclosporine. Drug transporters and other genes known to be involved in therapeutic responses will be examined for prognostic importance in each treatment cohort. We hypothesize that MDR1 will lose prognostic importance in the cyclosporine cohorts. The relationship of individual and clustered gene expression to complete remission, duration of remission, and survival will be assessed for the entire set of genes on the arrays. (3) Gene expression profiling of specimens from patients with relapsed pediatric AML enrolled in POG #9421 and #9720. Serial specimens at diagnosis and relapse are available in at least 39 cases, providing a great opportunity to identify genes which may be selected or induced by therapy. The outcome of these studies may guide the next generation of biologic and therapeutic studies in childhood AML, and make a
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significant contribution to the diagnosis, prognosis and development of rational therapeutics in this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HERB-OPIOID INTERACTIONS Principal Investigator & Institution: Shen, Danny D.; Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 10-SEP-2001; Project End 31-MAY-2004 Summary: (provided by applicant):Extract of SJW; Hypericum perforatum, has gained widespread popularity as an over-the-counter, natural antidepressant. Until recently, SJW was thought to be well tolerated and relatively safe. Within the past year, adverse metabolic interactions have been reported between SJW and several narrow therapeutic index drugs, notably cyclosporine indinavir, and digoxin. The interactions are now recognized to involve induction of two drug disposition mechanisms: cytochrome P450 3A4 enzyme and the active efflux pump, P-glycoprotein, both leading to profound reductions in blood or plasma drug concentration that compromises the therapeutic efficacy of the affected drug. Natural and synthetic opioids are the first-line agents for the palliative treatment of severe pain that results from cancer and cancer treatment. It is well recognized that depression is a co-morbid condition of severe and poorly controlled cancer-related pain. Given the widespread recognition of St. Johns wort as a "mood enhancer" and natural antidepressant, cancer pain patients receiving opioid analgesics may well turn to this herbal preparation for relief of depressive symptoms. The overall objective of this research proposal is to investigate if significant interactions occur between two widely used opioid analgesics - oxycodone and fentanyl and St. John wort extract through laboratory-based studies in healthy volunteers. The studies will assess the potential clinical significance of the interactions with respect to opioid analgesia efficacy and side effects, and provide scientific insights into the pharmacokinetic mechanisms underlying any observed interactions. The oxycodone arm of the study is designed to 1) investigate the induction of CYP3A4-mediated Ndemethylation which is the major detoxification pathway for oxycodone, and 2) resolve the inductive effects of SJW on intestinal and hepatic CYP3A4 through intravenous and oral administrations of a CYP3A-specific, in vivo catalytic probe -midazolam. The fentanyl arm of the study will 1) assess the effects of SJW on the brain uptake and efflux kinetics of fentanyl through pharmacokinetic-pharmacodynamic (PK-PD) modeling of miotic response over time during and following intravenous infusion of the opioid, and 2) to evaluate the changes in analgesia and side effects of fentanyl upon pretreatment with SJW that may have resulted from induction of Pgp at the BBB. A third arm of the study will assess whether SJW has analgesic properties of its own, or is capable of promoting opioid analgesia. Overall, the proposed research will provide a definitive assessment of the potential and clinical significance of adverse interactions between SJW and opioids in the context of cancer pain therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HUMAN NEURAL STEM CELLS IN PRIMATE PARKINSON'S MODEL Principal Investigator & Institution: Redmond, D Eugene.; Psychiatry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2005
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Summary: (provided by applicant): This project will study the hypothesis that human neural stem cells (hNSCs) implanted into monkeys can normalize parkinsonism resulting from the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). These primordial, uncommitted, pluripotent cells can be propagated in large numbers and then safely differentiated into most cell types of the nervous system, including dopamine-producing neurons. NSCs migrate to populate developing or degenerating brain regions, perhaps allowing a more functionally correct and effective reconstruction. Pilot studies now show engraftment of hNSCs in the brain of fetal, neonatal, infant, and adult monkeys, for at least a month. Dopamine depleted adult monkeys showed graftderived tyrosine hydroxylase positive cells and appropriate migration from the site of injection to dopamine-depleted areas. This project will test hypotheses in monkeys: (1) that hNSCs will survive, differentiate, and integrate in the brain of normal adult monkeys without immunological rejection or harmful overgrowth; (2) that hNSCs will eliminate parkinsonism after MPTP treatment, and that the presence of dopamine injury will influence their distribution and fate. NSCs will be identified and quantitated using genetic markers, immunohistochemistry, and multi-synaptic tract tracing. The following will be characterized and compared in normal monkeys and monkeys after MPTP: hNSC survival, migration, cell division, differentiation, connectivity, immunogenicity, stability of expression of a transgene (LacZ), apoptosis, and effect of host environment on all of these. In the dopamine-depleted parkinsonian monkey, dopamine and its metabolite concentrations, autoradiography of dopamine transporters, behavioral reversal of parkinsonism, dose effects, and synaptic connections will be studied over time courses of 7 days, 1, 3, 6, and 12 months. Comparisons will also be made with effects of primary fetal ventral mesencephalic tissue transplants in parkinsonian monkeys from prior and parallel studies. These studies will advance our understanding of the neurobiology and safety of human neural stem cells in a well established clinically relevant primate model of Parkinson's disease, and, if successful, support safe clinical studies in patients with Parkinson's disease in the future. The results will also advance understanding of useful methods for studying and treating a broad range of neurodegenerative, genetic, and traumatic conditions of the nervous system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNE PARAMETERS IN A STEROID SPARING CLINICAL TRIAL Principal Investigator & Institution: Reinsmoen, Nancy L.; Professor/Director; Pathology; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Studies of steroid withdrawal in selected low-risk recipients have been implemented to decrease the numerous post transplant side effects of steroids but have been associated with an increased rate of acute rejection. More recently, steroid avoidance immunosuppression protocols have been implemented. The short-term results show there is no increase in the rate of acute rejection; however, the long-term effects of these protocols on graft function and survival are not known. The current three-arm clinical trial of rapid discontinuation of prednisone at the University of Minnesota is designed to determine the best long-term steroid avoidance immunosuppressive protocol. Immune parameters are needed to investigate mechanisms of acute and chronic rejection and to determine if short- and long-term graft outcome can be predicted. Ideally, these immune parameters could identify recipients at high risk for acute, subacute, and chronic rejection. Our goal is to determine if measurement of pre- and post transplant responses to donor antigen can predict graft
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outcome, thereby allowing for individualization of immunosuppression and identifying potential points for intervention. The first specific aim is focused on investigating immune mechanisms involved in acute rejection using assays designed to determine if donor antigen-specific immune parameters, including ELISpot, intracellular ATP synthesis, and low levels of anti-HLA antibody can identify recipients at high risk for developing acute and sub-clinical rejection. The second specific aim, designed to study immune mechanisms associated with chronic rejection, outlines assays which test if donor antigen-specific direct and indirect recognition of donor antigen/peptides in ELISpot and flow cytometric assays can identify recipients at high risk for developing chronic rejection. Studies of the third specific aim are designed to determine if the measurement of intracellular ATP synthesis can accurately measure the immune response in the presence of the combined immunosuppressive reagents and can predict over-immunosuppression. These studies are important to quickly alert clinicians to any changes in immune status and overall response to the three immunosuppression regimes. Thus, the overall study is designed to use immune parameters to identify recipients at low vs. high risk for poor graft outcome, thereby allowing for individualization of immunosuppression aimed at improving long-term graft outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNE SYSTEM INFLUENCES ON SENSORY REGENERATION Principal Investigator & Institution: Warchol, Mark E.; Reserach Associate Professor; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: This subproject proposes to investigate the potential role of macrophagederived cytokines in regulating cellular kinetics of neurosensory epithelia in the cochlea and vestibular system. The Specific Aims have not changed substantially in this second revision. A first goal is to determine which cytokines, from a group of seven, affect cell proliferation rates in isolated epithelial cultures from the avian utricle and cochlea using BrdU labeling techniques. A second aim will examine the potential role of resident macrophages in regulating cell turnover in explants of the avian saccule and utricle via the application of 3 pharmacological agents (L-phenylalanine methyl ester, dexamethasone, interleukin-10) that have been shown to selectively inhibit cytokine production by macrophages in other systems. Cell proliferation and apoptosis-mediated cell death will be assessed by BrdU labeling and application of the TUNEL assay, respectively. Aim 3 will explore the influence of resident macrophages on the proliferation of hair cells in the noise-damaged avian cochlea by examining the effects of administrating in vivo the immunosuppressive agents dexamethasone and cyclosporine-A. A final aim seeks to determine whether macrophages are present in the utriculus of normal mice and/or are recruited to sites of gentamycin-induced damage in mammalian utricular neurosensory epithelium. These experiments also will examine whether the regenerative capacity in isolated utricles is affected by the lack of CSF-1 and/or resident macrophages in the osteopetrotic (op/op) mutant mouse. Additional work in support of subprojects 1 and 3 will evaluate the potential role of macrophages in regulating the regeneration of gustatory and olfactory receptors again using the op/op mutant mouse model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMMUNOMODULATION BY MHC CLASS II PEPTIDES Principal Investigator & Institution: Murphy, Barbara T.; Associate Professor; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029
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Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Verbatim from the applicant's abstract) The success of improved graft survival over the last decade has heightened the awareness of the long-term complication of classical immunosuppression, hence focusing future research on the development on tolerogenic strategies. It has become apparent that peptides play a central role in determining T cell responses to alloantigen. This has lead to an increasing interest in the potential use of synthetic peptides to manipulate T cell responses to foreign antigen. Peptides derived from both polymorphic and non-polymorphic regions of the MHC have been shown to significantly impact allograft survival in animals models, and clinical trials using non-polymorphic MHC peptides in humans are currently underway. Our preliminary data demonstrates that non-polymorphic MHC class II derived peptides inhibit the proliferative response to autoantigen, and alloantigen presented by both direct and indirect pathways. These immunomodulatory effects are mediated through the deletion of antigen presenting cells and T cell unresponsiveness. We hypothesize that the inhibitory peptides mediate their effects through binding to MHC class II, disrupting the interaction of the TCR with the MHC+peptide complex and thereby modulating the immune response. The aims of the research proposal are to investigate the mechanism of action mediating the immunomodulatory effects of these peptides and to determine their role in preventing allograft rejection. We will define the pathways leading to the induction of apoptosis in antigen presenting cells and determine the relative susceptibility of the different professional antigen presenting cells to deletion. T cell signaling patterns in unresponsiveness T cells will be investigated, and studies performed to determine whether the lack of T cell response to subsequent stimulation is mediated by anergy, deletion or immune deviation. The sequence specific nature of inhibition by the peptides will be evaluated by amino acid substitutions. Binding studies will performed to determine both the site of binding, and the relative binding affinity of the original and altered peptides. The ability of non-polymorphic MHC class II peptides to prolong allograft survival and induce tolerance will be evaluated in a mouse cardiac transplant model. Gene transfer of peptide constructs to cardiac allografts will be performed to investigate the benefits of local versus systemic delivery on graft survival. The mechanisms mediating long-term allograft survival will be investigated in vitro and in vivo. Peptides will be combined with other immunomodulators to develop novel tolerogenic strategies. These studies will help elucidate the potential role of MHC class II peptides in the prevention of transplant rejection and the induction of tolerance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMMUNOPHILIN LIGANDS IN IN VITRO MODEL OF HIV DEMENTIA Principal Investigator & Institution: Nath, Avindra; Professor; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: HIV infection frequently results in a dementing illness for which currently there is no effective treatment. The virus infects glial cells but the neurons are rarely infected yet, the uninfected neurons may degenerate. Hence there has been a great interest in developing neuroprotective and neurotrophic drugs that could be used for treatment of HIV dementia. In this project, we will explore two such immunophilin ligands with different mechanisms of actions. Current evidence suggests that they either stabilize intracellular pools of calcium or they prevent mitochondrial toxicity by actions on the mitochondrial transition pore. These drugs are of particular interest to us because
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we have previously extensively studied the neurotoxic properties of HIV proteins and shown that they cause massive changes in intracellular calcium levels and induce prominent oxidative stress. Using an in vitro human brain model, we will explore the ability of these drugs to protect against the neurotoxicity of HIV proteins and we will determine the mechanisms involved in such neuroprotection. We will also determine if these compounds have neurotrophic effects in this in vitro model when exposed to HIV proteins. Our experimental design will allow us to monitor and compare effects on neuronal and glial cell populations. This project will benefit from our extensive experience with the use of human fetal brain cultures, and in generating recombinant HIV proteins. This is a highly interactive project that will establish important interactions with other in vitro projects examining the use of these drugs for treatment of HIV peripheral neuropathy. Close collaborations with Guilford Pharrmaceuticals will allow us to explore the subcellular mechanisms involved in therapeutic efficacy of these compounds. Information gained from this project will also be critical for monitoring the animal studies and human trials proposed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNDROME
IMMUNOTHERAPY
OF
LOW
RISK
MYELODYSPLASTIC
Principal Investigator & Institution: Molldrem, Jeffrey J.; Chief, Section of Transplant Immunology; Blood & Marrow Transplantation; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Provided by applicant): Myelodysplastic syndrome (MDS) is a heterogeneous group of progressive, irreversible, hematopoietic stem cell disorders characterized by progressive cytopenia and for which there are no effective therapies. Experimental and clinical evidence indicates that lymphocytes from patients with MDS exert an inhibitory effect on autologous hematopoietic colony growth, and that this contributes to cytopenia. Immunosuppressive treatments that decrease the number of lymphocytes or suppress their function such as corticosteroids, cyclosporine, and antithymocyte globulin (ATG) have been shown to reverse that cytopenia, and in some cases to reduce the number of blasts in the marrow. How these lymphocytes recognize their target antigens and inhibit hematopoietic precursors is unknown. Identification of relevant hematopoietic target antigens, however, might lead to useful therapies for MDS, and would provide insight into other bone marrow failure states such as aplastic anemia where T lymphocytes are also thought to play a key role in the development of pancytopenia. As a strategy to search for those target antigens, we hypothesize that in myelodysplastic syndrome, lymphocyte inhibition of hematopoietic progenitors is mediated by clonal or oligoclonal activated T lymphocytes through MHC-restricted antigen recognition. The long-term goal of this project is to investigate whether clonal T cells associated with inhibition of marrow progenitors can be isolated from MDS patients and then used to further identify relevant target antigens. These clonal T cells could then be more specifically targeted in the treatment of MDS patients and identification of T cell target cells/antigens could help determine the proportional contribution of lymphocytes to the development of cytopenia in MDS. We have shown that patients with MDS who respond to ATG treatment have activated CD8+ lymphocytes that inhibit colony forming unit-granulocyte macrophage (CFU-GM) in a MHC class I-restricted manner. Dominant clonal and oligoclonal lymphocyte populations that are present in peripheral blood and bone marrow in some MDS patients are later replaced by a normal polyclonal distribution, which coincides with
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reestablishment of effective hematopoiesis after ATG treatment. The proposed studies will isolate and characterize clonal T cells from MDS patients, determine how these T cell clones suppress hematopoiesis, whether T cell-mediated inhibition of hematopoiesis is directed against dysplastic or normal progenitors, and whether additional T-celldirected immunosuppressive agents added to ATG treatment can enhance recovery from cytopenia in a randomized clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IN VITRO STUDIES OF HUMAN ANAPHYLAXIS Principal Investigator & Institution: Lichtenstein, Lawrence M.; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUN-1975; Project End 31-MAY-2005 Summary: This grant describes studies designed to increase our understand of the elements involved in the pathogenesis of human allergic disease, with a long range goal of improving the therapy of these illnesses. More specifically, we hypothesize that while both IgE containing cells-the basophils and mast cells-play a role in the allergic diathesis, the basophil plays the more prominent role in the chronic allergic processes which account for most of the morbidity and mortality. The basophil generates and is influenced by a variety of cytokines and our central focus is to understand the regulation of cytokine release as compared to the release of the more acute mediators, histamine and leukotrienes. Basophils release far more IL-4 and IL-13 than lymphocytes. These cytokines play an important role by causing B cells to make IgE and T cells to assume the proinflammatory phenotype (Th2). They also induce the adhesion molecules which lead to the accumulation of eosinophils, basophils and lymphocytes at the site of allergic inflammation. We have demonstrated that the mechanisms involved in the release of these two classes of mediators are quite different and consequently, that the pharmacologic control of their release will be different. We believe that these differences will have implications for the therapy of disease. This grant also funds studies which test the relevance of these in vitro studies in in vivo antigen challenge models involving the upper airways and skin. We also propose analysis of the changes induced by two powerful new therapeutic agents. The first involves treatment with humanized anti-IgE which decreases the serum IgE level by more than 99 percent and which reduces the number of IgE receptor molecules on basophil and mast cell surfaces by a like amount. The second involves immunotherapy involving allergen coupled to oligonucleotide sequences derived from bacterial DNA. This modified allergen has the characteristics which have been sought in the field for decades. That is, the allergenicity of the molecules are decreased while their immunogenicity is increased. This has been demonstrated in mice, dogs, primates and to a limited extent, in man. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INDUCTION OF IMMUNE TOLERANCE TO FASL-EXPRESSING ES CELL Principal Investigator & Institution: Sonntag, Kai-Christian; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): The potential of pluripotent embryonic stem (ES) cells to develop into functional mature cells or tissue has high implication in finding new treatments for diseases including neurodegenerative disorders. This includes the potential use of ES cells as cell replacement therapy in neurological diseases, such as
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Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and ischemia. However, survival of call grafts requires systemic immunosuppression, which severely compromises the entire host immune system leading to complications in clinical transplantation. An optimal therapy would be, therefore, the induction of specific tolerance to the donor cells by otherwise preserving functional immune responses. Fas ligand (FasL, CD178, or CD95L) is a type II membrane protein and is expressed in activated lymphocytes and cells in "immuneprivileged" sites such as the testis, the eye, and the CNS. Its receptor Fas (CD95 or Apo1), a type I membrane protein and a member of the TNF receptor family, is expressed on various immune-reactive hematopoietic cell types including activated NK and T calls, non-lymphoid calls such as immature myeloid cells, monocytes, and polymorphic mononucleocytes. Fas-expressing cells undergo apoptosis upon interaction with FasL, a process that is involved in regulating cellular immunity and it has been shown that FasL can be used as an immunomodulatory tool to protect allogeneic or xenogeneic cells against cellular immune responses. Here, I hypothesize that ES cell grafts in the brain, which express FasL, are protected against the host cellular immune response abolishing the need for systemic immunosuppressive drug treatment. For this, I will genetically engineer mouse ES cells to express FasL and test their survival ability in the host brain of rats without further immunosuppression. Furthermore, I will analyze the effects of FasL expression on transplanted cells towards modulating the host immune response. Results from this work will have implications for immunomodulation of ES cell grafts in both allogeneic and xenogeneic transplantation settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INDUCTION OF TRANSPLANT TOLERANCE Principal Investigator & Institution: Zhong, Robert; Canada Research Chair in Transplantation; University of Western Ontario 1151 Richmond St N London, On Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-MAY-2007 Description (provided by applicant): Our group has established that donorspecific tolerance in rodents and functional tolerance in primates can be induced using an epitope specific monoclonal antibody (mAb) that targets the CD45RB isoforms. We have also demonstrated that LF 15-195 (LF), an analogue of 15-deoxyspergualin (DSG), induces donor-specific tolerance in rodents and significantly prolongs renal allograft survival in primates. Recently, we found that combining these two approaches has a synergistic effect on the induction of tolerance in rodents, but this must be confirmed in primates, in which tolerance may be more difficult to establish or less durable. While mosque studies are currently underway in our laboratory to more precisely define the mechanisms by which LF and anti-CD45RB mAb induce tolerance, we believe that concurrent testing of this powerful novel approach in a non-human primate model is warranted to accelerate the development of a clinically useful approach to achieve tolerance in patients. We hypothesize that tolerance established in non-human primates using this strategy requires both 1) generation of regulatory T cells by CD45RB mAb; and 2) generation of a tolerogenic subset of dendritic cells (DC) by LF and that tolerance synergy in combination therapy is mediated by an interaction between these regulatory T cells and tolerogenic DC. The use of primates will also allow us to study, using clinical outcomes and functional genomics with cDNA microarrays, the potential effect of currently available immunosuppressive agents including calcineurin inhibitors cyclosporine (CsA), and non- calcineurin inhibitors such as rapamycine (Ra) on tolerance induced by this therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF ACTION OF CYTOKINES ON BRAIN AND PITUITARY Principal Investigator & Institution: Mccann, Samuel M.; Professor and Director; None; Lsu Pennington Biomedical Research Ctr 6400 Perkins Rd Baton Rouge, La 70808 Timing: Fiscal Year 2002; Project Start 01-APR-1995; Project End 31-MAR-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS UNDERLYING GRAFT-VERSUS-HOST DISEASE Principal Investigator & Institution: Laughlin, Mary J.; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: (As Adapted From the Investigator's Abstract): Umbilical cord blood (UCB) stem cells have emerged as novel treatment for patients requiring allogeneic grafting. The incidence and severity of graft-versus-host disease (GVHD) after UCB transplantation in these early clinical trials compares favorably to that observed in recipients of matched unrelated donors (MUD) or partially mismatched family member allogeneic grafts. It has been shown that stimulated lymphocytes from UCB have reduced production of cytokines including IFN-gamma and TNF-alpha, known to play an important role in GVHD pathophysiology. This laboratory has investigated the molecular mechanisms underlying this reduced cytokine production by analyzing expression of nuclear factor of activated T cells-1 (NFAT1) in UCB T cells. The applicants detected no constitutive expression of NFAT1 protein in non-stimulated UCB T cells, and although NFAT1 expression in UCB T cells was upregulated after prolonged (40 hr) T cell stimulation, it was only partially upregulated when compared to adult controls. These observations of minimal NFAT1 expression after stimulation correlated with reduced cytoplasmic IFN-gamma and TNF-alpha production in UCB T cells studied simultaneously. The first hypothesis underlying the work outlined in this application is that gene regulation of NFAT1, a central transcription factor involved in cytokine gene expression, differs between neonatal and adult T cells. Secondly, they hypothesize that that these fundamental differences in NFAT1 regulation between neonatal and adult T cells will elucidate underlying regulatory pathways mediating hyporesponsiveness of UCB T cells. To test these hypotheses, they will [Aim 1] compare in detail expression kinetics and gene regulation of NFAT1 in UCB and adult T cells. Then [Aim 2] in vitro studies will be performed to compare NFAT1 protein levels with surface expression of immunomodulatory molecules including CD40L, CTLA-4, and FasL on UCB T cells, and cytoplasmic expression of IFN-gamma and TNF-alpha, in the presence or absence of cyclosporine or FK506 (tacrolimus). Finally, [Aim 3] NFAT1 protein levels and surface expression T cells of immunomodulatory molecules will be compared in donor UCB and HLA-matched sibling T cells emerging during immune recovery after transplant. These studies may provide further insight into the regulation and expression of above described genes during neonatal and adult life. Moreover, since NFAT1 regulates the gene expression of cytokines and immunomodulatory molecules known to mediate GVHD, their studies may reveal new therapeutic approaches to the treatment and/or prophylaxis of GVHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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•
Cyclosporine
Project Title: MODELING HYDROPHOBIC AND HYDROPHILIC INTERACTIONS Principal Investigator & Institution: Berne, Bruce J.; Professor; Chemistry; Columbia Univ New York Morningside 1210 Amsterdam Ave, Mc 2205 New York, Ny 10027 Timing: Fiscal Year 2002; Project Start 01-JAN-1991; Project End 31-JUL-2006 Summary: (provided by applicant): Computer modeling of complex liquids and biological systems is an important tool in biochemistry. With the increasing power of modern computers, it is becoming possible to design new drugs and new biomimetic materials, and to gain understanding of molecular recognition, and the effects of mutations on protein folding. One of the major aims of this proposal is the invention, extension and application of new methods to accelerate the simulation and sampling of conformational states of biomolecular systems. Monte Carlo and molecular dynamics methods for sampling conformational states of biomolecules are often inherently quasiergodic. This means that starting in one stable conformation, not all other conformations can be reached on a practical time scale. We aim to devise methods for sampling conformation space in protein systems and other systems characterized by rough energy landscapes, and to apply these new methods to important problems involving the binding of peptides to enzymes and to conformational transitions of peptides.We aim to develop next generation polarizable force fields in order to deal a major impediment to rational drug design. Predictions of binding energies are dependent on the quality of the force field. Existing force fields do not account for known changes in atomic charges when a peptide undergoes a conformation change. Such effects require a chemically accurate polarizable force field that can correctly account for specific hydrogen bonding energies. During the preceding grant period, we based an assigning fluctuating charges and fluctuating dipoles on designated sites on the molecule. This modet has had remarkable success in predicting properties of water, ion solution, amino acids and dipeptides. We have shown that these methods will be used to study conformational dynamics in the (a) of the b-hairpin C-terminus of protein G; (b) the helix-coil transition of homo and hetero oligopeptides; (C) the binding of cyclosporin A to cyclophilin; and (d) conformational transitions in HIV-1 protease.The proposed research will provide new methods and algorithms as well as next generation force field for use in biological simulations. These methods wilt be used to study the binding of cyclosporin A to cvctoohilin and the conformational transitions in HIV-1 Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MODULATION OF MULTIDRUG RESISTANCE MECHANISMS Principal Investigator & Institution: Sikic, Branimir I.; Professor; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 15-APR-1990; Project End 31-MAY-2003 Summary: The purpose of this proposal is to conduct clinical trials of modulation of resistance to cytotoxic drugs. Studies of new modulators of MDR1/P-glycoprotein (Pgp) multidrug resistance (MDR) will continue. Additional areas of focus include: (1) modulation of other MDR mechanisms (the MDR-associated protein MRP, and the bcl-2 family of inhibitors of apoptosis); and (2) the use of P-gp inhibitors to enhance the oral bioavailability of taxanes and other P-gp substrate drugs. Aim 1: To conduct Phase I trials of modulation of multidrug resistance mechanisms. We will conduct 1-2 Phase I trials per year, defining toxicities, optimal doses and schedules, and drug disposition. Planned studies include: PSC 833 (PSC)/Doxil/paclitaxel; LY335979/mitoxantrone; LY335979/doxorubicin/paclitaxel; and other, new MDR1 modulators. Similar approaches will be applied to a new inhibitor of MRP, with doxorubicin and with
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etoposide; and antisense oligonucleotide drugs against bcl-2 and bcl-xl. We will choose these new agents based on animal toxicology, other preclinical data, and availability for clinical trials. An eventual goal is combined blockade of two mechanisms (e.g., MDR1 and MRP). Aim 2: To study pharmacokinetic interactions associated with modulation of drug resistance. An important issue with modulators of drug resistance is the effect of these drugs on normal tissue function and in particular on the disposition of cytotoxins. Pharmacokinetic studies will involve compartmental methods to further define drug interactions, and validation of optimal sampling strategies with Bayesian estimations. The effect of different modulators (PSC vs. LY335979) on the erythromycin breath test in patients will be used to dissect the role of cytochrome P450 3A4 in these interactions. Ancillary pharmacokinetic studies of mitoxantrone and etoposide for the ECOG and POG trials of MDR1 modulation in acute myeloid leukemias will also be supported. Aim 3: To enhance the oral bioavailability of MDR1-related drugs by co-administration with inhibitors of P-gp. Intestinal P-gp is a major barrier to the absorption of taxanes and other MDR1 related cytotoxins. We will co-administer modulators and cytotoxins in trials designed to enhance bioavailability, and potentially to increase the safety and convenience of chemotherapy. Patients will receive an initial course of the cytotoxin intravenously, followed by sequential courses of the cytotoxin orally together with increasing doses of the P-gp inhibitor. The first protocol in this aim will involve paclitaxel with PSC. Other cytotoxins of interest for this approach include taxotere, etoposide, and vinorelbine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR CONSEQUENCES OF SARCOMERE PROTEIN GENE MUTATIONS Principal Investigator & Institution: Seidman, Jonathan G.; Professor of Genetics; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2003 Summary: The central focus of this project is to define the signaling pathways that lead from sarcomere gene mutation to hypertrophic cardiomyopathy, dilated cardiomyopathy, dilated cardiomyopathy and/or heart failure. During the previous grant period we demonstrated that mutations in sarcomere protein genes cause familial hypertrophic cardiomyopathy (FHC). Many, if not all, FHC-causing mutations, create poison polypeptides that become incorporated into the growing sarcomere and create defective sarcomeres. However, we do not understand how these defective sarcomeres lead to dramatic changes in cardiac morphology and function. Some individuals bearing these mutations can live for many years without demonstrating any clinical signs of disease, while others develop disease symptoms early in childhood. To create tools to study these signaling pathways we have create two lines of mice; each line of mice bears a mutation that causes FHC in man. One line bears the Arg403Gln mutation in the alpha-cardiac myosin heavy chain gene, and the other line bears a truncation mutation in the cardiac myosin binding protein C gene. Heterozygous mice bearing these mutations develop features of FHC, whole homozygous mice bearing these mutations develop dilated cardiomyopathy and in one case, heart failure. We propose a series of experiments that should define the signaling pathways activated in these sarcomere defective mice. Specifically we propose to: 1) Identify molecules involved in the pathways that lead to dilated cardiomyopathy in MyBPC T/T mice and alphaMHC/403/403 mice. 2) Identify molecules in the pathways that lead to cardiac hypertrophy in heterozygous MyBPC/T/+ mice and alphaMHC/403/+ MICE. 3) Assess the mechanisms by which cyclosporin induces rapid development of cardiac
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hypertrophy in sarcomere protein gene mutant bearing mice. 4) Define the phenotype of compound heterozygous MyBPC/T/+ mice and alphaMHC/403/+ mice. 5) Assess treatment phenotype of compound heterozygous MyBPC/T/+ mice and alphaMHC403/+ mice. 5) Assess treatment modalities and environmental factors that affect the cardiac response to sarcomere protein gene mutations. During the past few years we, in collaboration with other projects and Core facilities supported by this SCOR center, have developed the methods necessary to characterize these murine models. In particular, we have benefitted from associated with Core B which provide echocardiographic facilities which are essential for evaluation of mouse cardiac structure and Core C which performed histologic analysis which are a significant part of phenotype analyses. Further, our choice of disease gene models came from studies performed in collaboration with project 1. The analysis of cardiac function were originally conducted in collaboration with Dr. Ingwall. In the next granting period we, in collaboration with projects 3 (Dr. Ingwall) and 4 (Dr. Neer) will evaluate further these mutant mice using expertise and equipment available in the Core facilities. In summary, we propose to continue our efforts to define the signaling pathways that lead to and from sarcomere protein gene mutation to dilated cardiomyopathy, FHC and heart failure. We recognize that these studies will receive significant benefits from our close association with the SCOR center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR DISSECTION OF THE PERMEABILITY TRANSITION PORE Principal Investigator & Institution: Forte, Michael A.; Senior Scientist; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Mitochondria play a pivotal role in cell survival and tissue development by virtue of their role in energy metabolism, regulation of cellular Ca 2+ homeostasis and apoptosis. Given this multifactorial role, Ca 2+ homeostasis, metabolism, and bioenergetics function as an integrated system since energy conservation is used to drive each process. Mitochondrial energy conservation (ATP production) requires the respiration-driven formation of a proton electrochemical potential difference (delta mu H) across the inner mitochondrial membrane (IMM), which is created by proton pumping by the respiratory complexes. Maintenance of the gradient demands a low permeability of the IMM to protons, charged species and solutes. Yet, mitochondria in vitro can easily undergo an IMM permeability increase to solutes with molecular masses of about 1,500 Da or lower. This permeability change, called the permeability transition (PT), is regulated by the opening of a membrane pore, the mitochondrial permeability transition pore (PTP). PTP opening in vitro has dramatic consequences on mitochondrial function (e.g., collapse of the delta mu H and depletion of pyridine nucleotides) and structure (release of cytochrome c) that lead to respiratory inhibition. This process has long been studied as a potential target for mitochondrial dysfunction in vivo and as a mediator of programmed cell death (PCD) through the release of cytochrome c and other intermembrane proteins active on the apoptotic machinery. However, despite detailed functional characterization over the last 30 years, the molecular components forming the PTP have been not been definitively established nor has the precise role of the PTP in vivo been defined. This proposal is based in the synergy possible through the combination of novel approaches available in our two laboratories. Our specific plans include the following aims: Aim 1: In screens for chemical inhibitors of the PTP, we have identified Ro 68-3400 in functional assays as a
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high affinity (nM) blocker of the PTP through covalent modification of isoform 1 of mammalian VDAC (VDAC1). Similar experiments have also demonstrated that yeast VDAC1 is specifically targeted by this compound. We plan to use our experience with both mammalian and yeast VDAC to pin-point the structural requirements for high affinity association of VDAC with this compound, examine other mammalian VDAC isoforms for their ability to be modified by Ro 68-3400 and test the sensitivity of mitochondria treated with this novel PTP blocker to proteins in the BCL-2 family. Aim 2: Traditionally, the PTP has been considered to be a dynamic multiprotein complex formed at inner/outer membrane contact sites through the interaction of the adenine nucleotide translocator (ANT) of the IMM, VDAC in the OMM and a matrix regulatory protein, mitochondrial cyclophilin D (CyP-D). However, evidence implicating the ANT in the PTP complex has not been supported by recent data. Therefore, in this aim we plan to take advantage of Ro 68-3400 as a specific tool to further define the core components forming the PTP, with a specific focus on the identification of the IMM partner for VDAC in the pore complex. Aim 3: Inhibition by cyclosporin A (CsA) and non-immunosuppressive analogs has become the standard diagnostic tool for the characterization of the PTP in isolated mitochondria, in living cells, and in vivo. The target of CsA in these studies, CyP-D, is the only component of the PTP whose role has been definitively established. The goal of this aim is to unambiguously resolve basic questions related to the influence of CyP-D on the PTP, the participation of the PTP in specific aspects of the apoptotic program, and its role in specific pathological processes of significance to human, disease through the use of mice in which the expression of CyP-D and MVDAC1 have been eliminated by "knock-out" strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR PHYSIOLOGY OF RECOVERY FROM MUSCLE ATROPHY Principal Investigator & Institution: Pavlath, Grace K.; Associate Professor; Pharmacology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-MAY-2006 Summary: A loss of skeletal muscle functional capacity occurs in disease, disuse and aging mostly attributable to a loss of muscle mass. Such losses of muscle mass contribute to weakness, impaired mobility and/or respiratory function, low quality of life and high health care costs. The overall goal of this proposal is to delineate cellular and molecular mechanisms that regulate growth of atrophied muscles. The relative importance of muscle precursor cell (mpc) pathways vs. myofiber pathways can vary depending on the type of muscle growth and may differ for the growth of an atrophied myofiber. Determining how much of the recovery from atrophy is dependent on mpc is important for designing therapeutic strategies to treat muscle atrophy. This proposal has 3 integrated parts: (1) To delineate the contribution of mpc and other muscle progenitor cells to growth of atrophied muscle (Aims 1 and 2). We will define the timing of mpc proliferation and fusion with myofibers during growth. Subsequently, we will analyze growth in muscles lacking mpc due to local irradiation. Finally, we will determine if the abundance and/or in vitro properties of newly identified muscle progenitor populations change in response to muscle atrophy or growth. (2) To enhance mpc proliferation and fusion using the drug curcumin as a means of stimulating recovery from atrophy (Aim 3). We have previously shown that curcumin effectively enhances the growth of regenerating muscles and now extend these studies to growth of atrophied muscle; (3) To study molecular signals that are activated during the growth of atrophied muscles (Aims 4 and 5). We will delineate the contribution of a known signaling pathway
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(calcineurin) as well as identify new molecules using microarray analysis, which may play a role in regulating muscle growth. The experiments in this proposal will reveal new information about growth of atrophied muscle and possibly new avenues of rehabilitative therapy for manipulating this growth process in disease, disuse and aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYCOPHENYLATE MOFETIL FOR TREATMENT OF CHRONIC GVHD Principal Investigator & Institution: Martin, Paul J.; Member; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Chronic graft-versus-host-disease (GVHD) occurs in 40 - 60% of patients who survive for more than 3 months after hematopoietic stem cell transplantation from an allogeneic donor for treatment of hematological malignancy. Apart from recurrent malignancy, chronic GVHD is the leading cause of death and morbidity in this patient population. High-dose glucocorticoids have long served as the mainstay of treatment for chronic GVHD, at the cost of considerable morbidity. Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to mycophenolic acid, which selectively inhibits inosine monophosphate dehydrogenase, thereby blocking the de novo pathway of purine synthesis in lymphocytes. Results from at least five phase II studies have suggested that MMF may be effective for treatment of steroid-refractory chronic GVHD. This application proposes a multi-center, phase III randomized doubleblind clinical trial to determine whether MMF is effective for treatment of newly diagnosed chronic GVHD. All patients in both arms of the study will receive prednisone and a calcineurin inhibitor (cyclosporine or tacrolimus) as standard therapy for chronic GVHD. Patients in one arm will be treated with MMF, while those in the other arm will be treated with an identical appearing placebo. Efficacy will be assessed according to the proportion of patients who have treatment success, defined as discontinuation of all immunosuppressive treatment within 2 years after enrollment, with resolution of all reversible manifestations of chronic GVHD and no secondary therapy. Enrollment of 115 patients in each arm will provide 90% power to detect an increase in the success rate from 22% to 42% with a two-sided alpha of 0.05. Health-related quality of life assessment from four well-validated instruments will be used to test the hypotheses that treatment with MMF leads to a decrease in symptom severity and an improvement in physical function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEAR-INFRARED VCD OF CHIRAL PHARMACEUTICALS Principal Investigator & Institution: Nafie, Laurence A.; Distinguished Professor; Chemistry; Syracuse University 113 Bowne Hall Syracuse, Ny 13244 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: APPLICANT'S The objective of the proposed research is to apply Fourier transform near-infrared vibrational circular dichroism (FT-near-IRVCD), as a new in situ probe of molecular chirality, to the analysis of pharmaceutical molecules and final formulated pharmaceutical products. Currently, there is no available technology for the determination of enantiomeric purity, absolute configuration or conformational states of chiral pharmaceutical molecules in situ as formulated products. We propose to combine the existing related technologies of FT mid-IR VCD spectroscopy, conventional FT nearIR absorption and reflection spectroscopy, and solid-phase mid-IR and UV-visible CD
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sampling methods to yield a new methodology for probing chiral pharmaceuticals. FTVCD instrumentation in the mid-infrared region has recently become commercially available as a sensitive probe of molecular structure and chirality. FT-near-IR spectroscopy has shown remarkable sensitivity and sampling flexibility in recent years for the determination of quality-control factors in wide varieties of products, such as food, chemicals and pharmaceuticals. The resulting new spectroscopic technique, FTnear-IR VCD, will possess the analytical capability to probe enantiomeric purity, absolute configuration, molecular conformation, and particle-size distribution in solids, in final formulated chiral pharmaceuticals, as well as any prior step in the synthesis and production process. In addition to solution-phase sampling, we will investigate the use of mulls, pellets, powders, films and spin-coated samples. The use of dual polarization modulation methods developed recently by the principal investigator to automatically correct CD baselines, will suppress birefringence effects in all solid samples, thus eliminating many problems of reproducibility in solid-phase CD sampling. Where possible, near-IR VCD will be correlated to mid-IR VCD using frequency assignments and 2D-FT-mid-IR/near-IR correlation spectroscopy. The research will proceed in stepwise fashion from existing mid-IR instrumentation and methods to the development of new near-IR instrumentation and methods. With FT-near-IR-VCD technology in hand, we will then develop sensitive analytical measures of first pure chiral pharmaceutical samples, including protein pharmaceuticals, and then excipients of various kinds. Pharmaceutical molecules of particular interest are propranolol, ephedra drugs, including ephedrine, norephedrine, pseudoephedrine, norpseudoephedrine, N-methyl ephedrine and N-methyl pseudoephedrine, the analgesics ibuprofen and naproxen, and cyclosporins and selected protein pharmaceuticals. The excipients to be studied include dextrose (glucose), sucrose, lactose, cyclodextrins and cellulose. After these studies, we will measure FT-near-IR-VCD of excipient-supported final pharmaceutical products. The sensitivity of FT-near-IR VCD to particle size, moisture Content and aggregation in protein pharmaceuticals will be determined. The ratio of pharmaceutical to excipient will be varied until proportions equivalent to those used for human administration are achieved. This will permit in situ quality of control of chiral and physical properties in final-stage pharmaceutical products. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUROPROTECTION AND RETINAL GANGLION CELL DEATH Principal Investigator & Institution: Grosskreutz, Cynthia L.; Assistant Professor of Ophthalmology; Massachusetts Eye and Ear Infirmary 243 Charles St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: Retinal ganglion cells die by apoptosis after optic nerve crush and in glaucoma, causing irreversible visual loss. Current therapies lower intraocular pressure, but are not designed specifically to prevent retinal ganglion cell death and blindness. Apoptosis can be initiated by at least two different pathways: activation of death receptors such as Fas, leading to recruitment of FADD, and caspase 8 to form the active caspase 8 containing death inducing signaling complex. This leads to cleavage and activation of downstream caspases and cell death. Alternatively, pro- apoptotic Bcl2 family members (dephosphorylated pBAD) can translocate to the mitochondrion, leading to release of cytochrome c, APAF-1, and activation of caspase-9, again initiating downstream caspases including caspase 3. We have observed that optic nerve crush induces rapid, stereotyped death of retinal ganglion cells, and that both of these pathways may well be involved. Although conceptualized as distinct pathways, they are likely points of intersection and regulation of these upstream initiating phenomenon.
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We propose that calcineurin activity is a major regulator of upstream caspases, because calcineurin inhibition protects against death receptor-initiated apoptosis and also prevents pBad phosphorylation. We demonstrated that treatment of rats with FK506, a widely clinically used immunosuppressant agent that is a potent calcineurin inhibitor, led to statistically significant retinal ganglion cell protection after optic nerve crush. The goals of the current application are (Aim 1) to determine whether inhibition of calcineurin underlies the observed neuroprotective effect of FK506, AND (Aim 2) to examine the effect of FK506 on the caspase 8/death receptor and pBad/cytochrome c initiating cascades. Aim 3 builds on the first 2 aims, and takes advantage of a microsurgical vascular sclerosis model of experimental glaucoma in the rat. We observe that RGC are lost over the course of several weeks by apoptosis, with many of the same characteristics as we observe in the subacute optic nerve crush model. We will now further characterize this model, and determine whether calcineurin inhibition by FK506 is neuroprotective in this setting. Taken together, the broad, long-term aims of the studies outlined in this application are to characterize the cell death pathways involved in retinal ganglion cell death so that neuroprotective treatments can be developed for diseases in which retinal ganglion cells die, such as glaucoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW ENGLAND PEDIATRIC ONCOLOGY CONSORTIUM Principal Investigator & Institution: Ferguson, William S.; Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923 Timing: Fiscal Year 2002; Project Start 01-JAN-1981; Project End 31-DEC-2002 Summary: The specific aims of the New England Pediatric Oncology Consortium (NEPOC) are: Development and enhanced productivity of a consortium of regional pediatric cancer centers (Brown University/Rhode Island Hospital; Dartmouth University/Dartmouth-Hitchcock Medical Center; Harvard University/Massachusetts General Hospital; SUNY at Stony Brook/Children's Medical Center at Stony Brook; University of Vermont/Medical Center Hospital-Vermont Regional Cancer Center) for the purposes of: A. Contributing to the understanding and treatment of children and adolescents with malignancies through: 1. Input into national cooperative studies through membership in the Pediatric Oncology Group (POG): a. Patient accrual: Achieve significant number and quality of patient entries on protocols; b. Study development and evaluation: Assist in the development of new protocols through committee memberships, institutional reviews of proposed protocol designs, analysis of study results, and proposal of new protocols for POG implementation based on NEPOC studies; c. Administration: Accept responsibilities for POG administrative functions. 2. Cooperative efforts within NEPOC (New England Pediatric Oncology Consortium) in studies of joint interest in the areas of childhood malignancies, particularly toward developing potential pilot studies for POG. B. Enhancement of the care of children and adolescents with cancer in the geographical areas served by the member institutions through: 1. Assuring comprehensive and modern management of children and adolescents with malignancies as a benefit of membership in POG; 2. Sharing staff expertise and investigative facilities at each of the member institutions; 3. Joint efforts in promotion of education of the local community in the area of cancer in children and adolescents. Through a centralized administration, this Consortium integrates the activities and resources (staff, facilities, patients) at each institution into a single program aimed at achieving these goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NFAT TRANSCRIPTION IN VASCULAR SMOOTH MUSCLE Principal Investigator & Institution: Murphy, Thomas J.; Associate Professor; Pharmacology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: (provided by the applicant): The immunosuppressants cyclosporin A (CsA) and FK506 cause a spectrum of serious side effects, including impaired cardiovascular function. This is not only a serious clinical problem, but also indicates that cellular processes affected by immunosuppressant are crucial for the maintenance of normal cardiovascular homeostasis. Through binding to either of two distinct cellular adapters, both drugs inhibit the phosphatase calcineurin. A family of transcription factors termed the nuclear factors of activated T-cells (NFAT) are well-known calcineurin substrates. Although initially considered T-cell restricted, studies indicate that NFAT isoforms are widely distributed in non-lymphoid tissues throughout the body. The applicant has published several studies supporting the general notion that NFAT can serve as a transcriptional effector for signaling evoked by various hormones, autacoids and growth factors within subsets of vascular smooth muscle and endothelial cells. We speculate that NFAT participates in the modulation of vascular gene expression programs elicited by such physiological agonists and that interference with NFAT mediated transcription may contribute to immunosuppressant drug toxicity. If so, on balance, NFAT likely serves as a key regulator of important homeostatic processes, and its targets would be of great interest to discover. General objectives of this project include deriving a better understanding of how NFAT mediated transcription operates in a vasculature smooth muscle cell context, and what genes it may be involved in regulating. To explore this, we will assess whether four distinct NFAT isoforms are differentially regulated and drive unique patterns of vascular gene expression. Since no NFAT gene targets in smooth muscle cells have been definitively described, we will carry forward studies that strongly support the hypothesis that NFATs trans-activate the COX-2 and IL-6 genes within VSMC. We will also study how co-activation of cAMPdependent kinase pathways modulate NFAT transcription. Lastly, we will examine the physiologic consequences of disrupted NFAT function by studying how CsA treatment and NFAT gene ablation influence vascular function using murine models. The project will exploit innovative and powerful recombinant gene expression techniques in cultured cell models, coupled with state-of-the-art physiological assessments. Our expected findings are likely to provide important new insights into the role of NFAT in vascular smooth muscle and its relationship to immunosuppressant-induced vascular dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NON MYELOABLATIVE HISTOINCOMPATIBLE STEM CELL TRANSPLANT Principal Investigator & Institution: Xun, Chang-Qing; Internal Medicine; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-MAR-2004 Summary: We have developed a nonmyelosblative allogeneic hematopoietic stem cell transplant (HSCT) regimen using low dose total body irradiation (TBI), 200cGy before and immunosuppressive agents, mycophenolate mofetil (MMF)and cyclosporine A (CSP) after grafting in a canine model based on the facts that both host versus graft (HVG) and graft versus host (GVH) reactions are mediated by T cells in the major histocompatible complex (MHC) identical setting. This regimen has now been translated
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successfully to clinical setting. However, only a minority of patients has human leukocyte antigen (HLA)-identical siblings who could serve as HSCT donors. The present proposal, therefore, seeks to address the development of a nonmyeloablative allotransplant regimen for MHC- haploidentical donors using dog leukocyte antigen (DLA)-haploidentical littermates. In that setting, host natural killer (NK) cells play an important role in HVG reactions, in addition to that played by host T-lymphocytes. We hypothesize that successful HSCT can be achieved by blockades of host T and NK cell immunities without myeloablation. We shall explore three approaches which will either reduce the immune reactivity of host T- cells, host NK cells or both. In specific aim one, we attempt to block host T cell reactions to donor alloantigens with costimulatory blockers, CTLA4lg and/or anti-CD40L monoclonal antibody (mAb). In specific aim two, newly developed anti canine killer mAbs will be tested to block host NK immunities. In specific aim three, a novel immunosuppressive agent, FTY 270 that induced profound peripheral blood lymphopenia involving both T and NK cells will be used to reduce host T and NK cells. The studies will commence using a low dose (450cGy) pretransplant TBI. We shall then attempt to successfully lower the TBI dose needed for successful engraftment and ultimately to establish engraftment solely with the use of non-toxic immunosuppressive agents. Post grafting immunosuppression with MMF1CSP will be an unalterable part of the proposed studies given its demonstrated benefit in preventing GVH disease (GVHD) and reducing HVG reactions. The primary end points of these studies will be stable engraftment that can be easily documented by DNA microsatellite marker analysis and the overall survivals. If successful, the regimen will be translated to humans and provide almost all patients requiring allogeneic HSCT a donor from family members. The applicant is committed to establishing an independent career in academic research as a clinician scientist in the area of hematopoietic stem cell transplantation. The long- term goals are to carry out translational studies that will lead to improvements in the treatment of cancer and other diseases with stem cell transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NON T CELL PRODUCED NOVEL T CELL GROWTH FACTORS Principal Investigator & Institution: Strom, Terry B.; Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: Based on in vitro studies, it is widely believed that IL-2 and IL-4, T cell produced TCGFs, play an absolutely essential role in the execution of T cell mediated phenomena. Nonetheless, an exclusive role for these T-cell produced TCGFs in supporting the clonal proliferation and activation of effector of T cells during T cell dependent reactions in vivo, e.g. rejection, has not been established. We believe that IL-2 and IL-4 are not absolutely necessary for graft rejection as other "novel" TCGFs can also support the proliferation of antigen activated T-cells. Indeed, our studies of IL-2-/single and IL-2-/-, IL-4-/- double gene knockout (DKO) islet cell allograft recipients indicate that other TCGFs can support vigorous islet allograft rejection. Insofar as IL-4 deficient mice do not produce IL-13, we believe that IL-7 and IL-15 (while not T-cell products) and IL-9 are potent TCGFs and are the most likely candidates for this role. We have detected greatly amplified IL-7 and IL-15 gene expression in acutely rejecting islet allografts of normal and IL-2-/- knockout recipients, as well as amplified gene expression in virtually all human renal allograft biopsies obtained from patients with acute rejection, but not other common causes of graft dysfunction (Strehlau et al., 1997). The possibility that expression of IL-7, IL-9 and IL-15 may play an important role in
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acute and chronic allograft rejection has received little attention. An understanding of the role of these TCGFs in allograft rejection is critically important in designing effective therapeutic strategies to promote long-term engraftment and tolerance. We will explore the role of these novel TCGFs and the therapeutic implications thereof during islet cell and cardiac allograft rejection by utilizing an IL-2 and IL-4-deficient system, the IL-2-/-, IL-4-/- DKO mouse, as well as normal mice as islet and cardiac allograft recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NOVEL ANTIFUNGAL DRUG TARGETS IN CRYPTOCOCCUS NEOFORMANS Principal Investigator & Institution: Heitman, Joseph B.; Professor; Molecular Genetics and Microbiology; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 31-MAY-2006 Summary: Fungal infections are increasingly common as a result of AIDS, transplantation, high dose chemotherapy, steroid treatment, antibiotic treatment, and invasive procedures. However, existing antifungal agents are limited to amphotericin B, flucytosine, and azoles, and drug resistant strains are emerging. We propose to elucidate signal transduction cascades regulating fungal growth and virulence as targets for antifungal drug development. We propose studies on both Candida albicans, the most common human fungal pathogen, and Cryptococcus neoformans, the leading cause of fungal meningitis and an important opportunistic fungal pathogen. We have discovered that the immunosuppressive drugs rapamycin, cyclosporin A, and FK506 have potent antifungal activity. In studies supported by this award, we have identified the fungal drug target proteins, including FKBP12, the Tor1 kinase, and two cyclophilin A homologs. Our studies demonstrate that the antifungal effects of rapamycin are mediated via a complex with FKBP12 that inhibits the fungal Tor1 kinase homolog. We have identified nonimmunosuppressive analogs of each of these drugs that retain antifungal activity. By genetic and biochemical approaches, we show that these analogs take advantage of structural differences between host and fungal enzymes, sparing immune function while impairing fungal cell growth. Finally, we have identified examples of potent synergistic drug interactions. For example, the calcineurin inhibitors cyclosporin A and FK506 are potently synergistic with azoles in Candida albicans. Here we propose to establish the cellular functions and targets of the rapamycin target protein Tor1. The TOR1 gene will be disrupted in diploid strains of C. neoformans to test if it is essential. Targets of the Tor kinase will be identified by genetic and two hybrid screens, and by analyzing gene expression with genome arrays. We will also identify the targets of the C. neoformans cyclosporin A target proteins, the Cpa1 and Cpa2 cyclophilins, which are important for cell growth and virulence. We will determine the molecular basis of synergistic drug interactions. First, we will identify a novel target of the FKBP12-FK506 complex that is synergistic with proton pump inhibitors in C. neoformans. Second, we will focus on the roles of FKBP12 and calcineurin in azole action in C. albicans, testing the hypothesis that calcineurin is either essential or becomes essential during cell membrane stress as a result of azole treatment. Finally, we will test rapamycin and nonimmunosuppressive rapamycin analogs, and the synergistic combination of calcineurin inhibitors and azoles, in animal models of cryptococcosis and candidiasis. Our long term goal is to identify unique targets and develop novel antifungal drug therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NOVEL ANTIOXIDANT CATALYST FOR TRANSPLANT REJECTION Principal Investigator & Institution: Jagtap, Prakash; Corporation 100 Cummings Ctr, Ste 419E Beverly, Ma 01915
Inotek
Pharmaceuticals
Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2005 Summary: (provided by the applicant): Immune-mediated rejection is the principal obstacle to the use of heart transplantation for the treatment of end-stage cardiac failure. Current immunosuppressive regimens have limited efficacy and are associated with substantial toxicity. A key final common pathway of allograft injury is mediated by the free radical nitric oxide and the potent oxidant, peroxynitrite, which is formed from the reaction of nitric oxide and superoxide anion. Inotek is developing a novel class of peroxynitrite decomposition catalysts that are dramatically protective in experimental models of oxidant-mediated inflammatory diseases, including autoimmune arthritis, diabetes, and colitis. These agents are fundamentally superior to conventional antioxidants: First, they act as catalysts, rather than scavengers, and are therefore not consumed in the decomposition of oxidant species. Second, their reaction rate is in excess of 100 million, more than I million fold faster than classic anti-oxidants such as Vitamin C and E. Third, they have profound activity against both peroxynitrite and hydrogen peroxide, and thus provide broad-spectrum protection against oxidative and nitrosative stress. In vivo studies confirm their dramatic potency, as evidenced by protection in various models of inflammation at oral doses in the microgram per kg range. In experimental disease models, they have been shown to eliminate colitis, increase survival in endotoxic shock, and profundly reduce tissue damage during ischemia-reperfusion. The specific aim of the present proposal is to determine the benefit of our lead peroxynitrite decomposition catalyst, INO-1080, in the prevention of organ dysfunction and cellular injury in an experimental rodent model of heterotopic cardiac allograft rejection. We will establish the synergy of INO-1080, alone and with sub-therapeutic dosing of cyclosporine A. Demonstration that INO-1080 prevents tissue injury and prolongs allograft survival would represent a breakthrough in the design of novel anti-inflammatory regimens to prolong allograft survival. Phase II funding would support pharamcokinetic, toxicology, and pharmacodynamic studies required for IND submission and FDA-sanctioned clinical Phase I trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ORAL EPITHELIAL CELL CYTOKINES CANDIDA & PMN ACTIVATION Principal Investigator & Institution: Dongari-Bagtzoglou, Anna I.; Interim Department Head; Periodontology; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2002; Project Start 29-SEP-2000; Project End 31-JUL-2004 Summary: (abstract verbatim) Oropharyngeal candidiasis is particularly prevalent in patients who are immunocompromised by disease or immunosuppressive treatment. Interestingly, even in immunocompromised patients invasive oral candidiasis is rare and seems to be associated with additional risk factors such as extreme neutropenia. One strategy for improving resistance to opportunistic pathogens is to define host cellular responses during the invasion process and enhance those responses that are relevant to defense mechanisms. Compelling experimental evidence suggests that the primary effector cell responsible for Candida clearance is the neutrophil. Neutrophils accumulate rapidly at the site of infection in the oral cavity and participate in the local control of Candida growth and invasion, yet very little is known about the host signals
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responsible for regulating these events. Several cytokines provide signals for neutrophil activation of antifungal functions, including interleukin-1 beta (IL-1b) and granulocyte macrophage colony stimulating factor (GM-CSF). In cases of T-helper cell depletion or inactivation, such as HIV disease or Cyclosporin A treatment, PMN are most likely potentiated in their anti-fungal function by stimulating cytokines derived from nonimmune cell. Epithelial cells are capable of synthesizing IL-1b and GM-CSF and maybe one of the few defenses remaining under CD+ T cell-deficient conditions. The central hypothesis of this project is that cytokines such as IL-1b and GM-CSF are released by oral epithelial cells upon interaction with Candida and act as local stimulators of neutrophil anti-fungal functions. Using a human oral epithelial cell Candida albicans coculture model system the applicants will first determine whether this microorganism can trigger secretion of these potent neutrophil activating cytokines by oral epithelial cells. Once this goal is accomplished, mechanisms eliciting Candida-mediated cytokine responses will be explored. Finally, they will perform functional assays for these epithelial cell-derived cytokines as they relate to neutrophil activation of Candida phagocytosis and killing, using isolated neutrophils from healthy, HIV+ and Cyclosporine A-treated individuals. Given the fact that most fungal infections take place in an immunocompromised host, neutrophil priming by non-immune cell derived cytokines may be of paramount importance, not just in the initiation of a protective inflammatory response, but also in the prevention of fungal invasion into the deeper connective tissues of the oral mucosa. The studies proposed herein will be crucial in identifying oral epithelial cell-derived cytokines with the potential to prime neutrophil antifungal function in vitro. Identification of such cytokines may have future therapeutic applications in the treatment of oral candidiasis in the severely immunocompromised host. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OXIDATIVE PHOSPHORYLATION IN CELL GROWTH AND DEATH Principal Investigator & Institution: Moraes, Carlos Torres.; Professor; Neurology; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 15-JAN-2001; Project End 31-DEC-2004 Summary: (Adapted from investigator's abstract): The PI proposes to study the effects of mtDNA oxidative phosphorylation (OXPHOS) defects in two aspects of cancer. There are two main goals: First, determine the role of OXPHOS defects in cell growth and tumor development; and second, determine the role of OXPHOS defects in cell death. The background is that somatic mtDNA mutations have been described in many colorectal tumors. However, their role in tumor growth is not understood. He plans to use three colorectal cancer cell lines with mtDNA mutations as models to study the phenotypic consequence of mtDNA mutations. The mtDNA from these cell lines will be transferred to an osteosarcoma cell line without mtDNA, and the effects on mitochondrial function and cell growth will be assessed. The effects of these and other mtDNA mutations in OXPHOS on reactive oxygen species production, cell growth, and apoptosis in vitro and in vivo will be examined. In a second specific aim, he will study the effect of genetically determined mitochondrial dysfunction on apoptosis. Osteosarcoma cell lines with and without mtDNA will be used to examine the effects of low mitochondrial membrane potential and impaired OXPHOS on susceptibility to apoptosis. The effects of Bcl-XL and Bax expression in differing mtDNA contexts will also be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OXIDATIVE STRESS SIGNALING IN GRAFT CORONARY DISEASE Principal Investigator & Institution: Robbins, Robert C.; Assistant Professor; Cardiothoracic Surgery; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Verbatim from the applicant's abstract) We propose to investigate the role that early myocardial oxadative stress signaling pathways have in the development of graft coronary artery disease (GCAD) following cardiac transplantation. In the established PVG donor to ACI recipient rat model, expression of bcl-2 decreases and nuclear factor kappa-B (NFkB) activity increases in the early reperfusion period. Inhibition of NFkB reduces reperfusion injury and GCAD in this model. In other models of ischemia and reperfusion BCL-2 has been shown to regulate NFkB activity. The overall hypothesis of this proposal is that myocardial oxidative stress following cardiac transplantation contributes to the development of graft coronary artery disease via a bcl2 associated mechanism. The specific aims of the proposed work are: 1) To delineate the dependence of early myocardial oxidative stress and NFkB activity on bcl-2 expression following cardiac transplantation; 2) To determine the effects of decreased or increased myocardial oxidative stress on bcl-2 expression and NFkB activity following cardiac transplantation; and 3) To determine the role that early post-transplantation myocardial bcl-2 expression and intracellular localization plays in the later development of graft coronary artery disease. This proposal utilizes transgenic mice to more clearly characterize the role that bcl-2 plays in NFkB activation and in the development of myocardial oxidative stress following cardiac transplantation. The knowledge gained in the transgenic experiments will contribute to the overall understanding of the effects of bcl-2 overexpression on the development of GCAD in the PVG to ACI model. Upon completion of this study, we will have demonstrated the potential of altering the signaling pathways of oxidative stress by graft specific modulation, which may have applicability for other solid organ transplantation and as a myocardial protection strategy for routine cardiac surgical procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PANCREAS AND ISLET TRANSPLANTATION IN HUMANS Principal Investigator & Institution: Robertson, R Paul.; Scientific Director and Ceo; Pacific Northwest Research Institute 720 Broadway Seattle, Wa 98122 Timing: Fiscal Year 2002; Project Start 01-DEC-1988; Project End 31-JUL-2006 Summary: (provided by applicant): The overall objective of these studies is to better understand pancreatic beta and alpha cell function in human recipients of successful pancreas and islet transplantation who are taking immunosuppressive drugs and to better ascertain metabolic consequences of hemi-pancreatectomy in human donors of pancreatic segments. The general intent of the work proposed is to continue our long term follow up of recipients and donors of pancreas transplantation and to initiate new studies of type 1 diabetic recipients of intrahepatic autoislet transplantation with a major emphasis on developing an understanding why initially successful alloislet recipients later develop islet failure; the mechanism of action by which immunosuppressive drugs are toxic to beta cells; and developing a better understanding of the failure of the intrahepatic alpha cell to secrete glucagon during hypoglycemia. The Specific Aims for this proposal are: Specific Aim # 1. To continue long-term, longitudinal studies of insulin secretory reserve and counterregulatory hormonal responses to hypoglycemia in successful recipients of pancreas transplants and in living donors of pancreatic segments to determine whether islet beta cell and alpha cell function are stable or undergo
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deterioration with time. Specific Aim # 2. To determine whether deterioration in glycemic control after successful alloislet transplantation in type 1 diabetic patients is related to resurgence of autoimmune disease, and/or toxic effects of immunosuppressive drugs, and/or the quantity and quality of islets transplanted and/or the development of obesity and insulin resistance. Specific Aim # 3. To determine, using human isolated islets, the immunosuppressive drug concentrationadverse biologic response relationships for islet hormonal secretion, apoptosis, and cellular replication. Specific Aim #4. To determine whether the glucagon response to hypoglycemia is consistently absent and the epinephrine response to hypoglycemia is consistently restored in successful type 1 diabetic recipients of alloislets. Specific Aim # 5. To determine whether the glucagon response that normally occurs during hypoglycemia is dependent on a decrease in insulin secretion from adjacent beta cells as a "switch off' signal. The metabolic testing of pancreas and islet recipients as well as hemi-pancreatectomized donors will take place at the University of Washington and the University of Minnesota GCRC's. The methods will include glucose potentiation of arginine induced insulin secretion, euglycemic hyperinsulinemic clamps, and hypoglycemic hyperinsulinemic clamps. The laboratory methods will include isolated human islets and studies of insulin promoter activity, insulin mRNA levels, insulin content, and insulin secretion. Studies of the mechanism of glucagon release during hypoglycemia and its disappearance in the absence of beta cells will be conducted in Sprague Dawley rats. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Luchtman-Jones, Lori; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: The Washington University Medical Center in St. Louis is one of the 39 full member institutions, 48 affiliate, 12 consortia and 9 CCOP institutions of the Pediatric Oncology Group who has pooled their patient resources and scientific expertise to study the natural history of childhood cancer, develop and compare effective therapeutic regimens and investigate the toxicity and effectiveness of new anticancer agents in the treatment of children with cancer. Additionally tumor specimens and occasionally normal tissue and blood samples are collected to determine more about the basic cancer biology and pathology of the disease. Group studies are ongoing in epidemiology, cancer control, pharmacology and pharmacokinetics. The investigators at the Washington University Medical Center include pediatric oncologists, radiologists, radiation oncologists, cytogenetists, neurologists, surgeons, and pathologists. All children with malignant disease are placed on cooperative group protocols if they are eligible and if informed consent is obtained. Data accessioned at the time the patient is placed on study protocol, during the study, and when off therapy is submitted to the Group Statistical Office for data analysis, interpretation and eventual publication. The investigators at Washington University Medical Center serve in multiple administrative and research capacities for the Group. The diagnostic studies, pathological findings, surgical procedure and therapeutic plan for all new patients and patients who relapse are discussed at the weekly Tumor Board Conference. The Principal Investigator has a phase I contract and works with 16 other POG institutions to establish the maximum tolerated dose of a new agent along with the pharmacology and, if indicated, the biologic response of the agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Ravindranath, Yaddanapudi; Pediatrics; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-JUN-1981; Project End 31-DEC-2002 Summary: This proposal is a request for funding for our continued involvement in the Pediatric Oncology Group (POG). The aims and objectives are to find better means of management for malignant diseases in children and adolescents, and thus increase disease-free survival rates. The Children's Hospital of Michigan (CHM) provides diagnostic evaluation and multimodal therapy for children throughout the State of Michigan. While there is one other Pediatric Oncology facility in the State, the Hematology/Oncology service sees almost all children and adolescents with malignant disease who live in the greater metropolitan Detroit area, and also sees large numbers of such children referred from other parts of the State (and from Canada) regardless of their ability to pay. Until 1979, the oncology service at CHM remained "independent". In September 1979, the CHM oncology team joined the pediatric division of the Southwest Oncology Group and in January 1981 joined the Pediatric Oncology Group, which appears to have even a greater potential for development of better treatment regimens for childhood malignant disease. At the time of referral and/or admission to CHM for possible malignancy, each child is seen and evaluated by the appropriate oncology team members. Following appropriate diagnostic evaluation, each child is presented and discussed at the Tumor Board, which meets weekly and is attended by pediatric oncologists, pathologists, radiologists, surgeons, surgical subspecialities, and radiotherapists. A plan of action is outlined for each child's management. All such children are registered with POG, and whenever judged appropriate, children are entered on POG treatment protocols. By our participation in such a cooperative children's cancer group, our investigators are able to share new information and ideas and gain access to new multimodal therapy regimens and investigational drugs which hopefully provide the best available care to these children. Our objectives in the coming years are: 1) increased participation in POG cancer biology and epidemiology studies; 2) to continue our leukemia biology studies particularly pharmacology studies in AML/T ALL, and 3) to develop new strategies for treatment of brain tumors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Grier, Holcombe E.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-1986; Project End 31-DEC-2002 Summary: The principal activity of this grant is to improve the care and treatment of children with cancer by participating in the Pediatric Oncology Group (POG). The three specific goals of the participation of the Dana-Farber Cancer Institute/Children's Hospital (DFCI/CH) and Maine Children's Cancer Program (MCCP) are to 1) enter and follow children with malignancies on appropriate Pediatric Oncology Group (POG) protocols 2) provide leadership in planning and executing POG protocols and 3) provide pilot clinical studies and scientific leadership to POG. 1) Patient entry: the referral patterns at the two institutions has not changed and the commitment to POG protocols remains high. Therefore, patients accrual will continue at the high level previously noted over the last grant period. 2) Leadership within POG: Drs. Weinstein and Grier respectively are the disease chairs for the Myeloid and Sarcoma Committees. The disease committee chairs have primary responsibility for all scientific and clinical
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activities within POG. Investigators from these institutions are currently or were in the last cycle chairs for 7 separate POG protocols and co chairs of 35 more. They also have 18 positions on disease or discipline committees within POG. Enthusiasm remains strong, and involvement at the current level will continue. 3) Pilot POG protocols and scientific leadership: Scientific leadership is detailed in part above. Dr. Arceci provided scientific leadership for and analyzed the samples of the MEC protocol (#9222) that piloted the use of multidrug resistance reversal agents (cyclosporine) in relapsed AML. This protocol provided the background for the about to open group wide AML up-front protocol (#9394) that will randomize whether or not patients will receive cyclosporine during maintenance therapy. DFCI ALL protocols have provided the background for one of the arms of the proposed new T- cell protocol (#9404). In addition, the background for the current stereotactic protocol (#9373) was in part developed at the Joint Center for Radiation Therapy and the DFCI. Finally, POG has embarked on a major effort to study the autologous transplant protocols for ALL (#9421) developed at the DFCl. Finally Dr. Lipshultz ran at DFCI/CH the pilot studies of late cardiac toxicity from anthracyclines that provides the background data for the randomized trial of enalapril for patients with elevated after load. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Castleberry, Robert P.; Professor of Pediatrics; Pediatrics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-MAR-1979; Project End 31-DEC-2002 Summary: The University of Alabama at Birmingham (UAB) is a leading contributor to the ongoing clinical and basic research activities of the Pediatric Oncology Group (POG) which are focused upon improving the care and cure for children with cancer. Current results of these trials are in some cases already published and are available in the Progress Report. The leadership from UAB in POG is evident in several areas: l) through enrollment of substantial numbers of assessable patients on Phase I, II and III therapeutic trials, including multidiscipline (surgery, chemotherapy, and radiotherapy) management studies; through participation in and development of Group-wide biological studies of selected hematopoietic and solid malignancies; through evolving, coordinating and reporting data from POG therapeutic trials; and by providing discipline and disease committee, and administrative leadership within the group. UAB will continue to enroll all eligible patients on active POG therapeutic and biological studies, including phase I investigations, and maintain high evaluability. UAB investigators will continue to coordinate clinical trials for children with neuroblastoma, bone tumors, and juvenile chronic myelogenous leukemia (JCML) and to assess the therapeutic utility of IL6. Further, UAB investigators will be principal to the development of new studies in neuroblastoma, brain tumors, JCML and acute myelogenous leukemia. UAB will continue to supervise laboratories for POG in the following areas: 1) Banded chromosomal analysis in newly diagnosed patients with lymphoid leukemia; 2) A required reference laboratory for children with JCML (POG #9265) studying the pathogenesis of myeloproliferation; 3) A required serum/plasma repository (POG #9047) with clinical and demographic data referenced on a computer data base; and 4) A non- mandatory reference laboratory to evaluate the biological and clinical significance of rnicrotubular associated protein (MAP) and tubulin isotype expression in neuroblastoma. UAB investigators will continue their scientific and administrative leadership roles on the Neuroblastoma and Other Embryonal Tumors, Myeloid Disease Core, Biologic Response Modifier Core, Executive, Principal
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Investigator Core, Clinical Research Associate Core, and Diagnostic Imaging Core Committees. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Kavan, Petr; Montreal Children's Hospital 2300 Tupper St Montreal, Pq Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The Pediatric Oncology Group (POG) is a multi-disciplinary, multiinstitutional research community which collaborates to increase knowledge of and improve treatment for cancer and leukemia in children and adolescents. The Montreal Children's Hospital/McGill University (MCH), a founding member, requests funding for itself and its two affiliates, the Children's Hospital of Eastern Ontario (CHEO) and the University of Sherbrooke Medical Center (USMC) to continue to participate fully in administrative and scientific activities of the POG during the next 5 years. We expect to enroll a total of 70 patients a year on therapeutic protocols for childhood leukemias, lymphomas, solid tumors and brain tumors, with continued emphasis on Phase I and II studies of new agents and coordination or co-coordination of a minimum of 13 protocols. We expect to enroll 110 patients per year on non-therapeutic studies of cancer etiology, epidemiology, biology, psychologic impact and late effects of therapy with particular emphasis on the pharmacology and molecular pharmacology of methotrexate in acute lymphoblastic leukemia (ALL). We will comply with all requirements of the POG constitution, with MR regulations governing ethical conduct of clinical research and with OPRR and IRB requirements for informed consent and protection of subjects from research risks. In addition to an anticipated doubling of patient accruals since 5 years ago, our major contributions to POG research will include: confirmation that the extent of accumulation of methotrexate polyglutamates by lymphoblasts in B-progenitor cell ALL correlates with event-free survival (EFS) and characterization of the mechanisms regulating this metabolism (Whitehead); promotion of new agent drug development through New Agents and Pharmacology Committee leadership (Whitehead and Bernstein) and protocol coordination (Bernstein, Baruchel); introduction of stereotactic and fractionated stereotactic radiation therapy in brain tumors (Freeman); coordination of treatment protocols of newly-diagnosed and relapsed B-progenitor cell ALL (Abish, Bernstein); introduction of new agents and combinations in recurrent lymphoid disease as Sub-committee Chair, Lymphoid Relapse (Bernstein); chemotherapy and surgery of brain tumors (Baruchel, Ventureyra); and study of the biology, including p53 gene mutations, and treatment of HIV-related lymphomas (Baruchel, Whitehead). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Link, Michael P.; Professor; Pediatrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The overall goal of this research proposal is for Stanford University, the University of Arizona, and the Kaiser Permanente Medical Centers of the South San Francisco Bay Area to continue their active involvement in Pediatric Oncology Group research activities. Stanford faculty and the University of Arizona faculty have already assumed key leadership positions in POG and have or have had major roles in the
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scientific and administrative aspects of the Group. Further, Stanford, the University of Arizona, and Kaiser have maintained excellent performance ratings in their participation in POG studies and have received commendations for the large numbers of evaluable patients placed on therapeutic protocols. Specifically: l) We plan to continue to enter patients on appropriate POG studies where they exist. The number of patient entries from Stanford has increased each year as appropriate POG studies become available. We anticipate that between 65 and 80 patients will be entered on front-line therapeutic studies each year from Stanford in addition to patients who will be entered from the affiliates; in addition, 40-50 patients or more will be entered on POG non-therapeutic studies. 2) We anticipate that the activities of individual investigators from Stanford and the University of Arizona will continue and increase during the period of this research proposal. Currently, our faculty serve as study coordinators for front- line therapeutic studies in lymphoma and leukemia, and they have coordinated and analyzed data from recently closed protocols in osteosarcoma, lymphoma, leukemia, and Ewing's sarcoma. Our faculty also serve key scientific and administrative roles as Group Vice Chair, Disease and Discipline Committee Chairmen and CoChairmen, as members of Disease and Discipline Core Committees, and as members of the Executive Committee. Thus, our faculty are in position to influence the future direction of the scientific activities of POG. 3) We anticipate that involvement of Stanford faculty in the laboratory scientific activities of POG will continue. The laboratories of Drs. Link and Cleary have served as immunology reference laboratories and molecular biologic reference laboratories for leukemia studies of POG. 4) We anticipate that non-POG related laboratory and clinical research conducted at Stanford University and its affiliates will become increasingly relevant to POG activities. Some of these activities have already been incorporated into POG laboratory and therapeutic studies and others are targeted for incorporation into future POG studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Kung, Faith H.; Associate Professor; Pediatrics; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: This proposal represents a request to support continued participation in the pediatric Oncology Group (POG). This cooperative research is devoted to the investigation of chemotherapeutic, immunological and molecular biological approaches to the treatment of acute leukemia and other neoplastic diseases of childhood. Significant disease free survival has been achieved and contributions have been made in clinical pharmacology, tumor immunology and biology of cancer. However the real objective of these studies is the eradication of neoplastic diseases by treatment. Studies are being designed to reflect an increasing intensity of attack on the neoplastic cell. The cooperative group technique permits prompt evaluation in series of reasonable size of promising leads in chemotherapy. These leads or new approaches are often suggested by the results of the group's own work in clinical oncology. Thus, a completed protocol often suggests new avenues to be explored in new protocols. POG led in the investigation in the immunophenotyping of acute lymphoblastic leukemia, NTX polyglutamates accumulation in leukemic cells, and N-myc gene amplication in neuroblastoma, correlated the findings with patient outcome, and then incorporated them in new treatment protocols designed to improve the survival of children with cancer. The Division of pediatric Hematology/Oncology at the University of California, San Diego has 24 years experience (10 years in CALGB and 14 in POG) in cooperative
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clinical trials. In the past 5 years the 4 consortium member institutions had entered 332 patients on both therapeutic and non- therapeutic studies and the satellites, 211 patients. Our investigators served on 12 committees, designed/coordinated 16 group protocol studies. We also contributed to 15 group publications/presentations. Our investigators will continue to design and chair therapeutic protocols,and serve on committees. Dr. Yu's laboratory will continue to explore new immunotherapeutic agents for Group use, and serve as the Group Reference Laboratory. We plan to continue our active participation in all phases of POG activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Lauer, Stephen J.; Professor of Pediatrics; Pediatrics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-MAR-2003 Summary: The Pediatric Oncology Program at Emory University is the only comprehensive children's cancer center in Georgia and one of the largest of its kind in the Southeast. It serves a racially, ethnically, and socioeconomically diverse population from metropolitan Atlanta, the State of Georgia, and other states including Alabama, Arkansas, the Carolinas, Florida, and Mississippi. Since the inception of the Pediatric Oncology Group (POG), Emory is consistently one of the largest single-institution contributors to POG clinical and laboratory studies. Emory is a center for Phase I and pilot POG trials and has initiated numerous protocols that have subsequently been implemented by POG. The specific aims of the Emory POG Program are: l) to continue as a major source of patients for POG-sponsored Phase I, pilot, groupwide, and intergroup studies; 2) to provide leadership by its investigators as POG Study Coordinators, Co- coordinators, and Core Committee members; 3) to develop innovative institutional clinical trials on which to base future POG investigations; and 4) to maintain strong basic and translational research programs in pediatric oncology. To address these aims, Emory investigators are Coordinators for several major POG studies, including standard-risk new ALL (#9405), high-risk new ALL (#9006), salvage chemotherapy in relapsed neuroblastoma (#9140), and chemotherapy vs. autologous bone marrow transplantation (ABMT) in AML (#8821). Emory POG members actively participate in POG Core Committees, Subcommittees, and new protocol development. Institutional pilot studies include therapy of relapsed AML with idarubicin and chlordeoxyadenosine, treatment of relapsed solid tumors with high-dose busulfan/melphalan and ABMT, transplantation of haploidentical CD34+ cells for relapsed ALL or AML, and vincristine plus dose-escalated cyclophosphamide and infusions of peripheral blood-derived progenitor cells in refractory solid tumors. Complementary laboratory research activities include molecular biology of ALL (mechanisms of IL-6- mediated autocrine growth and aberrations in tumor-suppressor genes); in vitro sensitivity of leukemia cells to antineoplastic agents mid biological response modifiers; mechanisms of resistance of AML cells to alkylating agents; molecular neuro-oncology; and xenogeneic models to evaluate normal and neoplastic human hematopoiesis. Investigators at Emory are participating in the POG laboratory study of methotrexate metabolism by ALL cells (ALinC #16) and coordinate the study of alterations in p53 tumor-suppressor gene pathways in relapsed ALL (SIMAL #l0). Taken together, these activities of the Emory POG Program will continue to contribute to our knowledge of the biology, therapy, and prevention of neoplastic diseases in infancy, childhood and adolescence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Breitfeld, Philip P.; Pediatrics; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The goal of the proposed research is to determine optimum care for children with all types of cancer. The research mechanism involves participation by pediatric investigators in a consortium of medical institutions in North Carolina and West Virginia in collaborative multidisciplinary clinical cancer research protocols generated through the Pediatric Oncology Group. The proposed research grant will allow for the continued participation of Duke University Medical Center, Charlotte Memorial Hospital, East Carolina University School of Medicine and West Virginia University School of Medicine in Pediatric Oncology Group activities. These activities involve studies of the epidemiology and tumor biology of selected neoplasms and the natural history and optimum multimodal therapy of all childhood malignancies. Cooperative studies among physicians from a group of medical centers allow for rapid accrual of a statistically significant number of children with cancer in order to define quickly both those avenues of biologic research which have immediate clinical relevance and those therapeutic approaches which provide prolonged disease-free survival. Through participation in cooperative studies, the entire medical community engaged in the care of children with cancer has a focal point to provide not only improved patient care but also improved multidisciplinary teaching and research. Our objectives for the coming years are: 1) to develop new protocols for the immunologic stratification and chemotherapeutic management of patients with malignant lymphoproliferative and myeloproliferative disorders; 2) to develop protocols for specific brain tumor therapy which take advantage of our expanding knowledge of the biology and pharmacologic sensitivity of human brain tumors in vitro and in vivo; 3) to expand our studies of the pharmacologic agents which influence intermediary metabolism, using our in vitro data as the basis for drug scheduling in clinical trials; 4) to expand our innovative groupwide epidemiology studies to include studies of neuroblastoma and T-cell malignancies which include laboratory investigation (immunologic, biochemical and cytogenetic) where relevant; 5) to expand our multidisciplinary therapeutic research efforts in other pediatric malignancies; and 6) to expand our outreach programs for patient care and education through our regional consortium. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Steuber, C P.; Pediatrics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: The concept of the pediatric cooperative cancer group was introduced over 30 years ago because of the rarity of pediatric malignant diseases and the vital importance of controlled trials to improve the outcome for such patients. For such a group to succeed, the collaborative contributions of individuals from a large variety of specialties and fields of research are absolutely essential. This multimodal organized approach to the treatment of childhood cancer through the cooperative group has welldemonstrated its value. The Section of Pediatric Hematology-Oncology at Baylor College of Medicine has been involved in the genesis of this kind of clinical research and has participated in the activities at even level. The current goals of the Section regarding cancer prevention, treatment, and research have lead to the recent development of the
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Texas Children's Cancer Center. The Center is a joint effort of Texas Children's Hospital and Baylor College of Medicine and is committed to providing the finest possible patient care, education and research in the areas of pediatric and adolescent cancer and hematological disorders. Major expansion of the clinic and research lab facility is underway. New faculty are being recruited to expand the current research program in the areas of gene therapy, bone marrow transplantation, molecular biology, clinical pharmacology, and experimental therapeutics. Additional personnel including data managers, pediatric nurse practitioners, and research personnel have been recruited to support the new faculty members and the expanded programs. In addition, outreach efforts are making the Center known to communities in Texas that would benefit from a service dedicated to the treatment of children with cancer. The development of the Texas Children's Cancer Center will enhance Baylor's contributions to the Pediatric Oncology Group (POG) by expanding the research and treatment programs that have so successfully contributed to POG throughout the years, by developing new and innovative treatment and research programs, and by increasing study populations for those programs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Meyer, William H.; Pediatrics; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 01-JAN-1978; Project End 31-DEC-2002 Summary: Children's Hospital of Oklahoma (CHO) at the University of Oklahoma is a member institution of the Pediatric Oncology Group. One of our primary goals is the enrollment of the majority of pediatric patients with cancer in the state of Oklahoma in a cooperative cancer program (POG). Participation in group studies guarantees optimal care for these patients and the opportunity to study in depth the natural history of childhood cancer, develop effective therapeutic regimens, and evaluate the toxicity. and effectiveness of new anti-cancer agents in the treatment of childhood cancer. In addition to the POG studies, institutional non- therapeutic protocols have been developed, i.e., evaluation of leukemic therapy on the central nervous system of newly diagnosed leukemic patients and longitudinal evaluation of coping mechanisms with stress among patients and parents of children with cancer. For all these programs, patient resources and scientific expertise are available in Children's Hospital of Oklahoma. The team at the University of Oklahoma is multidisciplinary. It consists of pediatric hematologistsoncologists, radiation therapists, radiologists, pediatric surgeons, immunologists, pathologists and psychologists. All protocols are reviewed by the Institutional Review Board and informed consent is obtained on all patients entered into these protocols. Protocol compliance remains a high priority. The evaluability rate for the last four years averaged 92.5%. St. Francis Hospital of Tulsa was previously considered a branch of CHO. At the request of the POG Operations Office, Tulsa has applied to become an affiliate institution. The University of New Mexico is also affiliated with the University of Oklahoma. It serves an economically disadvantaged population (native American Indians) which needs to be included in the population studied by cooperative cancer groups. The Pathology Department at the University of New Mexico has special expertise in molecular diagnostic hematopathology and in solid tumors which can benefit the research efforts of the Pediatric Oncology Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP Principal Investigator & Institution: Cohn, Susan L.; Associate Professor of Pediatrics; Children's Memorial Hospital (Chicago) Chicago, Il 606143394 Timing: Fiscal Year 2002; Project Start 01-DEC-1978; Project End 31-DEC-2002 Summary: The objectives of this project are to enroll children with cancer in clinical trials, to develop clinical trials and study the biologic behaviors of childhood cancer, and to improve and evaluate the disease- free survival of patients enrolled in these clinical trials. In order to achieve these goals, the member institutions of the Pediatric Oncology Group (POG) meet biannually to discuss, develop, and implement clinical trials for the most common childhood malignancies and to supply the reference research laboratories of the proper material or tissue necessary for the research. Since 1989, CMH has been one of the member institutions of POG who is actually involved in the accrual of children with cancer to clinical trials. CMH's faculty is also involved in the coordination of studies either as the Principal Investigator or co-Investigator. These protocols are POG 9443, POG 9240/41/42, POG 9135/6, POG 9410, NTWS #5. Participation in administrative activities within POG include the POG Chairperson, the POG Executive Officer, the Head of the Neuroblastoma Biology Committee, the Head of the Neuroblastoma Bone Marrow Transplant Working Group, along with members of the following committees: Non- Hodgkin's Lymphoma, Neuroblastoma, Bone Marrow Transplantation, Hodgkin's Disease, New ALL, Wilms' Tumor, Nursing, and Surgery, Radiotherapy, and Pathology Disciplines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP ACTIVITIES Principal Investigator & Institution: Winick, Naomi J.; Professor of Pediatrics; Pediatrics; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: This grant application seeks continued support for the Pediatric Oncology Group (POG) activities of The University of Texas Southwestern Medical Center (UT Southwestern) Consortium, which consists of UT Southwestern (Dallas), Cook-Ft. Worth Children's Medical Center (Ft. Worth), and Scott & White Clinic (Temple). Since joining POG in 1981, this partnership of children's cancer treatment and research centers in North Texas has grown to become POG's largest contributing member with regard to patients enrolled on therapeutic studies (over 100 annually). During the current grant cycle, consortium investigators have held administrative and scientific leadership positions on major Group committees, including Executive Committee, Principal Investigator's Committee, New ALL Committee, T-cell Committee, and Lymphoid Relapse Committee. UT Southwestern Consortium investigators have also served or are serving as study coordinators on multiple POG treatment protocols studying ALL (newly diagnosed patients with B-lineage and T-cell disease as well as following relapse), non-Hodgkin's lymphoma, bone marrow transplantation and new agents being explored in Phase I-II trials. UT Southwestern Consortium investigators have also had prominent roles in the arenas of data management, protocol development, molecular and pharmacologic monitoring in authorized POG reference laboratories, and supportive care. Results of pilot projects conducted at UT Southwestern have been instrumental in the construct of group-wide treatment strategies, especially involving use of methotrexate for B-lineage ALL. To support the UT Southwestern Consortium's continued commitment to POG research during the next 5 years, this new grant proposal describes personnel and facilities in the 3 consortium centers. Specifically,
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during 1996-2000 the Consortium aims to advance POG research by: (l) enrolling as many patients as possible on POG treatment, biological classification, and epidemiology protocols; (2) collecting, recording, and submitting research data in an accurate and timely fashion; (3) providing administrative and scientific expertise to the Group through continued active participation on major committees, including service as disease committee chairs and protocol coordinators; and (4) continuing to conduct innovative in-house pilot studies for subsequent use by the Group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP MEMBERSHIP Principal Investigator & Institution: Schwartz, Cindy L.; Associate Professor; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: The aim of this research is to improve the treatment of childhood cancer through participation in organized clinical trials with fellow members of the Pediatric Oncology Group. In addition, we intend to expand our understanding of these diseases by collaborative laboratory investigations. Multiple projects are described which reflect the intense commitment of our faculty to work within the Pediatric Oncology Group. Our faculty are leaders of the POG commitments in ALL phenotyping, Neuropathology, Bone Tumors, Hodgkins disease, Rhabdomyosarcoma, Radiation Oncology, Bone Marrow Transplantation, Myeloid disease, Germ Cell Tumors, Late Effects of Childhood Cancer Therapy, and Multiple Drug Resistance. Pediatrics is the program that describes patient accrual and protocol activity within the division of Pediatric Oncology at Johns Hopkins under the supervision of Dr. Cindy Schwartz as POG PI. The disciplines of Radiation Oncology, Pathology, Pediatric Surgery, Orthopedic Surgery, Neurosurgery and Nursing also play a major role in patient accrual and protocol activity. In addition, Fairfax Hospital under the direction of Dr. Jay Greenberg is an active affiliate of our institution. With the limited numbers of children admitted with any single oncologic diagnosis to an individual institution, it is clear that cooperative clinical research is required if significant advances are to be made. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PEDIATRIC ONCOLOGY GROUP PARTICIPATION Principal Investigator & Institution: Pui, Ching-Hon; Acting Chairman; St. Jude Children's Research Hospital Memphis, Tn 381052794 Timing: Fiscal Year 2002; Project Start 01-JAN-1982; Project End 31-DEC-2002 Summary: We propose continued participation in the Pediatric Oncology Group (POG). Our goals are as follows: (1) to improve cure rates for children with cancer through participation in Phase I, II, and III clinical trials designed to test new agents or concepts; and (2) to participate in laboratory-based research aimed at clarifying the basis of drug resistance and pathogenetic mechanisms of childhood cancers. We are committed to Group participation because we believe: (1) that collaborative efforts are both desirable and necessary for study of childhood cancers, since all are relatively rare; and (2) that well-designed randomized clinical trials provide the most definitive test of efficacy and general applicability of new therapies and that pooled intellectual resources are advantageous as well. Our contribution to the Group can be categorized as follows: (1) contribution of selected patients (those with rare tumors or less common stages of other cancers, n approximately 80-100/year) to Group studies; (2) administrative and scientific leadership (e.g., disease or discipline committee chairs, and protocol
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coordinators); (3) provision of multiple reference laboratories (flow cytometry analyses of leukemia and solid tumors, cell bank, AML cytogenetics, pharmacokinetics/pharmacodynamics, molecular genetics of leukemia and solid tumor); (4) regular presentation of results of in-house research to the group. Since our center has an unusually large number of patients and staff (both clinical and basic), the latter contribution assumes unusual importance. We have an extensive in-house developmental therapeutics program which is independent of, but complementary to, the Group's clinical research programs. We also have extensive programs in basic research. The aim of these programs, to determine the pathogenesis of pediatric neoplasia, is expected to positively influence the Group's central goal -- curing children with cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP STUDIES Principal Investigator & Institution: Mclean, Thomas W.; Pediatrics; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-1991; Project End 31-DEC-2002 Summary: The overall objective of the proposed research effort is to continue work towards determining the optimum care for children with all types of cancer. The research mechanism involves participation by pediatric investigators at the Bowman Gray School of Medicine in the development and execution of collaborative multidisciplinary clinical protocols of the pediatric Oncology Group. The proposed research grant will support the continued participation of the Bowman Gray School of Medicine as a full member of the pediatric Oncology Group. Our accomplishments in the past grant period are described in detail in the proposal. Our institutional goals for the five year period of this grant include: (1) continuing our high level of patient accrual and excellent clinical contributions to the POG including our outstanding patient evaluability and protocol compliance which has merited a letter of commendation from the operations office at every 6-month analysis in the past (2) maintaining our institutional involvement in POG leukemia studies and our representation on the new ALL core committee (3) continuation and further development of our multi-disciplinary institutional commitment to POG Hodgkin's disease activities (4) a major role on the POG cytogenetics committee including optimal use of our new reference laboratory status (5) increased institutional development of late effects studies in collaboration with the POG late effects efforts (6) expansion of our efforts in neuro-oncology including increased enrollment on brain tumor studies and investigator roles on the POG brain tumor committee (7) use of in situ studies of tumor cell ploidy in collaboration with POG and other investigators (8) continued contributions to the administrative aspects of the POG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CANCER CTR
PEDIATRIC
ONCOLOGY
GROUP--MIDWEST
CHILDREN'S
Principal Investigator & Institution: Camitta, Bruce M.; Pediatrics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-JAN-1983; Project End 31-DEC-2002 Summary: The primary objective of the Midwest Children's Cancer Center is to reduce the incidence of and mortality from childhood cancers. This is approached by: 1) providing the best possible patient care (diagnostic and therapeutic; 2) education of
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medical and nonmedical groups as to the types of, treatments for, and availability of care for different childhood cancers; and 3) clinical and laboratory research. Investigators at the Cancer Center include specialists in pediatric oncology, surgery, orthopedic surgery, neurosurgery, radiology, radiation therapy, pathology, neurology, psychology and nursing. All new patients are discussed at a multidisciplinary Tumor Board. The children are then treated on Pediatric Oncology Group (POG) or institutional protocols. Results are analyzed and reported regularly. The purpose for the Midwest Children's Cancer Center's participation in POG are: l) to enhance the probability of achieving the above objectives by collaboration with other institutions in the design and execution of clinical protocols; and 2) to evaluate, through laboratory investigations, aspects of tumor biology which result in successful and unsuccessful therapy. Pediatric tumors are relatively rare. The POG is composed of more than 50 member institutions. By pooling resources, biologic and therapeutic studies on these uncommon tumors are facilitated. Similar collaboration permits more rapid development of new drugs. In addition, participation in a common milieu promotes dissemination of information between institutions and investigators. If all children with cancer receive the best possible care, morbidity and mortality will be minimized. The Midwest Children's Cancer Center has been a major contributor to POG by: 1) patient accrual; 2) coordination of POG protocols; 3) institutional pilot studies that were advanced to POG studies; and 4) participation in POG disease and administrative committees. In the next grant period we will continue each of these activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PEDIATRIC ONCOLOGY GROUP--THE CAROLINAS CONSORTIUM Principal Investigator & Institution: Barredo, Julio C.; Professor; Pediatrics; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 15-JUN-1996; Project End 31-DEC-2002 Summary: (Adapted from the applicant's description): The institutions included in this proposal have been part of the Pediatric Oncology Group (POG) and received good performance scores during the past five years. There are two primary goals of this proposed research; the first is to accrue patients to the Group clinical trials in order to determine the optimal care of children with all types of cancers. The second is to contribute scientific expertise to the Group in areas of both patient care and tumor biology. This proposed research will allow participation in POG activities through a consortium effort of East Carolina University (ECU) School of Medicine, Carolinas Medical Center, Medical University of South Carolina (MUSC), Greenville Hospital, Presbyterian Hospital, and Memorial Mission Hospital (The Carolinas' Consortium). In addition to these clinical activities, their scientific efforts in next five years will include: (1) development of new protocols for the treatment of children with cancer focusing mainly on pediatric lymphomas; (2) expansion of studies of minimal marrow residual disease (using RT-PCR analysis) and assessment of new purging techniques in neuroblastoma; (3) participation in the laboratory evaluation of folylpolyglutamate synthetase (FPGS) in lymphoblasts of newly diagnosed patients; and (4) evaluation of the role hematopoietic growth factors in the treatment of pediatric malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHARMACODYNAMIC THRESHOLDS OF IMMUNOSUPPRESSION Principal Investigator & Institution: Sindhi, Rakesh K.; Children's Pittsburgh/Upmc Hlth Sys of Upmc Health Systems Pittsburgh, Pa 152132583
Hosp
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Timing: Fiscal Year 2002; Project Start 04-SEP-2001; Project End 31-MAY-2005 Summary: (provided by applicant): Acute rejection or side effects occur in nearly half of all transplant patients receiving immunosuppression. During our studies with regimens of (SRL) sirolimus+cyclosporine/tacrolimus (CsA/TAC), cytokine and costimulatory cell surface proteins (biomarkers), have demonstrated sensitivity to clinically relevant immunosuppressive drug concentrations in mitogen-stimulated peripheral blood lymphocytes (PBL) from normal and transplanted human subjects. Effect: concentration (pharmacodynamic, PD) relationships between biomarkers and drug concentrations also indicate ability to measure single- and multiple-agent effects within combination regiments, and to predict the amount of drug needed to inhibit a certain amount of biomarker, both for patient populations and individuals. However, prior to use as measures of immunosuppressive effect, the amount of biomarker inhibition associated with clinical conditions representing insufficient, excessive and adequate immunosuppression must be known. This may define safe amounts of drugs for children, who experience a higher incidence of life-threatening complications of immunosuppression such as post-transplant lymphoproliferative disorder. Therefore, the specific aim of this project is to measure biomarker expression during a planned pharmacokinetic (PK) evaluation of a SRL+TAC regimen in 40 children with liver transplants, relate it to amount of drug, and to determine whether the occurrence of acute rejection, side effects and stable post-transplant course can be related to threshold levels of biomarker inhibition or the amount of drug associated with such thresholds. During a sponsored clinical trial of SRL+TAC, our proposal will manage biomarker data as follows: 1. Measure mitogen-stimulated expression of the cytokines IL-2, TNF-alpha and IFN-gamma in T-cells, and of costimulatory proteins CD54 (intercellular adhesion molecule-1), CD86 (B7.2) and CD95 (Fas antigen) in B-cells, and the proliferative response of lymphocytes to donor antigen. This will be performed during PK studies planned in the clinical trial, and additionally, during rejection, side effects, and at 12, and 24 month after transplantiation. 2. PD modeling to predict biomarker thresholds or drug concentrations associated with them, which are related to the occurrence of acute rejection, side effects, and the stable post-transplant course. Potential benefits may include customized regimens in the future, and decreased complications in one-half of the nearly 40,000 new transplant recipients of solid organ and bone marrow grafts, each year. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PILOT TRANSPLANTATION
STUDY--CYCLOSPORINE
&
ISLET
CELL
Principal Investigator & Institution: Colgan, John; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-JAN-2008 Summary: Recent advances have shown that beta islet cell transplantation can provide long term, insulin independent control of type-1 diabetes. However, transplant recipients must undergo immunosuppressive therapy that causes islet cell dysfunction among other serious complications. Thus understanding how conventional immunosuppressive drugs affect islet cells as well as identifying alternative immunosuppressive therapies could greatly facilitate the routine use of islet cell transplantation as a curative. Cyclosporine is a clinically used immunosuppressant that causes diabetes and kidney failure. As an approach toward defining the mechanisms underlying the toxic and immunosuppressive effects of the drug, targeted disruption was used to create mice lacking cyclophilin A (CypA), an abundant cyctosolic protein
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Cyclosporine
that functions as the receptor for cyclosporine. CypA-deficient mice display normal immune function, but are resistant to immunosuppression by cyclosporine and suffer less toxicity. Thus, CypA-deficient mice provide a tool for dissecting the various effects of the drug. Regarding islet cell dysfunction, glucose regulation by wildtype and CypAdeficient islet cells in cyclosporine-treated mice can be compared. Maintenance of glucose regulation by CypA-deficient islet cells subjected to cyclosporine would indicate that the drug affects islet cells via interactions with CypA, and would point towards the involvement of specific regulatory pathways. How these pathways and their target genes are affected by cyclosporine could be further examined through molecular analysis of cultured wild-type and CypA-deficient islet cells. CypA-deficient mice also provide a way to identify the immune cells that must be targeted by cyclosporine in order to suppress transplant rejection. Genetically modified mice that are unable to generate specific immune cell types can be reconstituted with CypAdeficient cells via adoptive transfer. Reconstituted mice can then be treated with cyclosporine and challenged with allogeneic tissue in parallel with identically reconstituted animals not subjected to immunosuppression. The inability or ablility of mice reconstituted in different immune cell compartments to reject allogeneic tissue would provide an assay for determining the specific cell types that must be inhibited to prevent allograft rejection. Such knowledge could be applied toward the design of alternative immunosuppressive therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PODOCYTES & STRESS RESPONSE IN NEPHROTIC SYNDROME Principal Investigator & Institution: Smoyer, William E.; Pediatrics & Communicable Dis; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: Nephrotic syndrome is one of the most common forms of kidney disease in children. It is characterized by massive leakage of protein across the kidney's filtration barrier and dramatic structural changes in podocytes, which in part comprise the barrier. These changes include retraction (effacement) of the actin-rich podocyte foot processes with disruption of their actin filaments, and can be attenuated by treatment with reactive oxygen molecule scavengers, suggesting a link between NS and oxidant injury to podocytes. We recently detected a reported regulator of actin polymerization, heat shock protein 27 (hsp27), in normal podocytes, and reported induction of hsp27 in glomeruli during NS. We hypothesize that hsp27 has an important role in mediating the podocyte structural changes which occur in NS, via regulation of actin filament dynamics. We also hypothesize that hsp27 has an important role in the podocyte response to oxidant stress, and that the therapies commonly used to treat NS act by protecting podocytes from oxidant-induced injury via alterations in hsp27 expression and/or phosphorylation. To test these hypotheses we will: 1) Determine if induced changes in podocyte hsp27 expression and/or phosphorylation protect against NS, 2) Identify glomerular hsp27-binding proteins and measure changes in the interaction between hsp27 and the identified proteins during NS, and 3) Measure the protective effects of induced alterations in podocyte hsp27 on the podocyte stress response, and compare these effects to those resulting from podocyte treatment with corticosteroids, cyclosporine A, and cyclophosphamid (common treatments for NS). We will use both in vivo (PAN nephrosis in rats) and in vitro (PAN and protamine treatment of cultured "differentiated" podocytes) models of NS to determine if induction of hsp27 in vivo (whole animal hyperthermia, hsp27 transgenic animals) or in vitro (hsp27
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sense/antisense/phosphorylation mutant stable transfections) protects podocytes against foot process effacement and NS. A yeast two hybrid library from rat kidney glomeruli will be used to identify, and define hsp27-binding proteins, and alterations in their interactions with hsp27 during NS will be determined by biochemical analyses. Cultured "differentiated" podocytes transfected with hsp27 sense/antisense/phosphorylation mutants will be treated with stressors with specific biological relevance to NS (oxidant stress, actin filament disruption, heat shock) and the cellular stress response (survival, actin filament structure, induction of hsps and antioxidants) compared to that after treatment with drugs used for NS. Identification of a biologically important role for hsp27 in regulating podocyte structure in NS would permit the development of more highly targeted and less toxic therapies for this very common form of kidney disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: R21 PROJECT: ST. JOHN'S WORT VS. PLACEBO IN OCD Principal Investigator & Institution: Kobak, Kenneth A.; Senior Research Scientist; Dean Fdn for Health, Research & Educatn Research and Education Middleton, Wi 53562 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-JAN-2004 Summary: Obsessive compulsive disorder (OCD), a syndrome characterized by obsessions and compulsions, has a lifetime prevalence of 1-2%. Accumulating evidence in support of the serotonergic hypothesis on the etiology of OCD led to several serotonin reuptake inhibitors (SSRIs) being approved as a treatment for this disorder. However, even with adequate dose and duration non-response or partial response is the role. In addition, side effects with the SSRIs prompt the search for better tolerated compounds (e.g., drop-out rates in the multi-center trials of fluoxetine, fluvoxamine, sertraline, and paroxetine were 23%, 24%, 27%, and 20% respectively. There has been considerable worldwide interest in St. John's Wort (SJW) (Hypericum perforatum) as a treatment from mild to moderate depression. To date, there have been 23 randomized trials suggests SJW is more effective than placebo for the treatment of outpatients with mild to moderate depression. SJW is very well tolerated with mild side effects observed in only 2.5% of cases in a large drug monitoring study. SJW's mechanism of action is postulated by be via inhibition of the synaptosomal uptake of serotonin, and thus there is a suggestion that SJW may be effective for OCD. A recent 12- week open-label trial with 123 subjects with a fixed dose of 450 mg of hypericin twice daily found a significant change from baseline to endpoint, with a mean Y-BOCS change of 7.4 points (p=.002). Five of the 12 subjects previously failed to respond to a trial with an SSRI. The current study will be a 12-week, double-blind, placebo controlled parallel group study. The purpose of the study is to examine the efficacy and safety of SJW compared to placebo. Fifty subjects will be randomly assigned to SJW (Alterra bran, 450 mg, 1.35 hypericin) or matching placebo. This will be a fixed-dose design at 450 mg bid. An intent-to- treat analysis will be employed Subjects will be evaluated weekly for two weeks than biweekly thereafter. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATORY T CELLS IN CARDIAC ALLOGRAFT TOLERANCE Principal Investigator & Institution: Muniappan, Ashok; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005
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Cyclosporine
Summary: (provided by applicant): There is no reproducible technique for establishing donor specific tolerance in clinical transplantation. Dr. Madsen and his colleagues in the MGH Transplantation Biology Research Center (TBRC) have established a large animal model of cardiac allograft tolerance by co transplanting a kidney and heart allograft under a short course of cyclosporine A (CyA) in class IMHC disparate inbred miniature swine. Heart/kidney co transplantation provides the only consistent and reproducible model of nonablative cardiac allograft tolerance in large animals. However, the cell populations involved in the induction and maintenance of tolerance in this model have not been elucidated. Recent studies at the TBRC have indicated that the donor kidney and host thymus play a critical role in tolerant heart/kidney recipients. Based on this work, we hypothesize that host thymus-derived regulatory T cells, generated by cells or antigens derived from the donor kidney, are responsible for the induction of tolerance to cardiac allografts in heart/kidney recipients. We will test this hypothesis by performing a longitudinal in vitro characterization of regulatory T cells from different lymphoid compartments in tolerant heart/kidney recipients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REVERSIBLE PROTEIN PHOSPHORYLATION IN APICOMPLEXANS Principal Investigator & Institution: Barik, Sailen; Professor; Biochem and Molecular Biology; University of South Alabama Mobile, Al 366880002 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: The long-term goal of this proposal is to characterize the reversible protein phosphorylation pathways in reference to biochemical and genetic regulation in the Apicomplexan group of parasites. Protozan Apicomplexan parasites are exemplified by deadly pathogens such as Plasmodium that causes malaria, and Toxoplasma and Cryptosporidium that cause opportunistic infections in AIDS patients. Malaria, transmitted by mosquitoes, alone kills between 1.5 and 2.5 million people worldwide, mostly young children. The resurgence of drug-resistant parasites as well as pesticideresistant mosquitoes and the global transmission of the disease have produced an urgent need to understand the fundamental regulatory pathways of the parasite. Although our knowledge in this area is still rudimentary, a large body of evidence accumulated over the last two decades has shown that in higher animals a reversible protein phosphorylation provides a major mechanism of biochemical and genetic regulation. In this proposal, therefore, a combination of biochemistry and molecular biology will be employed to study selected Plasmodium protein phosphatases, key enzymes that are responsible for the dephosphorylation of specific phosphoproteins. The properties and regulation of these enzymes and their interactions with specific physiological inhibitors and drugs will be studied in- depth. The anti-parasitic drugs such as okadaic acid, a potent marine toxin, and cyclosporin, an immunosuppressant, will be used as tools in the analysis of the structure and function of specific protein phosphatases of the parasite. These results should form the cornerstone in the detailed elucidation of the regulatory pathways and possible drug-target interactions in Plasmodium in particular, and Apicomplexans in general. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SCREENING HERBS FOR DRUG INTERACTIONS Principal Investigator & Institution: Markowitz, John S.; Associate Professor; Pharmaceutical Sciences; Medical University of South Carolina P O Box 250854 Charleston, Sc 29425
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63
Timing: Fiscal Year 2002; Project Start 05-JUN-2001; Project End 31-MAY-2004 Summary: The use of herbal agents by the lay public and medical professionals has accelerated in the last decade. Additionally, there has been increasing interest by the NIH National Center for Complementary & Alternative Medicine (NCCAM) and others in the safety and efficacy of herbal medicines in the treatment of a variety of medical and psychiatric conditions. It has also become evident that herbal medications are being used concomitantly with conventional prescription and over-the-counter medications. However, the systematic evaluation of the potential of these agents to interact with conventional medications has been generally neglected. Compounding this problem is the fact that even single entity herbal products can contain a multitude of naturally occurring chemicals which serve as candidates for potential herb-drug interactions by inhibiting or inducing specific hepatic isozymes. Numerous reports document the importance of pharmacokinetic interactions involving inhibition or induction of the cytochrome P450 (CYP) enzyme system. Importantly, recent publications have documented that clinically significant herb-drug interactions can occur. Prominent examples include herb-induced reductions in plasma concentrations of the anti-HIV medication indinavir and the immunosuppressant cyclosporine by St. John's wort (Hypericum perforatum). In vitro screening studies are of limited value due to difficulties in approximating physiologic concentrations, assessing the influence of nonhepatic metabolism, and accounting for the contribution of active metabolites. However, based upon findings of the effects of concurrently administered herbs on the metabolism of enzyme specific probe drug substrates alprazolam (CYP 3A4) and dextromethorphan (CYP 2D6), the potential specificity and magnitude of CYP enzyme inhibition and/or induction can be determined in normal volunteers. In a preliminary study in human subjects using this validated probe drug technique assessing inhibitory effects only, the investigators found no effects of St. John's wort on CYP 3A4 or CYP 2D6. In the present proposal, the 10 most commonly used herbal products in the US will be systematically evaluated for inhibition of CYP 3A4 and 2136, and induction of CYP 3A4. Collectively, these enzyme systems are involved in the metabolism of approximately 80% of all marketed medications. A combination of probe drugs will be given to normal volunteers both in the absence and presence of herbal medications. The plasma and urine concentration of these agents and their respective metabolites will be determined in order to evaluate individual herbal products degree and specificity of enzyme inhibitory or inductive effects. This data will fill a void regarding the relative safety of combining specific herbal agents with conventional medications and will serve as the basis for further investigations of other isozymes and herb interactions. Further, the proposed studies will complement existing and future NCCAM studies of agents such as St. John's wort and Gingko biloba. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNTHETIC TRANSPLANTATION
INHIBITORS
OF
CD8+T
CELLS
IN
Principal Investigator & Institution: Korngold, Robert; Professor; Microbiology and Immunology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2005 Summary: CD8+ T cells play an important role in most transplantation reactions involving either MHC class I or multiple minor histocompatibility antigen (miHA) disparities. The CD8 molecule functions as a coreceptor for the T cell receptor (TCR) recognition of peptide antigens presented by MHC class I molecules on an appropriate
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Cyclosporine
antigen presenting cell. We have recently used a synthetic peptide analog mapping approach to study the structure/function relationship of the surfaces of CD8, and have unveiled sites potentially involved in class I MHC binding. Synthetic peptide mimics of these interactive sites appear to have inhibitory activity on the activation and effector function of CD8+ cytotoxic T lymphocytes (CTL) and therefore have potential as new immunoregulatory agents in allogeneic transplantation settings. In this regard, we will investigate the efficacy and mechanism of action of these CD8 inhibitors in two transplantation modalities - skin allograft rejection and graft-versus-host disease (GVHD). Skin allografts are recognized as a representative model for the classic rejection processes that occur in several types of solid organ transplantation. GVHD is a major, and often lethal, complication of clinical allogeneic bone marrow transplantation (BMT). The risk of GVHD can be reduced by HLA-matching of the marrow donor and recipient, with a matched sibling being the primary choice. However, even in this case GVHD is still prevalent (50-60 percent incidence), particularly due to disparities in minor histocompatibility antigens (miHA), which are capable of generating strong CD8+ T cell responses. In this proposal our specific aims are to: (1) determine the efficacy of inhibitors designed from the CDR2 and DE-loop surfaces of the CD8alpha molecule in the skin allograft and GVHD preclinical models; (2) determine the mechanism of action of the CD8 inhibitors; and (3) evaluate the immunocompetent status of BMT recipients in the GVHD models after treatment with the inhibitory agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: T-CELL MODULATION
GROWTH
FACTOR
PATHWAYS
AND
IMMUNE
Principal Investigator & Institution: Kirken, Robert A.; Integrative Biology and Pharmacology; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Organ failure associated with aging and advanced diabetes mellitus as well as severe autoimmune and inflammatory diseases represents severe medical problems. Despite major progress, achieving effective immunosuppression and long-term graft survival remains a serious obstacle that is complicated by their extreme side effects and toxicities associated with these first and second generation immunosuppressants including cyclosporine A and FK506. It is therefore essential to explore novel molecular aspects of T-cell activation and expansion so that safe and effective therapeutic strategies can be designed. Whereas cyclosporine targets T-cell receptor activation, several lines of evidence now justify a critical investigation of the later phase of T cell activity that is driven by interleukin-2 (IL2) family cytokines as new molecular targets for immune suppression. In this application, we present extensive and compelling preliminary data suggesting that pharmacological inhibition of IL2-induced Stat5 phosphorylation is remarkably effective against allograft rejection in animal models. The objective of this application is to investigate the effector pathways that regulate Stat5a/b activation and the genes they target. The principal hypothesis to be tested is that active Stat5 transcription factors are critical for T cell mediated immunity, and that in addition to the Jak3 tyrosine kinase, a yet-to-be identified Stat5 serine kinase is also important for mediating T cell responses. To accomplish the objective of this proposal, we will pursue three specific aims to 1) Determine the role that early and late phase T-cell surface receptors regulate Stat5a/b activation, 2) Functionally characterize and identify the 80 kDa proline-directed Stat5 serine kinase; and 3) Identify Stat5 target genes in human T cells using a genome-wide technology for trapping Stats response elements. This work is important, and may
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significantly advance the field by providing direct molecular rationale and preclinical evidence for a new immunosuppressive strategy that could replace or complement current treatments Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: T-CELLS IN LUNG INFLAMMATION Principal Investigator & Institution: Kao, Peter N.; Associate Professor; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-APR-1996; Project End 31-MAR-2006 Summary: (Applicant's Abstract): Lung inflammation involving activated T-cells is a characteristic feature of asthma, sarcoidosis, hypersensitivity pneumonitis and chronic allograft rejection after lung transplantation. T-cell activation triggers intracellular phosphorylations that lead to nuclear translocation of transcription factors in the NFkB/rel-homology family. In the nucleus of activated T-cells, global changes in chromatin structure allow access of transcription factors to their cognate binding sites. The IL-2 enhancer contains binding sites for NF-kB, AP-1, Oct-I and the purine-box regulator that binds to the antigen receptor response element/NF-AT target site. Purine-box regulator proteins of 45 kDa and 90 kDa were affinity-purified from the nucleus of activated Jurkat T-cells and partial amino acid sequence data were used to clone NP45 and NF9O cDNAs. NF45 and NF90 interact with the DNA-dependent protein kinase, Ku70 and Ku80. NF90 also interacts with dsRNA-activated protein kinase, PKR, and suppresses translation of specific mRNAs. Interleukin enhancer binding factor 3 (ILF3) is a longer form of NF90 that interacts with Protein Arginine Methyltransferase 1. NF45 and NF90 are autoantigens in murine lupus and human autoimmune diseases. Posttranslational modifications of NF45 and NF90/ILF3 during T-cell activation will be characterized and correlated with IL-2 expression. Triptolide is a diterpenoid triepoxide that inhibits NFkB and IL-2 transcription and T-cell activation through mechanisms that do not involve calcineurin. Triptolide reacts covalently with several nuclear proteins. Immunosuppressive and antiproliferative mechanisms of triptolide will be investigated by characterizing targets of triptolide and triptolide inhibition of transcription in vitro. The developmental phenotypes and immune system functions of mice with targeted disruptions of NF45 and NF90/ILF3 will be determined. The murine NF45 and NF90/ILF3 genes have been sequenced in entirety, targeting vectors generated, and embryonic stem cells screened for homologous recombination. Appropriate ES clones will be injected into blastocysts at the Stanford Transgenic Core facility. Increased understanding of T-cell activation and its modulation by immunosuppressant drugs will guide future therapies for lung inflammation, autoimmune diseases, cancer and AIDS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REJECTION
THE
CD40-CD154
PATHWAY
IN
CHRONIC
ALLOGRAFT
Principal Investigator & Institution: Chandraker, Anil K.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-MAY-2006 Summary: The aim of this proposal to examine and characterize the development of chronic kidney allograft rejection (chronic allograft nephropathy) and to study the effects of CD40-CD154 blockade on the development of this process. This topic has great clinical relevance for transplantation in general as chronic remains the major cause of
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Cyclosporine
renal allograft loss after the first year of transplantation. The applicant will utilize his background in the field of transplantation immunology and build o previous studies carried by the applicant and others. In particular the study will focus on the apparently discordant alloantigen dependent and independent factors that contribute to the process of chronic rejection and examine the role of the CD40-CD 154 pathway in this process. More specifically a new model of chronic renal allograft rejection in rats congenic for MHC will be set up and characterized. The advantages of this model are that it will provide a pure process of chronic rejection independent of the effects of immunosuppressive drugs. Having established the model the role of the CD40-CD 154 pathway will be examined in this model. This pathway has already been shown to be of critical importance in the development of acute rejection. This model can also be modified to test the effects o immunosuppressive drugs and how they modify the picture of clinical rejection and whether blockade of the CD40-CD154 pathway will be effected. Furthermore an established model of ischemia-reperfusion injury in the same host will be examined for the effects of CD40-CD 154 blockade in a setting where no alloantigen is present. Previous studies have indicated that prevention of T cell activation by blockade of the CD28-B7 pathway in this setting, can greatly ameliorate damage caused by ischemia-reperfusion injury. The processes involved in T cell activation in the absence of alloantigen are not well understood and examining the role CD40-CD154 pathway, ligation of which occurs earlier then the CD28-B7 costimulatory pathway will greatly help. These studies have broad implications to scientists working in area of chronic rejection. Understanding the mechanisms of how alloantigen dependent and independent pathways contribute to the overall process may provide novel therapeutic approaches for modulating the effects of chronic allograft rejection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF BMP-7 IN CHRONIC KIDNEY DISEASE Principal Investigator & Institution: Hruska, Keith A.; Professor of Pediatrics; Pediatrics; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 24-APR-2002; Project End 31-MAR-2006 Summary: Bone morphogenetic protein-7, BMP-7, is a critical renal morphogen that is required for development but continues to be expressed at high levels in adult renal tubular segments. Recent studies have demonstrated that BMP-7 prevents the tubulointerstitial nephritis associated with chronic renal injury. BMP-7 appears to function as a hormonal differentiation factor and one of its effects, as such, may be to suppress the transcription of genes activated by various renal injuries. This function would suggest strong therapeutic potential for such a hormone in its target tissues. The therapeutic targets of BMP-7 include the skeleton, the vasculature and the kidney. In the kidney, specific BMP-7 receptors are expressed in the collecting duct, proximal tubule and the glomerulus. The long-range objective of this application is to analyze the efficacy of BMP-7 in various forms of chronic kidney disease (CKD). The studies in the application will address two hypotheses. The first is that BMP-7 is an effective therapeutic agent in CKD. Since many forms of CKD are accompanied by a major tubulointerstitial component in their later stages, we propose that the usefulness of BMP-7 will be more general than disease specific. A second hypothesis to be tested is that replacement of BMP-7 in chronic kidney failure will maintain bone remodeling rates in the absence of secondary hyperparathyroidism. Recent data suggest that CKD is associated with a reduction in the osteoblast differentiation program such that in the absence of secondary hyperparathyroidism an adynamic bone disorder is observed. Studies in the application will demonstrate that BMP deficiency is a likely cause of the
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reduction in osteoblast differentiation produced by CKD. The specific aims of the application are to analyze the therapeutic effectiveness of BMP-7 in animal models of CKD; to analyze the effect of BMP-7 in the treatment of renal osteodystrophy; and to analyze the mechanism of action of BMP-7 in inhibiting renal fibrogenesis. Protocols are proposed to demonstrate the therapeutic effectiveness of BMP-7 in the streptozotocin rat model of diabetic nephropathy and of cyclosporine-induced arteriolopathy and nephrosclerosis. A murine 5/6 nephrectomy model will be used to test the effectiveness of BMP-7 in restoring osteoblast differentiation in CKD associated with suppression of secondary hyperparathyroidism. Successful completion of the proposed studies will significantly clarify the usefulness of BMP-7 in CKD, and encourage its development as a new therapeutic agent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF NEF AND CYCLOPHILIN A IN HIV-1 DISASSEMBLY Principal Investigator & Institution: Powell, Michael D.; Microbiology, Biochemistry & Immunology; Morehouse School of Medicine Atlanta, Ga 30310 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2006 Summary: (provided by applicant): The development of new HIV-1 antivirals is dependent on our understanding of the individual steps in viral replication. Perhaps the least understood aspect of HIV-1 replication is the process of disassembly. Our preliminary data suggest that the viral protein Nef and the cellular factor cyclophilin A (CyPA) are involved in some aspect of disassembly. We have shown that HIV-1 viruses that have their own nef deleted and replaced by HIV-2 or SIV Nef "in trans" become resistant to cyclosporine A treatment. This suggests some interdependence between Nef and CyPA. It has been previously shown that Nef and CyPA can directly interact. We have confirmed this result in our own lab using Far Western blots and SELDI mass spectrometry. We consider whether the interactions between Nef and CyPA and their potential interactions with CA in the viral core are important for replication. Our hypothesis is: that interaction between Nef, CyPA and CA are important for enhancement of viral infectivity. Our approach is summarized in three specific aims: 1. Characterize the ability of HIV-2 and SIV Nef to induce cyclophilin A independence in HIV-1 virions using a multi-round infectivity assay. 2. Determine if the interaction between HIV-1 Nef and CyPA is relevant to enhancement of infectivity. 3. Determine if the HIV-1, HIV-2 or SIV Nef proteins can directly or indirectly bind to CA protein. A better understanding of the relationship between Nef and CyPA will provide critical details about this poorly characterized step in replication, which could provide an attractive new target for antiviral therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THERAPEUTIC RESPONSE IN LGL LEUKEMIA Principal Investigator & Institution: Loughran, Thomas P.; Internal Medicine; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2002; Project Start 03-APR-2001; Project End 31-MAR-2006 Summary: (Applicant's Abstract) The broad long term of this proposal is to design better treatment for large granular lymphocyte (LGL) leukemia. LGL leukemia is a clonal lymphoproliferative disorder associated with autoimmune disease. Our central hypothesis is that LGL leukemia results from dysregulated apoptosis. The goal of this proposal is to understand the mechanisms of treatment response in this model by pursuing correlative laboratory studies associated with an ECOG trial. Patients with
68
Cyclosporine
neutropenia or anemia will initially receive oral methotrexate. Patients failing to respond to methotrexate will then receive oral cyclophosphamide. Samples from patients receiving cyclosporine on a CALGB study will also be evaluated. Each specific aim will test a postulated mechanism of treatment efficacy: Specific Aim 1: To determine if treatment induces apoptosis in leukemic LGL; Specific Aim 2: To determine if treatment results in decreased secretion of Fas ligand; Specific Aim 3: To determine if treatment response is related to constitutive STAT signaling and regulation of STATresponsive genes. Correlative studies in Specific Aim 1 include development of a predictive in vitro apoptotic assay and measurement of decoy Fas receptors on treatment. Mechanistic studies will investigate the mitochondrial-dependent apoptotic pathway induced by MTX. Correlative studies in Specific Aim 2 will measure levels of Fas ligand on treatment. Mechanistic studies will examine regulation of Fas ligand gene transcription. Correlative studies in Specific Aim 3 will measure levels of STAT activation and Mcl-1 protein expression on treatment. Treatment effects on expression of STAT-regulated genes will be examined using microarray analyses. Results of these studies should identify important molecular targets for drug development in hematologic malignancies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DISEASE
TRANSGENIC
XENOTRANSPLANTS
FOR
HUNTINGTON'S
Principal Investigator & Institution: Isacson, Ole; Professor; Mc Lean Hospital (Belmont, Ma) Belmont, Ma 02478 Timing: Fiscal Year 2002; Project Start 01-JAN-1992; Project End 31-MAR-2004 Summary: (Verbatim from the Applicant's Abstract) Brain cell transplantation research has shown that structural and functional repair of the adult brain is possible. We are testing the functional hypothesis that embryonic striatal neurons can replace neurons lost in adult primate striatum and improve signs of Huntinton's disease (HD). The lack of an optimal human donor cell source in a clinical scenario has led us to utilize zenogeneic (here transgenic pig) embryonic donor cells. Our preliminary in vivo data show that successful xenografts survival in the primate brain requires immunosuppression by cyclosporine, azathiopirne, methylprednisolone and complement inhibition (CD59 transgenic donor tissue and monoclonal antibodies against complement C5). To test the functional hypothesis, we proposed the following experiments: We will transplant CD59 complement aggregation inhibitor expressing transgenic porcine fetal striatal (E35 LGE) cells to the caudate-putamen of non-human primate (Macaca mulatta) with neuronal loss similar to that seen in HD. To determine how functional recovery depends on survival and growth of porcine striatal transplants, we will collect physiological in vivo data by PET/MRI/MRS and behavioral data by examining motor and cognitive function. The physiological analysis of LBE graft function by in vivo imaging and behavioral assays is followed by detailed morphological studies. Combine, these studies will provide essential data on the relationship between structural and functional integration of embryonic neuronal xenografts in a HD primate model. These experiments will improve our knowledge of basal ganglia function and plasticity, as well as determine parameters for optimal cell transplantation in patients with neurological disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TREATMENT OF CHILDHOOD CANCER Principal Investigator & Institution: Brecher, Martin L.; Roswell Park Cancer Institute Corp Buffalo, Ny 14263 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-DEC-2002 Summary: Cooperative trials in pediatric cancer patients have played a major role in the remarkable improvement in cure of childhood cancers. Because most childhood cancers are rare, it is only through this mechanism that adequate numbers of patients can be accrued in reasonable lengths of time for randomized controlled studies. The Department of Pediatrics at Roswell Park Cancer Institute (RPCI) has actively participated in cooperative group trials via the Pediatric Oncology Group (POG) to answer treatment questions which would be impossible to answer were we to conduct only single institution studies. Some pediatric solid tumors are so rare that national intergroup studies are required. We also participate in these intergroup studies. RPCI investigators are coordinators for a number of POG protocols including front-line studies for the treatment of advanced Hodgkin's disease, advanced small non- cleaved cell lymphoma, non-rhabdomyosarcoma soft tissue sarcomas, acute lymphoblastic leukemia in relapse, the National Wilms Tumor Study, brain tumors in infants, and the Intergroup Ewing's Sarcoma Study. Roswell Park investigators have also developed POG phase II studies of continuous infusion 5-fluouracil and the combination of cisplatin, ifosfamide and etoposide. Roswell Park investigators chair the Wilms Tumor Committee, the Neuroscience Subcommittee of the Brain Tumor Committee, and cochair the Pathology Discipline Core Committee, as well as being active on a number of other POG Core Committees. They have made major contributions over the last few years in the areas of solid tumor oncology, neuro- oncology and the treatment of lymphoid malignancies. We are strongly committed to the interdisciplinary approach to pediatric cancer and have established collaboration with the necessary clinical specialties including Radiation Medicine, Pediatric Surgery, Pediatric Neurology, Neurosurgery, and Orthopedic Surgery, as well as with researchers in immunology, pharmacology and molecular biology. As more children are cured of their cancers, the identification and prevention, when feasible, of complications of therapy have become imperative. We have been a major contributor to the identification and understanding of the long-term medical and psychosocial effects of the treatment of leukemia, Hodgkin's disease, and a number of solid tumors, both through the cooperative group mechanism and through institutional studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TREATMENT IMPAIRMENTS
OF
NEGATIVE
SYMPTOMS
&
COGNITIVE
Principal Investigator & Institution: Carpenter, William T.; Director; Psychiatry; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 15-JAN-2000; Project End 31-DEC-2003 Summary: The present proposal is a four site multi-center study designed to assess the efficacy of the glutamatergic agents, d-cycloserine and glycine, for the treatment of persistent negative symptoms and cognitive impairments in patients with schizophrenia. These manifestations of schizophrenia account for much of the long-term morbidity, impaired social and occupational functioning, and poor quality of life observed in patients with schizophrenia. Persistent negative symptoms may either by primary (deficit symptoms) or secondary. A present, conventional and novel antipsychotics have limited efficacy for secondary negative symptoms, and there are no
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known effective treatments for deficit symptoms. There are also no known agents with robust efficacy for cognitive impairments. The long-term objective of this application is to develop an effective treatment for persistent negative symptoms, both primary and secondary and cognitive impairments. The Specific Aims are to examine whether: 1) decycloserine and/or glycine is superior to placebo for the treatment of persistent primary and secondary negative symptoms; and 2) d- cycloserine and/or glycine is superior to placebo in the treatment of persistent primary secondary and secondary negative symptoms, and 2) d- cycloserine and/or glycine is superior to placebo in the treatment of cognitive impairments in deficit and non-deficit patients. Secondary goals include: a) to establish a standard clinical trial methodology to assess the therapeutic efficacy of potential treatments of persistent negative symptoms and cognitive impairments.; and b) to describe the relationship between cognitive impairments, as assessed by neuropsychological test performance, and negative symptoms in the clinical trial context. The study will be a 16 double-blind parallel groups comparison of adjunctive medication (i.e., trial context) The study will be a 16 week double-blind, parallel groups comparison of adjunctive medication (i.e., d-cylcoserine and glycine) and placebo. Neuropsychological tests will be used to assess cognitive functioning, and will be administered at baseline and at the end of the study. The study will provide new information on the efficacy of d- cyclosporine and glycine for both persistent primary and secondary negative symptoms and its effect on cognitive functioning. 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 “cyclosporine” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for cyclosporine in the PubMed Central database: •
Activation and Cellular Localization of the Cyclosporine A-sensitive Transcription Factor NF-AT in Skeletal Muscle Cells. by Abbott KL, Friday BB, Thaloor D, Murphy TJ, Pavlath GK.; 1998 Oct 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=25565
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Atypical dissemination of the highly neurotropic Borna disease virus during persistent infection in cyclosporine A-treated, immunosuppressed rats. by Stitz L, Schilken D, Frese K.; 1991 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=240537
3 4
Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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Combined use of an immunotoxin and cyclosporine to prevent both activated and quiescent peripheral blood T cells from producing type 1 human immunodeficiency virus. by Bell KD, Ramilo O, Vitetta ES.; 1993 Feb 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45883
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Comparison of immunosuppressive effects of cyclosporine A in a murine model of systemic candidiasis and of localized thrushlike lesions. by Krause MW, Schaffner A.; 1989 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=259855
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Effect of cyclosporine on the response of normal human lymphocytes to cytomegalovirus in vitro. by Converse PJ, Hess AD, Tutschka PJ, Santos GW.; 1983 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=264630
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Effects of cyclosporine in experimental cryptococcal meningitis. by Perfect JR, Durack DT.; 1985 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=262129
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Functional effects on glomerular hemodynamics of short-term chronic cyclosporine in male rats. by Thomson SC, Tucker BJ, Gabbai F, Blantz RC.; 1989 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=303772
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Fungicidal Synergism of Fluconazole and Cyclosporine in Candida albicans Is Not Dependent on Multidrug Efflux Transporters Encoded by the CDR1, CDR2, CaMDR1, and FLU1 Genes. by Marchetti O, Moreillon P, Entenza JM, Vouillamoz J, Glauser MP, Bille J, Sanglard D.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153326
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Human polymorphonuclear leukocyte interaction with cyclosporine A. by Weinbaum DL, Kaplan SS, Zdziarski U, Rinaldo CR Jr, Schroeder KK.; 1984 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=264249
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Immunosuppressive and Nonimmunosuppressive Cyclosporine Analogs Are Toxic to the Opportunistic Fungal Pathogen Cryptococcus neoformans via CyclophilinDependent Inhibition of Calcineurin. by Cruz MC, Del Poeta M, Wang P, Wenger R, Zenke G, Quesniaux VF, Movva NR, Perfect JR, Cardenas ME, Heitman J.; 2000 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=89641
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Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog. by Rosenwirth B, Billich A, Datema R, Donatsch P, Hammerschmid F, Harrison R, Hiestand P, Jaksche H, Mayer P, Peichl P, et al.; 1994 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=284634
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Intravenous cyclosporine activates afferent and efferent renal nerves and causes sodium retention in innervated kidneys in rats. by Moss NG, Powell SL, Falk RJ.; 1985 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=391475
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Investigation of potential interaction of ciprofloxacin with cyclosporine in bone marrow transplant recipients. by Kruger HU, Schuler U, Proksch B, Gobel M, Ehninger G.; 1990 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=171756
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Phytohemagglutinin-induced activity of cyclic AMP (cAMP) response elements from cytomegalovirus is reduced by cyclosporine and synergistically enhanced by cAMP. by Niller HH, Hennighausen L.; 1990 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=249401
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Potent Synergism of the Combination of Fluconazole and Cyclosporine in Candida albicans. by Marchetti O, Moreillon P, Glauser MP, Bille J, Sanglard D.; 2000 Sep; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90072
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Pretreatment with cyclosporine and anti-interleukin 2 receptor antibody abrogates the anti-idiotype response in rat recipients of cardiac allografts. by Tanaka K, Tilney NL, Stunkel KG, Hancock WW, Diamantstein T, Kupiec-Weglinski JW.; 1990 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=54749
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 cyclosporine, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “cyclosporine” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for cyclosporine (hyperlinks lead to article summaries): •
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A comparison between cyclosporine and tacrolimus-based immunosuppression for renal allografts: renal function and blood pressure after 5 years. Author(s): Muirhead N, House A, Hollomby DJ, Jevnikar AM. Source: Transplantation Proceedings. 2003 November; 35(7): 2391-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14611965
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 comparison between the efficacy of systemic and local azithromycin therapy in treatment of cyclosporine induced gingival overgrowth in kidney transplant patients. Author(s): Nafar M, Ataie R, Einollahi B, Nematizadeh F, Firoozan A, Poorrezagholi F. Source: Transplantation Proceedings. 2003 November; 35(7): 2727-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14612094
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A cost-effectiveness analysis of tacrolimus versus cyclosporine microemulsion following kidney transplantation. Author(s): Craig AM, McKechnie T, McKenna M, Klein W, Schindler TM. Source: Transplantation Proceedings. 2002 August; 34(5): 1646. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176519
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A novel immunosuppressive drug, FTY720, prevents the cancer progression induced by cyclosporine. Author(s): Tanaka T, Takahara S, Hatori M, Suzuki K, Wang J, Ichimaru N, Suzuki S, Morozumi K, Okuyama A, Yamanaka H. Source: Cancer Letters. 2002 July 26; 181(2): 165-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175531
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A prospective, randomized study of coadministration of ketoconazole and cyclosporine a in kidney transplant recipients: ten-year follow-up. Author(s): el-Agroudy AE, Sobh MA, Hamdy AF, Ghoneim MA. Source: Transplantation. 2004 May 15; 77(9): 1371-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15167592
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A randomised trial comparing the efficacy and safety of tacrolimus with microemulsified cyclosporine after liver transplantation. Author(s): Timmermann W, Erhard J, Lange R, Reck T, Kockerling F, Muller A, Jung C, Dietl KH, Kremer B, Kirste G, Schareck W, Golling M, Klar E; German FK 506 Liver Multicenter Trial Group. Source: Transplantation Proceedings. 2002 August; 34(5): 1516-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176463
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A randomized controlled trial of methotrexate and cyclosporine in the treatment of psoriasis. Author(s): Bigby M. Source: Archives of Dermatology. 2004 March; 140(3): 347-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15023778
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A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (NEORAL) and sirolimus in renal transplantation. I. Drug interactions and rejection at one year. Author(s): Ciancio G, Burke GW, Gaynor JJ, Mattiazzi A, Roth D, Kupin W, Nicolas M, Ruiz P, Rosen A, Miller J. Source: Transplantation. 2004 January 27; 77(2): 244-51. Erratum In: Transplantation. 2004 April 15; 7797): 1131. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14742989
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A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year. Author(s): Ciancio G, Burke GW, Gaynor JJ, Mattiazzi A, Roth D, Kupin W, Nicolas M, Ruiz P, Rosen A, Miller J. Source: Transplantation. 2004 January 27; 77(2): 252-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14742990
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A randomized prospective double-blind placebo-controlled study of gallopamil, calcium antagonist of the verapamil type, in stable cyclosporine-treated renal transplant recipients. Author(s): Gossmann J, Mondorf U, Dietz A, Kramer W, Kachel HG, Geiger H, Scheuermann EH. Source: Transplantation Proceedings. 2002 August; 34(5): 1767-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176568
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A three arm study comparing immediate tacrolimus therapy with ATG induction therapy followed by either tacrolimus or cyclosporine in adult renal transplant recipients. Author(s): Charpentier B; European Tacrolimus vs Microemulsified Cyclosporin Study Group. Source: Transplantation Proceedings. 2002 August; 34(5): 1625-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176511
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A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients. Author(s): Charpentier B, Rostaing L, Berthoux F, Lang P, Civati G, Touraine JL, Squifflet JP, Vialtel P, Abramowicz D, Mourad G, Wolf P, Cassuto E, Moulin B, Rifle G, Pruna A, Merville P, Mignon F, Legendre C, Le Pogamp P, Lebranchu Y, Toupance O, Hurault De Ligny B, Touchard G, Olmer M, Purgus R, Pouteil-Noble C, Glotz D, Bourbigot B, Leski M, Wauters JP, Kessler M. Source: Transplantation. 2003 March 27; 75(6): 844-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12660513
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Acute cellular rejection in liver transplant recipients under cyclosporine immunosuppression: predictive factors of response to antirejection therapy. Author(s): Andreu H, Rimola A, Bruguera M, Navasa M, Cirera I, Grande L, GarciaValdecasas JC, Rodes J. Source: Transplantation. 2002 June 27; 73(12): 1936-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131692
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Addition of sirolimus to cyclosporine delays the recovery from delayed graft function but does not affect 1-year graft function. Author(s): Stallone G, Di Paolo S, Schena A, Infante B, Battaglia M, Ditonno P, Gesualdo L, Grandaliano G, Schena FP. Source: Journal of the American Society of Nephrology : Jasn. 2004 January; 15(1): 22833. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14694177
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Additive effects of oxidized low-density lipoproteins and cyclosporine on endothelin-1 production of renal arterial endothelial cells. Author(s): Enderlein M, Gross P. Source: Transplantation Proceedings. 2003 June; 35(4): 1581-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826225
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Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients. Author(s): Kuzuya T, Kobayashi T, Moriyama N, Nagasaka T, Yokoyama I, Uchida K, Nakao A, Nabeshima T. Source: Transplantation. 2003 September 15; 76(5): 865-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14501869
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An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment. Author(s): Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT. Source: Journal of Neurochemistry. 2004 February; 88(4): 821-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14756802
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An open-label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination. Author(s): Machado PG, Felipe CR, Hanzawa NM, Park SI, Garcia R, Alfieri F, Franco M, Silva HT Jr, Medina-Pestana JO. Source: Clinical Transplantation. 2004 February; 18(1): 28-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15108768
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Analysis of survivors more than 10 years after heart transplantation in the cyclosporine era: Stanford experience. Author(s): Shiba N, Chan MC, Kwok BW, Valantine HA, Robbins RC, Hunt SA. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2004 February; 23(2): 155-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14761762
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Assessment of cyclosporine therapeutic monitoring with C2 concentrations in stable renal allograft recipients. Author(s): Diaz JM, Sainz Z, Guirado LL, Montanes R, Picazo M, Garcia-Camin R, Alcaraz A, Sola R. Source: Transplantation Proceedings. 2003 August; 35(5): 1783-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962794
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Basiliximab-sirolimus-prednisone induction regimen followed by delayed low-dose cyclosporine in renal transplant recipients of living donors. Author(s): Langer RM, Hong DM, Katz SM, Van Buren CT. Source: Transplantation Proceedings. 2002 December; 34(8): 3162-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12493406
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Behcet's disease with relapsing cutaneous polyarteritis-nodosa-like lesions, responsive to oral cyclosporine therapy. Author(s): Vikas A, Atul S, Singh R, Sarbmeet L, Mohan H. Source: Dermatology Online Journal [electronic Resource]. 2003 December; 9(5): 9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14996382
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Beneficial effects of converting liver transplant recipients from cyclosporine to tacrolimus on blood pressure, serum lipids, and weight. Author(s): Neal DA, Gimson AE, Gibbs P, Alexander GJ. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2001 June; 7(6): 533-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11443583
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Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Author(s): List AF, Kopecky KJ, Willman CL, Head DR, Persons DL, Slovak ML, Dorr R, Karanes C, Hynes HE, Doroshow JH, Shurafa M, Appelbaum FR. Source: Blood. 2001 December 1; 98(12): 3212-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11719356
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Benefit of mycophenolate mofetil in patients with cyclosporine A-induced nephropathy after lung transplantation. Author(s): Zuckermann A, Birsan T, Thaghavi S, Kupilik N, Deviatko E, Dekan G, Wolner E, Klepetko W. Source: Transplantation Proceedings. 1999 February-March; 31(1-2): 1160-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10083518
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Benefits of cyclosporine microemulsion (Neoral) C(2) monitoring are sustained at 1 year in de novo liver transplant recipients. Author(s): Lake JR; Neo-INT-06 Study Group. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3092-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750328
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Benefits of mycophenolate mofetil in cardiac transplant recipients with cyclosporineinduced nephropathy. Author(s): Sanchez V, Delgado JF, Blasco T, Dalmau R, Morales JM, Escribano P, Tello R, Hernandez J, Velazquez T, Sotelo T, Gomez-Sanchez MA, Saenz de la Calzada C. Source: Transplantation Proceedings. 1999 September; 31(6): 2515-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10500695
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Bilateral femoral avascular necrosis in a man with psoriasis: responsibility of topical corticosteroids and role of cyclosporine. Author(s): Reichert-Penetrat S, Trechot P, Barbaud A, Gillet P, Schmutz JL. Source: Dermatology (Basel, Switzerland). 2001; 203(4): 356-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11752834
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Bilateral mandibular cysts associated with cyclosporine use: a case report. Author(s): De Biase A, Ottolenghi L, Polimeni A, Benvenuto A, Lubrano R, Magliocca FM. Source: Pediatric Nephrology (Berlin, Germany). 2001 December; 16(12): 993-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11793087
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Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients. Author(s): Asberg A, Hartmann A, Fjeldsa E, Bergan S, Holdaas H. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2001 November; 1(4): 382-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12099384
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Biliary lipid composition after liver transplantation: effect of allograft function and cyclosporine. Author(s): Ko CW, Kowdley KV, Haigh WG, Lee SP. Source: Liver Transplantation and Surgery : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 1998 July; 4(4): 258-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9649637
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Biodegradable nanoparticles as a delivery system for cyclosporine: preparation and characterization. Author(s): Molpeceres J, Aberturas MR, Guzman M. Source: Journal of Microencapsulation. 2000 September-October; 17(5): 599-614. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11038119
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Bioequivalence of a new cyclosporine a formulation to Neoral. Author(s): David-Neto E, Kakehashi E, Alves CF, Pereira LM, de Castro MC, de Mattos RM, Sumita NM, Romano P, Mendes ME, Nahas WC, Ianhez LE. Source: Therapeutic Drug Monitoring. 2004 February; 26(1): 53-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14749551
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Blood cyclosporine C0 and C2 concentrations and cytomegalovirus infections following lung transplantation. Author(s): Monforte V, Bullich S, Pou L, Bravo C, Lopez R, Gavalda J, Roman A. Source: Transplantation Proceedings. 2003 August; 35(5): 1992-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962872
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Body-weight-independent dosing of cyclosporine micro-emulsion and three times weekly maintenance regimen in severe psoriasis. A randomised study. Author(s): Thaci D, Brautigam M, Kaufmann R, Weidinger G, Paul C, Christophers E. Source: Dermatology (Basel, Switzerland). 2002; 205(4): 383-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12444336
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Bone histopathology and densitometry comparison between cyclosporine a monotherapy and prednisolone plus azathioprine dual immunosuppression in renal transplant patients. Author(s): Cueto-Manzano AM, Konel S, Crowley V, France MW, Freemont AJ, Adams JE, Mawer B, Gokal R, Hutchison AJ. Source: Transplantation. 2003 June 27; 75(12): 2053-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12829911
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Bone loss after renal transplantation: role of hyperparathyroidism, acidosis, cyclosporine and systemic disease. Author(s): Heaf J, Tvedegaard E, Kanstrup IL, Fogh-Andersen N. Source: Clinical Transplantation. 2000 October; 14(5): 457-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11048990
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Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A. Author(s): Monegal A, Navasa M, Guanabens N, Peris P, Pons F, Martinez de Osaba MJ, Rimola A, Rodes J, Munoz-Gomez J. Source: Calcified Tissue International. 2001 February; 68(2): 83-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11310351
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Bone remodeling effect of cyclosporine protects against steroid-induced osteopenia. Author(s): Westeel FP, Mazouz H, Oprisiu R, Fournier A. Source: Kidney International. 2001 July; 60(1): 380. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11422777
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Breast-feeding by a cyclosporine-treated mother. Author(s): Munoz-Flores-Thiagarajan KD, Easterling T, Davis C, Bond EF. Source: Obstetrics and Gynecology. 2001 May; 97(5 Pt 2): 816-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11336764
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Cardiovascular risk profile after conversion from cyclosporine A to tacrolimus in stable renal transplant recipients. Author(s): Baid-Agrawal S, Delmonico FL, Tolkoff-Rubin NE, Farrell M, Williams WW, Shih V, Auchincloss H, Cosimi AB, Pascual M. Source: Transplantation. 2004 April 27; 77(8): 1199-202. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15114085
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Changes in renal function in long-term survivors of liver transplantation: a comparison between cyclosporine microemulsion and tacrolimus therapy. Author(s): Charco R, Cantarell C, Castells LI, Bilbao I, Hidalgo E, Capdevila L, Margarit C. Source: Transplantation Proceedings. 2002 August; 34(5): 1548-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176478
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Circadian variation of cyclosporine A in renal transplanted patients. Author(s): Reyna Rodriguez C, Jung Cook H, Gonzalez Lopez EH, Nava A. Source: Rev Alerg Mex. 2004 January-February; 51(1): 9-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15119750
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Clinical benefit of monitoring cyclosporine C2 and C4 in long-term liver transplant recipients. Author(s): Barakat O, Peaston R, Rai R, Talbot D, Manas D. Source: Transplantation Proceedings. 2002 August; 34(5): 1535-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176472
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Combination therapy with methotrexate and cyclosporine A in juvenile idiopathic arthritis. Author(s): Ravelli A, Moretti C, Temporini F, Rossi F, Magni-Manzoni S, Pistorio A, Martini A. Source: Clin Exp Rheumatol. 2002 July-August; 20(4): 569-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12175118
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Control of a relapse and induction of long-term remission of Wegener's granulomatosis by cyclosporine. Author(s): Ghez D, Westeel PF, Henry I, Pruna A, Fournier A, Lassoued K. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2002 August; 40(2): E6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12148127
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Conversion from cyclosporine A to tacrolimus in pediatric kidney transplant recipients with chronic rejection: changes in the immune responses. Author(s): Ferraris JR, Tambutti ML, Cardoni RL, Prigoshin N. Source: Transplantation. 2004 February 27; 77(4): 532-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15084930
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Conversion from cyclosporine to tacrolimus is preferred by pediatric renal transplant recipients: a focus on opinions and outcomes. Author(s): Sundberg AK, Smith LD, Somerville KT, Cox R, Sherbotie JR. Source: Transplantation Proceedings. 2002 August; 34(5): 1951-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176640
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Conversion of cyclosporine to tacrolimus for refractory or persistent myocardial rejection. Author(s): Chan MC, Kwok BW, Shiba N, Cantin B, Valantine HA, Hunt SA. Source: Transplantation Proceedings. 2002 August; 34(5): 1850-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176601
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Cyclosporine A enhances leukocyte binding by human intestinal microvascular endothelial cells through inhibition of p38 MAPK and iNOS. Paradoxical proinflammatory effect on the microvascular endothelium. Author(s): Rafiee P, Johnson CP, Li MS, Ogawa H, Heidemann J, Fisher PJ, Lamirand TH, Otterson MF, Wilson KT, Binion DG. Source: The Journal of Biological Chemistry. 2002 September 20; 277(38): 35605-15. Epub 2002 July 10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12110686
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Cyclosporine A for heavy proteinuria in a child with Henoch-Schonlein purpura nephritis. Author(s): Someya T, Kaneko K, Fujinaga S, Ohtaki R, Hira M, Yamashiro Y. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2004 February; 46(1): 111-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15043680
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Cyclosporine absorption profiling and therapeutic drug monitoring using C(2) blood levels in stable renal allograft recipients. Author(s): Einecke G, Mai I, Diekmann F, Fritsche L, Neumayer HH, Budde K. Source: Transplantation Proceedings. 2002 August; 34(5): 1738-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176557
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Cyclosporine and low-dose ketoconazole in renal transplant recipients: a singlecenter experience. Author(s): Carbajal H, Soltero L, Rodriguez-Montalvo C, Valdes A. Source: Transplantation. 2004 April 15; 77(7): 1038-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15087768
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Cyclosporine bioequivalence study: quantification using fluorescence polarization immunoassay (FPIA) and radioimmunoassay (RIA). Author(s): Mendes GD, de Oliveira CH, Sucupira M, Donato JL, Moreno RA, De Nucci G. Source: Int J Clin Pharmacol Ther. 2004 February; 42(2): 125-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15180174
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Cyclosporine does not influence serum cholesterol in kidney transplant recipients. Author(s): Matzkies FK, Keuthage W, Kobelt V, Hillebrand U, Gerhardt U, Suwelack B, Hohage H. Source: Transplantation Proceedings. 2002 August; 34(5): 1795-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176580
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Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase. Author(s): List AF, Kopecky KJ, Willman CL, Head DR, Slovak ML, Douer D, Dakhil SR, Appelbaum FR. Source: Blood. 2002 September 1; 100(5): 1910-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176916
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Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. Author(s): Cho ML, Cho CS, Min SY, Kim SH, Lee SS, Kim WU, Min DJ, Min JK, Youn J, Hwang SY, Park SH, Kim HY. Source: Arthritis and Rheumatism. 2002 May; 46(5): 1202-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12115224
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Cyclosporine-associated facial paralysis in a child with renal transplant. Author(s): Ozkaya O, Kalman S, Bakkaloglu S, Buyan N, Soylemezoglu O. Source: Pediatric Nephrology (Berlin, Germany). 2002 July; 17(7): 544-6. Epub 2002 June 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12172772
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Cyclosporine-based quadruple induction therapy versus tacrolimus-based dual immunosuppression after liver transplantation: ten-year follow-up. Author(s): Jonas S, Guckelberger O, Muller AR, Langrehr JM, Settmacher U, Tullius SG, Steinmuller T, Neuhaus P. Source: Transplantation Proceedings. 2002 August; 34(5): 1504-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176459
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CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Author(s): Anglicheau D, Thervet E, Etienne I, Hurault De Ligny B, Le Meur Y, Touchard G, Buchler M, Laurent-Puig P, Tregouet D, Beaune P, Daly A, Legendre C, Marquet P. Source: Clinical Pharmacology and Therapeutics. 2004 May; 75(5): 422-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15116055
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Danger of systemic cyclosporine for corneal graft. Author(s): Algros MP, Angonin R, Delbosc B, Cahn JY, Kantelip B. Source: Cornea. 2002 August; 21(6): 613-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131043
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De novo hemolytic uremic syndrome after kidney transplantation in patients treated with cyclosporine a sirolimus combination. Author(s): Langer RM, Van Buren CT, Katz SM, Kahan BD. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3236-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750387
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De novo hemolytic uremic syndrome after kidney transplantation in patients treated with cyclosporine-sirolimus combination. Author(s): Langer RM, Van Buren CT, Katz SM, Kahan BD. Source: Transplantation. 2002 March 15; 73(5): 756-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11907423
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Defining the risk of elective cyclosporine withdrawal in stable kidney transplant recipients. Author(s): Anjum S, Andany MA, McClean JC, Danielson B, Kasiske BL. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2002 February; 2(2): 179-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12099521
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Diabetes mellitus after transplant: relationship to pretransplant glucose metabolism and tacrolimus or cyclosporine A-based therapy. Author(s): Sato T, Inagaki A, Uchida K, Ueki T, Goto N, Matsuoka S, Katayama A, Haba T, Tominaga Y, Okajima Y, Ohta K, Suga H, Taguchi S, Kakiya S, Itatsu T, Kobayashi T, Nakao A. Source: Transplantation. 2003 November 15; 76(9): 1320-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627910
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Dialysis induces cyclosporine a resistance: induction therapy with bolus ATGFresenius increases cyclosporine sensistivity. Author(s): Abudher MN, Davenport A, Fernando ON, Powis SH, Moorhead JF, Varghese Z. Source: Transplantation Proceedings. 2003 February; 35(1): 210-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591368
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Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Author(s): Klein IH, Abrahams A, van Ede T, Hene RJ, Koomans HA, Ligtenberg G. Source: Transplantation. 2002 March 15; 73(5): 732-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11907418
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Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Author(s): Holt S, Moore K. Source: Transplantation. 2002 March 15; 73(5): 673-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11907407
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Differential effect of diarrhea on FK506 versus cyclosporine A trough levels and resultant prevention of allograft rejection in renal transplant recipients. Author(s): Maes BD, Lemahieu W, Kuypers D, Evenepoel P, Coosemans W, Pirenne J, Vanrenterghem YF. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2002 November; 2(10): 989-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12484345
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Differential influence of two cyclosporine formulations on everolimus pharmacokinetics: a clinically relevant pharmacokinetic interaction. Author(s): Kovarik JM, Kalbag J, Figueiredo J, Rouilly M, Frazier OL, Rordorf C. Source: Journal of Clinical Pharmacology. 2002 January; 42(1): 95-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11808830
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Discoid lupus erythematosus in a patient receiving cyclosporine for liver transplantation. Author(s): Obermoser G, Weber F, Sepp N. Source: Acta Dermato-Venereologica. 2001 August-September; 81(4): 319. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11720195
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Diurnal cyclosporine dosing optimizes exposure and reduces the risk of acute rejection after kidney transplantation. Author(s): Browne BJ, Holt CO, Emovon OE. Source: Clinical Transplantation. 2001; 15 Suppl 6: 51-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11903387
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Donor lymphocyte infusion followed by interferon-alpha plus low dose cyclosporine A for modulation of donor CD3 cells activity with monitoring of minimal residual disease and cellular chimerism in a patient with first hematologic relapse of chronic myelogenous leukemia after allogeneic bone marrow transplantation. Author(s): Leda M, Ladon D, Pieczonka A, Boruczkowski D, Jolkowska J, Witt M, Wachowiak J. Source: Leukemia Research. 2001 April; 25(4): 353-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11248334
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Dose-adjusted cyclosporine c2 in a patient with jejunoileal bypass as compared to seven other liver transplant recipients. Author(s): Chenhsu RY, Wu Y, Katz D, Rayhill S. Source: Therapeutic Drug Monitoring. 2003 December; 25(6): 665-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14639052
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Double-blind, crossover, comparative study of doxazosin and enalapril in the treatment of hypertension in renal transplant patients under cyclosporine immunosuppression. Author(s): Martinez-Castelao A, Hueso M, Sanz V, Rejas J, Sarrias J, Alsina J, Grinyo JM. Source: Transplantation Proceedings. 2002 February; 34(1): 403-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959345
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Dramatic efficacy of cyclosporine A in macrophage activation syndrome. Author(s): Ravelli A, Viola S, De Benedetti F, Magni-Manzoni S, Tzialla C, Martini A. Source: Clin Exp Rheumatol. 2001 January-February; 19(1): 108. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11247313
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Dyslipidemia during sirolimus therapy in liver transplant recipients occurs with concomitant cyclosporine but not tacrolimus. Author(s): Trotter JF, Wachs ME, Trouillot TE, Bak T, Kugelmas M, Kam I, Everson G. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2001 May; 7(5): 401-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11349259
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Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporinebased immunosuppressive regimen: incidence, risk factors, progression, and prognosis. Author(s): Chueh SC, Kahan BD. Source: Transplantation. 2003 July 27; 76(2): 375-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883196
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Early cyclosporine treatment of incipient toxic epidermal necrolysis induced by concomitant use of lamotrigine and sodium valproate. Author(s): Hashim N, Bandara D, Tan E, Ilchyshyn A. Source: Acta Dermato-Venereologica. 2004; 84(1): 90-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15040495
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Early elimination of cyclosporine in kidney transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions. Author(s): Ruiz JC, Campistol JM, Mota A, Prats D, Gutierrez JA, Castro A, Garcia J, Morales JM, Grynio JM, Gomez JM, Arias M. Source: Transplantation Proceedings. 2003 August; 35(5): 1669-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962750
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Early or delayed onset of cyclosporine by sequential immunosuppression? Author(s): Wienand P, Schroder T, Baldamus C. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1992; 5 Suppl 1: S121-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621753
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Effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients. Author(s): Taylor PJ, Kubler PA, Lynch SV, Allen J, Butler M, Pillans PI. Source: The Annals of Pharmacotherapy. 2004 February; 38(2): 205-8. Epub 2003 December 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14742751
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Effect of azithromycin in the treartment of cyclosporine-induced gingival hyperplasia in renal transplant recipients. Author(s): Kwun WH, Suh BY, Kwun KB. Source: Transplantation Proceedings. 2003 February; 35(1): 311-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591416
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Effect of high-density lipoprotein associated cyclosporine on hepatic metabolism and renal function. Author(s): Kim T, Callahan SM, Wasan KM, Brunner LJ. Source: Pda J Pharm Sci Technol. 2003 September-October; 57(5): 341-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14677627
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Effect of switching from cyclosporine to tacrolimus on exhaled nitric oxide and pulmonary function in patients with chronic rejection after lung transplantation. Author(s): Verleden GM, Dupont LJ, Van Raemdonck D, Vanhaecke J. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 August; 22(8): 908-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12909472
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Effects of immediate switch from cyclosporine microemulsion to tacrolimus at first acute rejection in renal allograft recipients. Author(s): Briggs D, Dudley C, Pattison J, Pfeffer P, Salmela K, Rowe P, Tyden G; European Tacrolimus Renal Rejection Study Group. Source: Transplantation. 2003 June 27; 75(12): 2058-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12829912
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Efficacy and safety of tacrolimus compared with cyclosporine microemulsion in kidney transplantation: twelve-month follow-up. Author(s): Montagnino G, Kramer BK, Arias M; European Tacrolimus vs Cyclosporin Microemulsion Renal Transplantation Study Group. Source: Transplantation Proceedings. 2002 August; 34(5): 1635-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176515
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Efficacy and safety of tacrolimus compared with cyclosporine microemulsion in primary simultaneous pancreas-kidney transplantation: 1-year results of a large multicenter trial. Author(s): Bechstein WO, Malaise J, Saudek F, Land W, Fernandez-Cruz L, Margreiter R, Nakache R, Secchi A, Vanrenterghem Y, Tyden G, Van Ophem D, Berney T, Boucek P, Landgraf R, Kahl A, Squifflet JP; EuroSPK Study Group. Source: Transplantation. 2004 April 27; 77(8): 1221-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15114089
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Efficacy of cyclosporine treatment in multifocal motor neuropathy. Author(s): Nemni R, Santuccio G, Calabrese E, Galardi G, Canal N. Source: Journal of Neurology. 2003 September; 250(9): 1118-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14504978
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Efficacy of low-dose mycophenolate mofetil therapy for Taiwanese renal transplantation patients receiving primary cyclosporine immunosuppression. Author(s): Tsai MK, Hu RH, Lee CJ, Lee PH. Source: J Formos Med Assoc. 2002 September; 101(9): 616-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12645188
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Efficacy of mycophenolate mofetil combined with very low-dose cyclosporine microemulsion in long-term liver-transplant patients with renal dysfunction. Author(s): Cantarovich M, Tzimas GN, Barkun J, Deschenes M, Alpert E, Tchervenkov J. Source: Transplantation. 2003 July 15; 76(1): 98-102. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865793
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Enhanced expression of enterocyte P-glycoprotein depresses cyclosporine bioavailability in a recipient of living donor liver transplantation. Author(s): Masuda S, Goto M, Kiuchi T, Uemoto S, Kodawara T, Saito H, Tanaka K, Inui K. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2003 October; 9(10): 1108-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14526408
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Enhancement of transmucosal permeation of cyclosporine by benzalkonium chloride. Author(s): van der Bijl P, van Eyk AD, Gareis AA, Thompson IO. Source: Oral Diseases. 2002 May; 8(3): 168-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12108761
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Enhancement of transmucosal permeation of cyclosporine by benzalkonium chloride. Author(s): Van der Bijl P, Van Eyk AD, Gareis AA, Thompson IO. Source: Advances in Experimental Medicine and Biology. 2003; 528: 567-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12918766
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Epidermal overexpression of interleukin-19 and -20 mRNA in psoriatic skin disappears after short-term treatment with cyclosporine a or calcipotriol. Author(s): Romer J, Hasselager E, Norby PL, Steiniche T, Thorn Clausen J, Kragballe K. Source: The Journal of Investigative Dermatology. 2003 December; 121(6): 1306-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14675174
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Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure. Author(s): Kovarik JM, Eisen H, Dorent R, Mancini D, Vigano M, Rouilly M, Hsu CH, Rordorf C. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 October; 22(10): 1117-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550821
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Experience with the use of basiliximab in liver transplantation--use in pediatric and adult recipients in combination with cyclosporine or tacrolimus. Author(s): Petz W, Spada M, Bertani A, Lucianctti A, Casagrande F, Guizzetti M, Corno V, Colledan M, Strazzabosco M, Gridelli B. Source: Transplantation Proceedings. 2002 August; 34(5): 1966-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176648
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Factors affecting long-term renal allograft survival in cyclosporine-treated kidney transplants. Author(s): Tanabe K, Ishikawa N, Tokumoto T, Takahashi K, Oshima T, Fuchinoue S, Toma H. Source: Transplantation Proceedings. 1998 August; 30(5): 1805-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9723291
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Factors affecting long-term survival (>10 years) after cardiac transplantation in the cyclosporine era. Author(s): John R, Rajasinghe HA, Itescu S, Suratwalla S, Lietz K, Weinberg AD, Kocher A, Mancini DM, Drusin RE, Oz MC, Smith CR, Rose EA, Edwards NM. Source: Journal of the American College of Cardiology. 2001 January; 37(1): 189-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11153736
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Factors influencing cyclosporine blood concentration-dose ratio. Author(s): Garcia-Saiz M, Lopez-Gil A, Alfonso I, Boada JN, Armijo JA. Source: The Annals of Pharmacotherapy. 2002 February; 36(2): 193-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11847933
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Factors predicting the long-term success of maintenance cyclosporine monotherapy after kidney transplantation. Author(s): Hurault de Ligny B, Toupance O, Lavaud S, Bauwens M, Peyronnet P, Le Meur Y, Ryckelynck JP, Jolly D, Leroux-Robert C, Touchard G. Source: Transplantation. 2000 April 15; 69(7): 1327-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10798748
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Failure of cyclosporine A in controlling Schoenlein-Henoch purpura. Author(s): Catalano C, Fabbian F, Bordin V, Di Landro D. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1998 June; 13(6): 1605-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9641209
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Fatal cytophagic histiocytic panniculitis after a short response to cyclosporine. Author(s): Guitart J, Sethi R, Gordon K. Source: Journal of the European Academy of Dermatology and Venereology : Jeadv. 1998 May; 10(3): 267-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9643334
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Fatal outcome due to cyclosporine neurotoxicity with associated pathological findings. Author(s): Gopal AK, Thorning DR, Back AL. Source: Bone Marrow Transplantation. 1999 January; 23(2): 191-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10197808
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Fatty acid composition of low-density lipoprotein in renal transplant recipients treated with cyclosporine. Author(s): Cofan F, Zambon D, Laguna JC, Ros E, Casals E, Cofan M, Campistol JM, Oppenheimer F. Source: Transplantation Proceedings. 2002 February; 34(1): 374-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959334
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Feasibility of changing therapeutic cyclosporine monitoring from C(0) to C(2) in stable renal recipients: narrower coefficient of variation with C(2) monitoring. Author(s): Chueh SC, Liao CH, Chang CJ, Lai MK. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3100-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750332
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First-pass metabolism of cyclosporine A in human intestine: inhibition by diltiazem. Author(s): Preuner JG, Lehle K, Eichinger H, Rupprecht L. Source: Transplantation Proceedings. 1998 September; 30(6): 2545-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9745480
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Flow cytometric detection of IL-6 production by CD14+ cells: the effect of in vitro addition of cyclosporine-A and prednisolone. Author(s): Degiannis D, Kapsalis A, Thalassinos A, Koniavitou K. Source: Transplantation Proceedings. 1998 August; 30(5): 2392-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9723515
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Follow-up study of children with nephrotic syndrome treated with a long-term moderate dose of cyclosporine. Author(s): Hino S, Takemura T, Okada M, Murakami K, Yagi K, Fukushima K, Yoshioka K. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 1998 June; 31(6): 932-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9631836
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Forearm vasorelaxation in hypertensive renal transplant patients: the impact of withdrawal of cyclosporine. Author(s): van den Dorpel MA, van den Meiracker AH, Lameris TW, Weimar W, Man in't Veld AJ. Source: Journal of Hypertension. 1998 March; 16(3): 331-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9557926
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Formation of peroxynitrite in vascular endothelial cells exposed to cyclosporine A. Author(s): Navarro-Antolin J, Lopez-Munoz MJ, Klatt P, Soria J, Michel T, Lamas S. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2001 May; 15(7): 1291-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11344117
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FPIA and EMIT methods compared for cyclosporine monitoring in heart transplant patients. Author(s): Fatio R, Sutsch G, Pei P, Follath F, Kiowski W. Source: Clinical Chemistry. 1998 March; 44(3): 693-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9510894
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Frequency of recurrent lupus nephritis among ninety-seven renal transplant patients during the cyclosporine era. Author(s): Stone JH, Millward CL, Olson JL, Amend WJ, Criswell LA. Source: Arthritis and Rheumatism. 1998 April; 41(4): 678-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9550477
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Frequency of switch from cyclosporine to FK 506 before and after Neoral use in pediatric liver transplantation. Author(s): Gridelli B, Colledan M, Lucianetti A, Ulla L, Riva S, Segalin A, Fassati LR, Torre G. Source: Transplantation Proceedings. 1998 August; 30(5): 1861-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9723311
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Functional quantification of cyclosporine A and FK506 in human whole blood by flow cytometry, using the green fluorescent protein as an interleukin-2 reporter gene. Author(s): Taupin JL, Merville P, McBride T, Potaux L, Moreau JF. Source: Journal of Immunological Methods. 2001 October 1; 256(1-2): 77-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11516757
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Gemtuzumab ozogamicin, fludarabine, cytarabine and cyclosporine combination regimen in patients with CD33+ primary resistant or relapsed acute myeloid leukemia. Author(s): Tsimberidou A, Cortes J, Thomas D, Garcia-Manero G, Verstovsek S, Faderl S, Albitar M, Kantarjian H, Estey E, Giles FJ. Source: Leukemia Research. 2003 October; 27(10): 893-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860008
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Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high-risk myelodysplastic syndromes. Author(s): Tsimberidou A, Estey E, Cortes J, Thomas D, Faderl S, Verstovsek S, GarciaManero G, Keating M, Albitar M, O'Brien S, Kantarjian H, Giles F. Source: Cancer. 2003 March 15; 97(6): 1481-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12627513
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Gender-dependent racial difference in disposition of cyclosporine among healthy African American and white volunteers. Author(s): Min DI, Lee M, Ku YM, Flanigan M. Source: Clinical Pharmacology and Therapeutics. 2000 November; 68(5): 478-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11103750
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Gender-related assessment of cyclosporine/prednisolone/sirolimus interactions in three human lymphocyte proliferation assays. Author(s): Ferron GM, Pyszczynski NA, Jusko WJ. Source: Transplantation. 1998 May 15; 65(9): 1203-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9603169
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Gene expression of the renal endothelin system in renal transplant recipients on cyclosporine A based immunosuppression. Author(s): Asberg A, Attramadal H, Midtvedt K, Sund S, Hartmann A, Berg KJ. Source: Transplantation. 1999 April 15; 67(7): 1056-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10221493
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Generic substitution for cyclosporine: what should we be looking for in new formulations? Author(s): Johnston A, Holt DW. Source: Transplantation Proceedings. 1998 August; 30(5): 1652-3. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9723228
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93
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Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Author(s): Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, Weimar W, van Gelder T. Source: Clinical Pharmacology and Therapeutics. 2003 September; 74(3): 245-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12966368
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Glipizide treatment of post-transplant diabetes does not interfere with cyclosporine pharmacokinetics in renal allograft recipients. Author(s): Sagedal S, Asberg A, Hartmann A, Bergan S, Berg KJ. Source: Clinical Transplantation. 1998 December; 12(6): 553-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9850449
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Glomerular growth under cyclosporine treatment in childhood nephrotic syndrome. Author(s): Jeong HJ, Kim JH, Kim PK, Choi IJ. Source: Clinical Nephrology. 2001 April; 55(4): 289-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11334314
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Glucose metabolism in heart transplant recipients treated with FK506 or cyclosporine. Author(s): Sahar G, Berman M, Ben-Gal T, Sahar E, Kogan A, Michowitch R, Saute M, Kramer M, Sagie A, Shapira Y, Aravot D, Vidne BA. Source: Transplantation Proceedings. 2003 March; 35(2): 678. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12644092
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Glucose metabolism in the first 3 years after renal transplantation in patients receiving tacrolimus versus cyclosporine-based immunosuppression. Author(s): van Duijnhoven EM, Christiaans MH, Boots JM, Nieman FH, Wolffenbuttel BH, van Hooff JP. Source: Journal of the American Society of Nephrology : Jasn. 2002 January; 13(1): 21320. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11752040
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Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Author(s): Kunert KS, Tisdale AS, Gipson IK. Source: Archives of Ophthalmology. 2002 March; 120(3): 330-7. Erratum In: Arch Ophthalmol 2002 August; 120(8): 1099. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11879137
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Good response to cyclosporine therapy in patients with myelodysplastic syndromes having the HLA-DRB1*1501 allele. Author(s): Okamoto T, Okada M, Yamada S, Takatsuka H, Wada H, Tamura A, Fujimora Y, Takemoto Y, Kakishita E. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2000 February; 14(2): 344-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10673759
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Graft survival following living-donor renal transplantation: a comparison of tacrolimus and cyclosporine microemulsion with mycophenolate mofetil and steroids. Author(s): Bunnapradist S, Daswani A, Takemoto SK. Source: Transplantation. 2003 July 15; 76(1): 10-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12865780
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Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial. Author(s): Locatelli F, Zecca M, Rondelli R, Bonetti F, Dini G, Prete A, Messina C, Uderzo C, Ripaldi M, Porta F, Giorgiani G, Giraldi E, Pession A. Source: Blood. 2000 March 1; 95(5): 1572-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10688810
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Granulocyte colony-stimulating factor-supported combined immunosuppressive therapy (antilymphocyte globulin, cyclosporine, and methylprednisolone) in patients with aplastic anemia: tolerability, efficacy, and changes in the progenitor cell compartment. Author(s): Meidlinger P, Knobl P, Jager U, Gisslinger H, Pabinger I, Weltermann A, Lechner K, Geissler K. Source: Annals of Hematology. 1999 July; 78(7): 299-304. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10466441
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Greater variability of dose-corrected cyclosporine C2 concentrations in renal recipients with acute rejection. Author(s): Chueh SC, Liao CH, Lai MK. Source: Transplantation Proceedings. 2003 February; 35(1): 234-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591378
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Growth acceleration on cyclosporine monotherapy after liver transplantation in children. Author(s): Falkenstein K, Dunn S. Source: Transplantation Proceedings. 1998 August; 30(5): 1969-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9723356
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Guess what! Malignant pyoderma responding to cyclosporine. Author(s): Cardinali C, Giomi B, Caproni M, Fabbri P. Source: European Journal of Dermatology : Ejd. 2001 November-December; 11(6): 595-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11701420
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Health-related quality-of-life outcomes of sirolimus-treated kidney transplant patients after elimination of cyclosporine A: results of a 2-year randomized clinical trial. Author(s): Oberbauer R, Hutchison B, Eris J, Arias M, Claesson K, Mota A, Kreis H, Kleinman L, Wang F, Chen J, Revicki DA; Rapamune Maintenance Regimen Study Group. Source: Transplantation. 2003 April 27; 75(8): 1277-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12717216
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Hemolytic-uremic syndrome in association with both cyclosporine and tacrolimus. Author(s): Abraham KA, Little MA, Dorman AM, Walshe JJ. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2000; 13(6): 443-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11140243
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High inducibility of heat shock protein 72 (hsp72) in peripheral blood mononuclear cells of aplastic anaemia patients: a reliable marker of immune-mediated aplastic anaemia responsive to cyclosporine therapy. Author(s): Takami A, Nakao S, Tatsumi Y, Wang H, Weihua Z, Yamazaki H, Yasue S, Shiobara S, Matsuda T, Mizoguchi H. Source: British Journal of Haematology. 1999 August; 106(2): 377-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10460594
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High-dose intravenous cyclosporine in steroid refractory attacks of inflammatory bowel disease. Author(s): Hermida-Rodriguez C, Cantero Perona J, Garcia-Valriberas R, Pajares Garcia JM, Mate-Jimenez J. Source: Hepatogastroenterology. 1999 July-August; 46(28): 2265-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10521978
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Higher immunosuppressive efficacy of mycophenolate mofetil in combination with FK 506 than in combination with cyclosporine A. Author(s): Glanemann M, Klupp J, Langrehr JM, Schroer G, Platz KP, Stange B, Settmacher U, Bechstein WO, Neuhaus P. Source: Transplantation Proceedings. 2000 May; 32(3): 522-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10812095
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High-performance liquid chromatographic method for therapeutic drug monitoring of cyclosporine A and its two metabolites in renal transplant patients. Author(s): Brozmanova H, Grundmann M, Safarcik K, Jegorov A. Source: J Chromatogr B Biomed Sci Appl. 2000 November 10; 749(1): 93-100. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11129082
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Histological patterns of rejection using oral microemulsified cyclosporine and tacrolimus (FK506) as monotherapy induction after orthotopic liver transplantation. Author(s): Chau TN, Quaglia A, Rolles K, Burroughs AK, Dhillon AP. Source: Liver. 2001 October; 21(5): 329-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11589769
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Histopathological findings according to Banff-97 classification system comparing tacrolimus versus cyclosporine. Author(s): Rodrigo E, Escallada R, Fernandez-Fresnedo G, Ruiz JC, Pinera C, Herraez I, Cotorruelo JG, Zubimendi JA, de Francisco AL, Arias M. Source: Transplantation Proceedings. 2002 August; 34(5): 1719-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176550
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Histopathological findings in heart transplant patients under tacrolimusmycophenolate mofetil versus cyclosporine microemulsion-azathioprine. Author(s): Sgrosso JL, Ferrer J, Araujo G, Romeo L, Parisi C, Vazquez MC. Source: Transplantation Proceedings. 2002 February; 34(1): 115-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959214
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HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Author(s): Drewe J, Gutmann H, Fricker G, Torok M, Beglinger C, Huwyler J. Source: Biochemical Pharmacology. 1999 May 15; 57(10): 1147-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11230802
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HLA-DR4 predicts haematological response to cyclosporine in T-large granular lymphocyte lymphoproliferative disorders. Author(s): Battiwalla M, Melenhorst J, Saunthararajah Y, Nakamura R, Molldrem J, Young NS, Barrett AJ. Source: British Journal of Haematology. 2003 November; 123(3): 449-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14617004
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Homogenous enzyme immunoassay for cyclosporine in whole blood using the EMIT 2000 cyclosporine specific assay with the COBAS MIRA-plus analyzer. Author(s): Kimura S, Iyama S, Yamaguchi Y, Kanakura Y. Source: Journal of Clinical Laboratory Analysis. 2001; 15(6): 319-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11793432
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HP12: a highly purified Helleborus species extract strongly potentiates the T-cell suppressive effect of cyclosporine A. Author(s): Terness P, Dufter C, Linke S, Kerek F, Jung T, Watzlik A, Opelz G. Source: Transplantation Proceedings. 1999 February-March; 31(1-2): 1174-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10083524
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Hypercholesterolemia in long-term survivors of liver transplantation: a comparison between cyclosporine and FK 506. Author(s): Charco R, Cantarell C, Vargas V, Capdevila L, Esteban R, Lazaro JL, Margarit C. Source: Transplantation Proceedings. 1998 June; 30(4): 1489. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9636605
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Hyperhomocysteinemia in renal transplant recipients with cyclosporine. Author(s): Kim SI, Yoo TH, Song HY, Hwang JH, Lee HY, Han DS, Moon JI, Kim YS, Park KI, Paeng KJ, Choi KH. Source: Transplantation Proceedings. 2000 November; 32(7): 1878-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11119981
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Hyperlipidemia in pediatric kidney transplant recipients treated with cyclosporine. Author(s): Chavers BM, Hardstedt M, Gillingham KJ. Source: Pediatric Nephrology (Berlin, Germany). 2003 June; 18(6): 565-9. Epub 2003 April 24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12712377
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Hypersensitivity pneumonitis probably caused by cyclosporine. A case report. Author(s): Roelofs PM, Klinkhamer PJ, Gooszen HC. Source: Respiratory Medicine. 1998 December; 92(12): 1368-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10197232
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Hypersensitivity to cyclosporine (Neoral) and successful desensitization. Author(s): Sumpton JE, White CT, Rieder MJ, D'Souza SJ. Source: Transplantation Proceedings. 2001 September; 33(6): 3015-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11543829
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Hypertension in heart transplant recipients: more than just cyclosporine. Author(s): Eisen HJ. Source: Journal of the American College of Cardiology. 2003 February 5; 41(3): 433-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12575971
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Hypomagnesemia and mild rhabdomyolysis in living related donor renal transplant recipient treated with cyclosporine A. Author(s): Cavdar C, Sifil A, Sanli E, Gulay H, Camsari T. Source: Scandinavian Journal of Urology and Nephrology. 1998 December; 32(6): 415-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9925008
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Immunosuppressive regimen in lung transplantation: initial intravenous mycophenolate mofetil and cyclosporine avoid cytolytic induction and allow for rapid steroid tapering. Author(s): Fieguth HG, Simon A, Scherer M, Klesius AA, Wiedenmann DE. Source: Transplantation Proceedings. 2002 August; 34(5): 1879-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176611
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Immunosuppressive therapy with antithymocyte globulin and cyclosporine for prolonged marrow failure after hemophagocytic syndrome. Author(s): Kaito K, Otsubo H, Takei Y, Usui N, Kobayashi M. Source: Annals of Hematology. 2003 November; 82(11): 699-701. Epub 2003 September 05. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12961029
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Impact of cyclosporine dosing frequency on graft function and survival after the conversion from sandimmun to neoral in stable kidney transplanted patients. Author(s): Sampaio EL, Park SI, Felipe CR, Silva HT Jr, Pestana JO. Source: Transplantation Proceedings. 2002 December; 34(8): 3153-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12493405
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Impact of physical properties of formulations on bioavailability of active substance: current and novel drugs with cyclosporine. Author(s): Andrysek T. Source: Molecular Immunology. 2003 July; 39(17-18): 1061-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12835077
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Implication of cholesterol in cyclosporine pharmacodynamics in minimal change nephrotic syndrome. Author(s): Hirano T, Kawamura T, Fukuda S, Kohsaka S, Yoshikawa N, Yoshida M, Oka K. Source: Clinical Pharmacology and Therapeutics. 2003 December; 74(6): 581-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14663460
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Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination. Author(s): Gonwa TA, Hricik DE, Brinker K, Grinyo JM, Schena FP; Sirolimus Renal Function Study Group. Source: Transplantation. 2002 December 15; 74(11): 1560-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12490789
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Improved survival after lung transplantation in patients treated with tacrolimus/mycophenolate mofetil as compared with cyclosporine/azathioprine. Author(s): Izbicki G, Shitrit D, Aravot D, Sulkes J, Saute M, Sahar G, Kramer MR. Source: Transplantation Proceedings. 2002 December; 34(8): 3258-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12493439
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Improvement of cardiovascular risk factors in heart transplant recipients after conversion from cyclosporine to tacrolimus: a role of the TGF-beta system. Author(s): van Riemsdijk IC, Baan CC, Balk AH, Vantrimpont PM, Maat LP, Weimar W. Source: Transplantation Proceedings. 2002 August; 34(5): 1864-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176606
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Increased cyclosporine blood levels after nisoldipine administration in a renal transplant recipient. Author(s): Fourtounas C, Kopelias I, Kiriaki D, Agroyannis B. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2002 November; 15(11): 586-8. Epub 2002 September 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12461666
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Infliximab salvage therapy after cyclosporine in an acute flare of chronic ulcerative colitis. Author(s): Lam EC, Bailey RJ. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 2003 March; 17(3): 198-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12677271
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Influence of long term cyclosporine therapy on insulin and its precursors secretion in patients after heart transplantation. Author(s): Zielinska T, Zakliczynski M, Szewczyk M, Zielinska-Kukla A, Foremny J, Kalarus Z, Religia Z, Zembala M. Source: Ann Transplant. 2003; 8(1): 10-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12848377
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Inhibitory effect of FK506 and cyclosporine A on the growth and invasion of human liver cancer cells. Author(s): Sakai M, Miyake H, Tashiro S, Okumura Y, Kido H. Source: J Med Invest. 2004 February; 51(1-2): 63-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15000258
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Insensitivity to cyclosporine may explain the HLA-DRw6 recipient effect. Author(s): Kudlacek S, Zlabinger GJ, Pohanka E, Hamilton G, Rosenmayr A, Kovarik J. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1992; 5 Suppl 1: S556-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621875
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Insights into cyclosporine A-induced atherosclerotic risk in transplant recipients: macrophage scavenger receptor regulation. Author(s): Jin S, Mathis AS, Rosenblatt J, Minko T, Friedman GS, Gioia K, Serur DS, Knipp GT. Source: Transplantation. 2004 February 27; 77(4): 497-504. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15084924
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International experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection. Author(s): Sarahrudi K, Estenne M, Corris P, Niedermayer J, Knoop C, Glanville A, Chaparro C, Verleden G, Gerbase MW, Venuta F, Bottcher H, Aubert JD, Levvey B, Reichenspurner H, Auterith A, Klepetko W. Source: The Journal of Thoracic and Cardiovascular Surgery. 2004 April; 127(4): 1126-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15052212
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Intravenous cyclosporine in severe ulcerative colitis: how low can you go? Author(s): Regueiro M. Source: Inflammatory Bowel Diseases. 2004 March; 10(2): 170. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15168819
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Intravenous cyclosporine therapy in recurrent nephrotic syndrome after renal transplantation in children. Author(s): Salomon R, Gagnadoux MF, Niaudet P. Source: Transplantation. 2003 March 27; 75(6): 810-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12660507
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Is oral azithromycin effective for the treatment of cyclosporine-induced gingival hyperplasia in cardiac transplant recipients? Author(s): Strachan D, Burton I, Pearson GJ. Source: Journal of Clinical Pharmacy and Therapeutics. 2003 August; 28(4): 329-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12911686
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Itraconazole-induced rhabdomyolysis and acute renal failure in a heart transplant recipient treated with simvastatin and cyclosporine. Author(s): Vlahakos DV, Manginas A, Chilidou D, Zamanika C, Alivizatos PA. Source: Transplantation. 2002 June 27; 73(12): 1962-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131698
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Joint pain and arthritis in renal transplant recipients and correlation with cyclosporine therapy. Author(s): Kart-Koseoglu H, Yucel AE, Isiklar I, Turker I, Akcali Z, Haberal M. Source: Rheumatology International. 2003 July; 23(4): 159-62. Epub 2003 February 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12856139
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Ketoconazole alters cyclosporine pharmacokinetic profile and may predispose to acute rejection. Author(s): Dominguez J, Kompatzki A, Foradori A, Norambuena R. Source: Transplantation Proceedings. 2003 November; 35(7): 2522-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14612002
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Kidney function in cyclosporine-treated paediatric pulmonary transplant recipients. Author(s): Tsimaratos M, Viard L, Kreitmann B, Remediani C, Picon G, Camboulives J, Sarles J, Metras D. Source: Transplantation. 2000 May 27; 69(10): 2055-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10852596
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Kidney transplantation in children younger than 1 year using cyclosporine immunosuppression. Author(s): Humar A, Nevins TE, Remucal M, Cook ME, Matas AJ, Najarian JS. Source: Annals of Surgery. 1998 September; 228(3): 421-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9742925
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Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Author(s): Flechner SM, Goldfarb D, Modlin C, Feng J, Krishnamurthi V, Mastroianni B, Savas K, Cook DJ, Novick AC. Source: Transplantation. 2002 October 27; 74(8): 1070-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12438948
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Kidneys from border-age donors in the cyclosporine era: long-term function and outcome. Author(s): Berardinelli L, Pasciucco A, Pozzoli E, Ferraresso M, Carini M, Vegeto A. Source: Transplantation Proceedings. 1999 February-March; 31(1-2): 294-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10083113
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Lack of citalopram effect on the pharmacokinetics of cyclosporine. Author(s): Liston HL, Markowitz JS, Hunt N, DeVane CL, Boulton DW, Ashcraft E. Source: Psychosomatics. 2001 July-August; 42(4): 370-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11496034
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Lack of effect of cyclosporine in lichen amyloidosis associated with atopic dermatitis. Author(s): Akar A, Tastan HB, Demiriz M, Erbil H. Source: European Journal of Dermatology : Ejd. 2002 November-December; 12(6): 612-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12459544
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Late failures in renal transplant recipients under cyclosporine treatment. Author(s): Ponticelli C, Villa M, Cesana B, Montagnino G, Tarantino A. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3325-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750422
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Lichen amyloidosis associated with atopic dermatitis: clinical resolution with cyclosporine. Author(s): Behr FD, Levine N, Bangert J. Source: Archives of Dermatology. 2001 May; 137(5): 553-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11346332
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Lichen amyloidosus associated with Kimura's disease: successful treatment with cyclosporine. Author(s): Teraki Y, Katsuta M, Shiohara T. Source: Dermatology (Basel, Switzerland). 2002; 204(2): 133-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11937739
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Life-threatening hypothyroidism associated with administration of cyclosporine in a patient treated with reduced-intensity hematopoietic stem-cell transplantation for metastatic renal-cell carcinoma. Author(s): Imataki O, Kim SW, Kojima R, Hori A, Hamaki T, Sakiyama M, Murashige N, Satoh M, Kami M, Makimoto A, Takaue Y. Source: Transplantation. 2003 March 27; 75(6): 898-907. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12660521
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Linear correlation between sirolimus and cyclosporine trough levels in renal transplant patients. Author(s): Lee CY, Tsai MK, Hu RH, Lee PH. Source: Transplantation Proceedings. 2003 February; 35(1): 238-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591380
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Lipid-lowering long-term effects of six different statins in hypercholesterolemic renal transplant patients under cyclosporine immunosuppression. Author(s): Martinez-Castelao A, Grinyo JM, Gil-Vernet S, Seron D, Castineiras MJ, Ramos R, Alsina J. Source: Transplantation Proceedings. 2002 February; 34(1): 398-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959343
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Longer term outcome of steroid refractory ulcerative colitis treated with intravenous cyclosporine without subsequent oral cyclosporine maintenance therapy. Author(s): Rolny P, Sadik R. Source: International Journal of Colorectal Disease. 2002 March; 17(2): 67-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12014423
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Longer-term risks associated with 10-year survival after heart transplantation in the cyclosporine era. Author(s): Shiba N, Chan MC, Valantine HA, Gao SZ, Robbins RC, Hunt SA. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 October; 22(10): 1098-106. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550819
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Long-term beneficial effects of azathioprine addition to ongoing cyclosporineprednisone protocol in renal transplantation. Author(s): Pascual J, Marcen R, Orofino L, Quereda C, Teruel JL, Mampaso F, Liano F, Villafruela JJ, Ortuno J. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1992; 5 Suppl 1: S107-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621748
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Long-term effects of chronic cyclosporine nephropathy on outcome of renal allografts. Author(s): Takeda A, Morozumi K, Haba T, Katayama A, Tominaga Y, Uchida K. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3379-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750445
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Long-term graft survival with or without donor-specific transfusion in cyclosporine era in one haplo-identical living-related renal transplant recipients beyond the first year: a 19-year experience. Author(s): Satoh S, Sugimura J, Omori S, Seino K, Fujizuka I. Source: The Tohoku Journal of Experimental Medicine. 2002 August; 197(4): 201-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12434995
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Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Author(s): Oberbauer R, Kreis H, Johnson RW, Mota A, Claesson K, Ruiz JC, Wilczek H, Jamieson N, Henriques AC, Paczek L, Chapman J, Burke JT; Rapamune Maintenance Regimen Study Group. Source: Transplantation. 2003 July 27; 76(2): 364-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12883194
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Long-term outcome of systemic cyclosporine treatment following penetrating keratoplasty. Author(s): Inoue K, Kimura C, Amano S, Sato T, Fujita N, Kagaya F, Kaji Y, Tsuru T, Araie M. Source: Japanese Journal of Ophthalmology. 2001 July-August; 45(4): 378-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11485770
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Long-term renal effects of low-dose cyclosporine in uveitis-treated patients: followup study. Author(s): Isnard Bagnis C, Tezenas du Montcel S, Beaufils H, Jouanneau C, Jaudon MC, Maksud P, Mallet A, LeHoang P, Deray G. Source: Journal of the American Society of Nephrology : Jasn. 2002 December; 13(12): 2962-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12444215
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Long-term results of donor-specific blood transfusion with cyclosporine in living related kidney transplantation. Author(s): Otsuka M, Yuzawa K, Takada Y, Taniguchi H, Todoroki K, Fukao K, Koyama A, Akaza H. Source: Nephron. 2001 June; 88(2): 144-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11399917
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Long-term use of cyclosporine in cardiac transplantation: the Pitie experience. Author(s): Dorent R, Tezenas S, Ghossoub JJ, Leger P, Lendvai N, Vaissier E, Levasseur JP, Eslami M, Pavie A, Gandjbakhch I. Source: Transplantation Proceedings. 2002 May; 34(3): 831-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12034199
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Low dose cyclosporine-a therapy in severe aplastic anaemia. Author(s): Rai M, Singh VP, Shukla J, Sundar S, Jha VC. Source: J Assoc Physicians India. 2001 October; 49: 966-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11848327
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Lung deposition and pharmacokinetics of cyclosporine after aerosolization in lung transplant patients. Author(s): Burkart GJ, Smaldone GC, Eldon MA, Venkataramanan R, Dauber J, Zeevi A, McCurry K, McKaveney TP, Corcoran TE, Griffith BP, Iacono AT. Source: Pharmaceutical Research. 2003 February; 20(2): 252-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12636164
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Markers of oxidative stress in cyclosporine-treated and tacrolimus-treated children after liver transplantation. Author(s): Granot E, Elinav H, Kohen R. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2002 May; 8(5): 469-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12004347
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MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. Author(s): Mai I, Stormer E, Goldammer M, Johne A, Kruger H, Budde K, Roots I. Source: Journal of Clinical Pharmacology. 2003 October; 43(10): 1101-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517192
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Merkel cell carcinoma developing after antithymocyte globulin and cyclosporine therapy for aplastic anemia. Author(s): Takabayashi M, Sakai R, Sakamoto H, Iemoto Y, Kanamori H, Inayama Y, Ishigatsubo Y. Source: Anti-Cancer Drugs. 2003 March; 14(3): 251-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12634621
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Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. Author(s): Heydendael VM, Spuls PI, Opmeer BC, de Borgie CA, Reitsma JB, Goldschmidt WF, Bossuyt PM, Bos JD, de Rie MA. Source: The New England Journal of Medicine. 2003 August 14; 349(7): 658-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917302
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Modifications in cyclosporine (CsA) microemulsion blood concentrations by olestra. Author(s): Terrill CJ, Lill J, Somerville KT, Sherbotie JR. Source: Journal of Renal Nutrition : the Official Journal of the Council on Renal Nutrition of the National Kidney Foundation. 2003 January; 13(1): 26-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12563620
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Modifications in lipoprotein surface charge alter cyclosporine A association with lowdensity lipoproteins. Author(s): Wasan KM, Sivak O. Source: Pharmaceutical Research. 2003 January; 20(1): 126-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12608546
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Monitoring cyclosporine of pre-dose and post-dose samples using nonextraction homogeneous immunoassay. Author(s): Loor R, Pope L, Boyd R, Wood K, Bodepudi V. Source: Therapeutic Drug Monitoring. 2004 February; 26(1): 58-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14749552
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Monitoring of NFAT-regulated gene expression in the peripheral blood of allograft recipients: a novel perspective toward individually optimized drug doses of cyclosporine A. Author(s): Giese T, Zeier M, Schemmer P, Uhl W, Schoels M, Dengler T, Buechler M, Meuer S. Source: Transplantation. 2004 February 15; 77(3): 339-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14966405
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Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil. Author(s): Vincenti F, Monaco A, Grinyo J, Kinkhabwala M, Roza A. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2003 March; 3(3): 306-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12614286
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Multiple organ failure in a kidney transplant patient receiving both colchicine and cyclosporine. Author(s): Minetti EE, Minetti L. Source: Journal of Nephrology. 2003 May-June; 16(3): 421-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12832745
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Mycophenolate mofetil and cyclosporine therapy in membranous nephropathy. Author(s): Cattran DC. Source: Semin Nephrol. 2003 May; 23(3): 272-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12838495
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Mylotarg, fludarabine, cytarabine (ara-C), and cyclosporine (MFAC) regimen as postremission therapy in acute myelogenous leukemia. Author(s): Tsimberidou AM, Estey E, Cortes JE, Garcia-Manero G, Faderl S, Verstovsek S, Thomas DA, Ferrajoli A, Keating MJ, O'Brien S, Kantarjian HM, Giles FJ. Source: Cancer Chemotherapy and Pharmacology. 2003 December; 52(6): 449-52. Epub 2003 September 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=13680159
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Neither acute rejection nor immunosuppressant drug therapy (cyclosporine or tacrolimus) correlates with expression of either CD40 or CD154 on peripheral blood cells among human cardiac transplant patients. Author(s): Domenech N, Crespo-Leiro MG, Moscoso I, Paniagua MJ, Naya C, Muniz J, Vazquez-Rodriguez JM, Castro-Beiras A. Source: Transplantation Proceedings. 2003 August; 35(5): 1994-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962873
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Neoral (cyclosporine) C2 monitoring in renal transplant recipients: a single-center experience in Asia. Author(s): Wong HS, Morad Z. Source: Transplantation Proceedings. 2003 February; 35(1): 230-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12591376
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Neoral dose monitoring using 2-hour cyclosporine post-dose levels in stable children with liver transplants: improvement in renal function. Author(s): Shapiro R, Waissman I, Mor E, Kleper R, Nussinovitch M, Dinari G, Ben-Ari Z. Source: Pediatric Transplantation. 2003 December; 7(6): 450-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14870892
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Neoral dose monitoring with cyclosporine 2-hour postdose levels (C(2)) in different renal transplant patient age groups. Author(s): Rosati A, Bertoni E, Zanazzi M, Di Maria L, Ciuti R, Piperno R, Moscarelli L, Biagini M, Salvadori M. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3106-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750335
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Nephrotic syndrome in a bone marrow transplant recipient after cyclosporine withdrawal. Author(s): Bernis C, Camara R, Garcia Sanchez A, Martinez MA, Selgas R. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 November; 18(11): 2457. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14551395
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New approaches to individualizing cyclosporine dose. Author(s): Cantarovich M. Source: Transplantation. 2004 February 15; 77(3): 357-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14983877
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New concepts in cyclosporine monitoring. Author(s): Keown PA. Source: Current Opinion in Nephrology and Hypertension. 2002 November; 11(6): 61926. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12394607
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New strategies of cyclosporine monitoring in heart transplantation: initial results. Author(s): Arizon del Prado JM, Aumente Rubio MD, Cardenas Aranzana M, Lopez Malo de Molina MD, Segura Saint-Gerons J, Lopez Granados A, Rodriguez Esteban E, Ruiz Ortiz M, Romo Penas E, Munoz Carvajal I, Gonzalez Rodriguez JR, Segura SaintGerons C, Valles Belsue F, Concha Ruiz M. Source: Transplantation Proceedings. 2003 August; 35(5): 1984-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12962870
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New strategies to optimize clinical outcomes with cyclosporine in liver transplantation. Author(s): Levy GA. Source: Gastroenterologia Y Hepatologia. 2002 April; 25(4): 289-93. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11975883
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Nocardia asteroides lung abscess in acute ulcerative colitis treated with cyclosporine. Author(s): Stack WA, Richardson PD, Logan RP, Mahida YR, Hawkey CJ. Source: The American Journal of Gastroenterology. 2001 July; 96(7): 2255-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11467663
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Obesity in transplant patients: case report showing interference of orlistat with absorption of cyclosporine and review of literature. Author(s): Barbaro D, Orsini P, Pallini S, Piazza F, Pasquini C. Source: Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2002 March-April; 8(2): 1246. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11942778
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One year evolution of bone mineral density in kidney transplant recipients receiving tacrolimus versus cyclosporine. Author(s): El Haggan W, Barthe N, Vendrely B, Chauveau P, Berger F, Aparicio M, Potaux L. Source: Transplantation Proceedings. 2002 August; 34(5): 1817-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176589
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One-center comparison between primary immunosuppression based on neoral cyclosporine and tacrolimus for renal transplantation. Author(s): Pascual J, Marcen R, Burgos FJ, Tenorio MT, Merino JL, Arambarri M, Villafruela JJ, Liano F, Mampaso F, Ortuno J. Source: Transplantation Proceedings. 2002 February; 34(1): 94-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11959200
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One-year cyclosporine prophylaxis reduces the risk of developing extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation. Author(s): Mengarelli A, Iori AP, Romano A, Cerretti R, Cerilli L, De Propris MS, Fenu S, Moleti ML, De Felice L, Girelli G, Arcese W. Source: Haematologica. 2003 March; 88(3): 315-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12651271
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One-year follow-up of a Brazilian randomized multicenter study comparing tacrolimus versus cyclosporine in kidney transplantation. Author(s): Campos HH, Abbud Filho M; Brazilian Tacrolimus Study Group. Source: Transplantation Proceedings. 2002 August; 34(5): 1656-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176523
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One-year glomerular filtration rate predicts graft survival in pediatric renal recipients: a randomized trial of tacrolimus vs cyclosporine microemulsion. Author(s): Filler G, Trompeter R, Webb NJ, Watson AR, Milford DV, Tyden G, Grenda R, Janda J, Hughes D, Offner G, Klare B, Zacchello G, Brekke IB, McGraw M, Perner F, Ghio L, Balzar E, Friman S, Gusmano R, Stolpe J. Source: Transplantation Proceedings. 2002 August; 34(5): 1935-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176634
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Open questions concerning cyclosporine therapy in ulcerative colitis. Author(s): Molnar T, Szepes Z, Nagy F, Szenohradszki P, Lonovics J. Source: Gastroenterology. 2004 May; 126(5): 1495-6; Author Reply 1496. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15131824
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Oral cyclosporine but not tacrolimus reduces renal transplant blood flow. Author(s): Nankivell BJ, Chapman JR, Bonovas G, Gruenewald SM. Source: Transplantation. 2004 May 15; 77(9): 1457-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15167607
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Oral dosing of tacrolimus and cyclosporine microemulsion--results from a large multicenter study in renal transplantation. Author(s): Dietl KH; European Renal Transplantation Study Group. Source: Transplantation Proceedings. 2002 August; 34(5): 1659-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176524
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Outcome and prognosis of cyclosporine-related hemolytic-uremic syndrome in kidney graft recipients: clinical and histopathologic study of 13 cases. Author(s): Bren AF, Kandus A, Koselj M, Buturovic J, Lindic J, Kovac D, Ponikvar R, Vizjak A, Ferluga D. Source: Transplantation Proceedings. 2002 November; 34(7): 3005-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12431685
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Pancreas transplantation in cross-match-positive recipients using cyclosporine- or tacrolimus-based immunosuppression. Author(s): Khwaja K, Wijkstrom M, Gruessner A, Noreen H, Sutherland DE, Gruessner RW. Source: Transplantation Proceedings. 2002 August; 34(5): 1901-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176621
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Patient management by cyclosporine C2 monitoring. Author(s): Jorga A, Johnston A, Holt DW. Source: Transplantation. 2004 January 27; 77(2): 323-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14743006
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Pharmacokinetic interactions between sirolimus and microemulsion cyclosporine when orally administered jointly and 4 hours apart in healthy volunteers. Author(s): Zimmerman JJ, Harper D, Getsy J, Jusko WJ. Source: Journal of Clinical Pharmacology. 2003 October; 43(10): 1168-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517200
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Pharmacokinetics of daclizumab and mycophenolate mofetil with cyclosporine and steroids in renal transplantation. Author(s): Pescovitz MD, Bumgardner G, Gaston RS, Kirkman RL, Light S, Patel IH, Nieforth K, Vincenti F. Source: Clinical Transplantation. 2003 December; 17(6): 511-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14756266
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Posterior leukoencephalopathy with cyclosporine. Author(s): Chow KM, Szeto CC. Source: Clinical Nephrology. 2003 October; 60(4): 297-8; Author Reply 298. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14579949
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Post-operative conversion from cyclosporine to tacrolimus in heart transplantation: a single-center experience. Author(s): Cantin B, Kwok BW, Shiba N, Valantine HA, Hunt SA, Chan MC. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2003 July; 22(7): 723-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12873539
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Pregnancy in kidney recipients under cyclosporine. Author(s): Berardinelli L, Dallatana R, Beretta C, Raiteri M, Tonello G, Quaglia F, Vegeto A. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1992; 5 Suppl 1: S480-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621852
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Pretransplantation conditioning influence on the occurrence of cyclosporine or FK506 neurotoxicity in allogeneic bone marrow transplantation. Author(s): Bartynski WS, Zeigler ZR, Shadduck RK, Lister J. Source: Ajnr. American Journal of Neuroradiology. 2004 February; 25(2): 261-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14970028
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Prospective analysis of thrombotic microangiopathy after renal transplantation: comparison between cyclosporine and tacrolimus immunosuppression. Author(s): Tanabe K, Tokumoto T, Ishida H, Shimmura H, Omoto K, Makiyama K, Toda F, Toma H. Source: Transplantation Proceedings. 2002 August; 34(5): 1819-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176590
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Prospective randomized pilot study of steroid withdrawal with mycophenolate mofetil in long-term cyclosporine-treated patients: 4-year follow-up. Author(s): Budde K, Geissler S, Hallebach G, Waiser J, Fritsche L, Bohler T, Neumayer HH. Source: Transplantation Proceedings. 2002 August; 34(5): 1703-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176544
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Quality of life in kidney recipients: comparison of tacrolimus and cyclosporinemicroemulsion. Author(s): Reimer J, Franke GH, Philipp T, Heemann U. Source: Clinical Transplantation. 2002 February; 16(1): 48-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11982615
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Quantitation of cyclosporine-sensitive and -resistant allospecific cytotoxic cells at birth. Author(s): Haque KM, Truman C, Dittmer I, Donaldson C, Laundy G, Dudley J, Hows J, Bradley BA. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2000; 13 Suppl 1: S471-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11112056
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Quantitative morphometry of renal biopsies prior to cyclosporine in nephrotic syndrome. Author(s): Smoyer WE, Gregory MJ, Bajwa RS, Johnson KJ, Bunchman TE. Source: Pediatric Nephrology (Berlin, Germany). 1998 November; 12(9): 737-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9874317
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Quantitative MR diffusion mapping and cyclosporine-induced neurotoxicity. Author(s): Coley SC, Porter DA, Calamante F, Chong WK, Connelly A. Source: Ajnr. American Journal of Neuroradiology. 1999 September; 20(8): 1507-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10512238
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Quiz page. Stones in the kidney allograft and bladder. Nephrolithiasis is common after transplantation. Cyclosporine often leads to chronic hyperuricemia and the formation of uric acid stones. Author(s): Canas G. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2003 January; 41(1): Xli. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12500253
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Randomized conversion from cyclosporine to tacrolimus in renal transplant patients: improved lipid profile and unchanged plasma homocysteine levels. Author(s): Artz MA, Boots JM, Ligtenberg G, Roodnat JI, Christiaans MH, Hene RJ, Blom HJ, Demacker PN, Hilbrands LB. Source: Transplantation Proceedings. 2002 August; 34(5): 1793-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176579
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Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Author(s): Van Assche G, D'Haens G, Noman M, Vermeire S, Hiele M, Asnong K, Arts J, D'Hoore A, Penninckx F, Rutgeerts P. Source: Gastroenterology. 2003 October; 125(4): 1025-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517785
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Randomized, open-label preference study of two cyclosporine capsule formulations (usp modified) in stable solid-organ transplant recipients. Author(s): Steinberg SM, Venuto RC, Kuruvila CK, Taylor DO, Anil Kumar MS, Groothuis JR, Ryan J, Greco R, Yeldandi V, Ashraf T, Boodhoo T; Prefer Study Group. Source: Clinical Therapeutics. 2003 July; 25(7): 2037-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12946549
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Recalcitrant oral pyoderma gangrenosum in a child responsive to cyclosporine. Author(s): Park HJ, Han BG, Kim YC, Cinn YW. Source: The Journal of Dermatology. 2003 August; 30(8): 612-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12928531
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Relationship between development of nephrotoxicity and blood concentration of cyclosporine A in bone-marrow transplanted recipients who received the continuous intravenous infusion. Author(s): Kagawa Y, Sawada J, Yamada S, Matsuda H, Kageyama S, Masuya M, Shiku H, Kojima M. Source: Biological & Pharmaceutical Bulletin. 2003 August; 26(8): 1115-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12913261
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Relationship between endomyocardial biopsy score and cyclosporine 2-h post-dose levels (C) in heart transplant patients receiving anti-thymocyte globulin induction. Author(s): Cantarovich M, Giannetti N, Cecere R. Source: Clinical Transplantation. 2004 April; 18(2): 148-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15016128
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Reversible posterior leukoencephalopathy due to oral cyclosporine in severe ulcerative colitis. Author(s): Sood A, Midha V, Sood N. Source: Indian J Gastroenterol. 2003 November-December; 22(6): 233-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15030042
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Reversible posterior leukoencephalopathy syndrome in a child with cerebral Xlinked adrenoleukodystrophy treated with cyclosporine after bone marrow transplantation. Author(s): Chan AK, Bhargava R, Desai S, Joffe A. Source: Journal of Inherited Metabolic Disease. 2003; 26(6): 527-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14605498
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Review of the properties and mechanisms of action of cyclosporine with an emphasis on dermatological therapy in dogs, cats and people. Author(s): Robson D. Source: The Veterinary Record. 2003 June 21; 152(25): 768-72. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12846287
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Risk factors for acute rejection in 806 cyclosporine-treated renal transplants: a multivariate analysis. Author(s): Mota A, Figueiredo A, Cunha MF, Bastos M, Pratas J, Furtado L. Source: Transplantation Proceedings. 2003 May; 35(3): 1061-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12947856
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Simple determination of cyclosporine in human whole blood by high-performance liquid chromatography. Author(s): Amini H, Ahmadiani A. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 October 5; 795(2): 209-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14522025
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Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. Author(s): Morales JM, Wramner L, Kreis H, Durand D, Campistol JM, Andres A, Arenas J, Negre E, Burke JT, Groth CG; Sirolimus European Renal Transplant Study Group. Source: American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2002 May; 2(5): 436-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12123209
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Spontaneous remission of Epstein-Barr virus-negative non-Hodgkin's lymphoma after withdrawal of cyclosporine in a patient with refractory anemia. Author(s): Ogata M, Kikuchi H, Ono K, Ohtsuka E, Gamachi A, Kashima K, Nasu M. Source: International Journal of Hematology. 2004 February; 79(2): 161-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15005345
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Stabilization of pyoderma gangrenosum ulcer with oral cyclosporine prior to skin grafting. Author(s): Zakhireh M, Rockwell WB, Fryer RH. Source: Plastic and Reconstructive Surgery. 2004 April 15; 113(5): 1417-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15060355
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Subcutaneous panniculitic T-cell lymphoma in children: response to combination therapy with cyclosporine and chemotherapy. Author(s): Shani-Adir A, Lucky AW, Prendiville J, Murphy S, Passo M, Huang FS, Paller AS. Source: Journal of the American Academy of Dermatology. 2004 February; 50(2 Suppl): S18-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14726859
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Successful conversion from cyclosporine to tacrolimus for gastric motor dysfunction in a lung transplant recipient. Author(s): Verleden GM, Besse T, Maes B. Source: Transplantation. 2002 June 27; 73(12): 1974-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131703
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Successful management of severe chronic autoimmune hemolytic anemia with low dose cyclosporine and prednisone in an infant. Author(s): Yarali N, Fisgin T, Kara A, Duru F. Source: Turk J Pediatr. 2003 October-December; 45(4): 335-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14768800
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Successful treatment of progressive NK cell lymphoma with allogeneic peripheral stem cell transplantation followed by early cyclosporine tapering and donor leukocyte infusions. Author(s): Makita M, Maeda Y, Takenaka K, Shinagawa K, Sunami K, Hiramatsu Y, Fujii N, Ishimaru F, Ikeda K, Niiya K, Yoshino T, Harada M. Source: International Journal of Hematology. 2002 July; 76(1): 94-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12138904
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Sustained cyclosporine-induced erythropoietic response in identical male twins with diamond-blackfan anemia. Author(s): Bobey NA, Carcao M, Dror Y, Freedman MH, Dahl N, Woodman RC. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 November; 25(11): 914-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14608205
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Switching monitoring of emulsified cyclosporine from trough level to 2-hour level in stable liver transplant patients. Author(s): Langers P, Cremers SC, den Hartigh J, Veenendaal RA, ten Hove WR, Ringers J, Lamers CB, van Hoek B. Source: Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2004 February; 10(2): 183-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14762854
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Tacrolimus versus cyclosporine in primary simultaneous pancreas-kidney transplantation: preliminary results at 1 year of a large multicenter trial. Author(s): Land W, Malaise J, Sandberg J, Langrehr J; EUROSPK Study Group. Source: Transplantation Proceedings. 2002 August; 34(5): 1911-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176625
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Tacrolimus/mycophenolate mofetil vs cyclosporine A/Azathioprine after simultaneous pancreas and kidney transplantation: five-year results of a randomized study. Author(s): Woeste G, Wullstein C, Dette K, Pridohl O, Lubke P, Bechstein WO. Source: Transplantation Proceedings. 2002 August; 34(5): 1920-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176629
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Ten-year results of a randomised prospective study of FK506 versus cyclosporine in management of primary orthotopic liver transplantation. Author(s): Chen JW, Pehlivan M, Gunson BK, Buckels JA, McMaster P, Mayer D. Source: Transplantation Proceedings. 2002 August; 34(5): 1507-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176460
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The effect of lipoprotein-associated cyclosporine on drug metabolism and toxicity in rats. Author(s): Kim T, Lu SK, Brunner LJ. Source: Pda J Pharm Sci Technol. 2003 November-December; 57(6): 410-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14765557
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Thirteen years' experience in pediatric liver transplantation: differences between tacrolimus and cyclosporine. Author(s): Zajicek A, Esquivel C, Millan M, Cox K, Berquist R, Berquist W. Source: Transplantation Proceedings. 2002 August; 34(5): 1976-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176653
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Ticlopidine-induced marrow aplasia treated with cyclosporine. Author(s): Ertorer ME, Gokcel A, Savas L, Kocak R. Source: Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2002 April; 8(2): 183-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12121061
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Topical cyclosporine 0.5 per cent and preservative-free ketorolac tromethamine 0.5 per cent in vernal keratoconjunctivitis. Author(s): Kosrirukvongs P, Luengchaichawange C. Source: J Med Assoc Thai. 2004 February; 87(2): 190-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15061303
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Topical cyclosporine in the management of shield ulcers. Author(s): Cetinkaya A, Akova YA, Dursun D, Pelit A. Source: Cornea. 2004 March; 23(2): 194-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15075890
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Transplantation: toxicokinetics and mechanisms of toxicity of cyclosporine and macrolides. Author(s): Serkova N, Christians U. Source: Curr Opin Investig Drugs. 2003 November; 4(11): 1287-96. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14758767
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Trial of metronidazole vs. azithromycin for treatment of cyclosporine-induced gingival overgrowth. Author(s): Chand DH, Quattrocchi J, Poe SA, Terezhalmy GT, Strife CF, Cunningham RJ. Source: Pediatric Transplantation. 2004 February; 8(1): 60-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15009842
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Unusual corneal deposit after the topical use of cyclosporine as eyedrops. Author(s): Kachi S, Hirano K, Takesue Y, Miura M. Source: American Journal of Ophthalmology. 2000 November; 130(5): 667-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11078849
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Urinary retinol binding protein is a good marker of progressive cyclosporine nephrotoxicity after heart transplant. Author(s): Camara NO, Matos AC, Rodrigues DA, Pereira AB, Pacheco-Silva A. Source: Transplantation Proceedings. 2001 May; 33(3): 2129-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11377474
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Urticaria and cyclosporine. Author(s): Galindo Bonilla PA, Borja Segade J, Gomez Torrijos E, Feo Brito F. Source: Allergy. 2002 July; 57(7): 650-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12100312
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Use of cyclosporine. Author(s): Paul LC. Source: Transplantation. 2002 September 27; 74(6): 754-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12369581
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Use of cytotoxic agents and cyclosporine in the treatment of autoimmune disease. Part 2: Inflammatory bowel disease, systemic vasculitis, and therapeutic toxicity. Author(s): Langford CA, Klippel JH, Balow JE, James SP, Sneller MC. Source: Annals of Internal Medicine. 1998 July 1; 129(1): 49-58. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9653000
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Use of mycophenolate mofetil in liver transplant recipients experiencing renal dysfunction on cyclosporine or tacrolimus-randomized, prospective, multicenter study results. Author(s): Hodge EE, Reich DJ, Clavien PA, Kim-Schluger L. Source: Transplantation Proceedings. 2002 August; 34(5): 1546-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12176477
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Use of sirolimus to facilitate cyclosporine avoidance or steroid withdrawal in kidney transplant recipients. Author(s): Hricik DE. Source: Transplantation Proceedings. 2003 May; 35(3 Suppl): 73S-78S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742471
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Usefulness of cyclosporine A on rapidly progressive interstitial pneumonia in dermatomyositis. Author(s): Miyake S, Ohtani Y, Sawada M, Inase N, Miyazaki Y, Takano S, Miyasaka N, Yoshizawa Y. Source: Sarcoidosis Vasc Diffuse Lung Dis. 2002 June; 19(2): 128-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12102608
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Usefulness of finger thermography to assess cyclosporine toxicity after heart transplantation. Author(s): Doutreleau S, Gautherie M, Lonsdorfer E, Rouyer O, Epailly E, Eisenmann B, Piquard F, Geny B. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3318-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750420
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Variability of cyclosporine exposure and its relevance to chronic allograft nephropathy: a case-control study. Author(s): Stoves J, Newstead CG. Source: Transplantation. 2002 December 27; 74(12): 1794-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12499901
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Vascular endothelial function in cyclosporine and tacrolimus treated renal transplant recipients. Author(s): Ovuworie CA, Fox ER, Chow CM, Pascual M, Shih VE, Picard MH, TolkoffRubin NE. Source: Transplantation. 2001 October 27; 72(8): 1385-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11685108
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Vascular graft thrombosis after pancreas transplantation: comparison of the FK 506 and cyclosporine eras. Author(s): Kandaswamy R, Humar A, Gruessner AC, Harmon JV, Granger DK, Lynch S, Sutherland DE, Gruessner RW. Source: Transplantation Proceedings. 1999 February-March; 31(1-2): 602-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10083254
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Which calcineurin inhibitor is preferred in renal transplantation: tacrolimus or cyclosporine? Author(s): Vanrenterghem YF. Source: Current Opinion in Nephrology and Hypertension. 1999 November; 8(6): 669-74. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10630811
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Whole-blood calcineurin activity is not predicted by cyclosporine blood concentration in renal transplant recipients. Author(s): Caruso R, Perico N, Cattaneo D, Piccinini G, Bonazzola S, Remuzzi G, Gaspari F. Source: Clinical Chemistry. 2001 September; 47(9): 1679-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11514403
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Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression. Author(s): Singh D, Alexander J, Owen A, Rustom R, Bone M, Hammad A, Roberts N, Park K, Pirmohamed M. Source: Transplantation. 2004 February 27; 77(4): 557-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15084935
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Withdrawal of cyclosporine in renal transplant recipients with acute tubular necrosis improves renal function. Author(s): Kahn D, Botha JF, Pascoe MD, Pontin AR, Halkett J, Tandon V. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2000; 13 Suppl 1: S82-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11111968
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Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study. Author(s): Smak Gregoor PJ, de Sevaux RG, Ligtenberg G, Hoitsma AJ, Hene RJ, Weimar W, Hilbrands LB, van Gelder T. Source: Journal of the American Society of Nephrology : Jasn. 2002 May; 13(5): 1365-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11961025
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Withdrawal of steroids from a cyclosporine-based regimen: pro. Author(s): Ponticelli C. Source: Transplantation Proceedings. 1998 August; 30(5): 1782-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9723281
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Withdrawal versus continuous cyclosporine therapy in kidney transplant recipients of one-haplotype-matched donors. Author(s): Chew-Wong A, Alberu J, Abasta-Jimenez M, Alvarez-Sandoval E, GabilondoNavarro F, Correa-Rotter R. Source: Transplantation Proceedings. 1999 February-March; 31(1-2): 1106-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10083494
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Within-patient controlled assessment of the influence of basiliximab on cyclosporine in pediatric de novo renal transplant recipients. Author(s): Kovarik JM, Korn A, Chodoff L. Source: Transplantation Proceedings. 2001 November-December; 33(7-8): 3172-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11750361
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CHAPTER 2. NUTRITION AND CYCLOSPORINE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and cyclosporine.
Finding Nutrition Studies on Cyclosporine 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 “cyclosporine” (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 “cyclosporine” (or a synonym): •
Concurrent administration of water-soluble vitamin E can increase the oral bioavailability of cyclosporine a in healthy dogs. Author(s): Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA. Source: Fischer, J R Harkin, K R Freeman, L C Vet-Ther. 2002 Winter; 3(4): 465-73 15283593
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Disparate effects of chronic and acute theophylline on cyclosporine A nephrotoxicity. Author(s): Laboratoire de Nephrologie-Hemapherese-Transplantation (UPRES EA 563) and Service de Pediatrie 2, Centre Hospitalier Universitaire, 10 Bd Marechal de Lattre de Tassigny, 21034 Dijon Cedex, France.
[email protected] Source: Prevot, A Liet, Jean Michel Semama, Denis S Justrabo, E Guignard, Jean Pierre Gouyon, Jean Bernard Pediatr-Nephrol. 2002 June; 17(6): 418-24 0931-041X
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Effect of cyclosporine a on hepatic compensatory growth: role of calcium status. Author(s): Centre de Recherche, Centre Hospitalier de l'Universite de Montreal, Hopital Saint-Luc, Montreal, Quebec, Canada. Source: Provencher, S J Gascon Barre, M J-Pharmacol-Exp-Ther. 2002 October; 303(1): 5865 0022-3565
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Effects of paclitaxel, cyclophosphamide, ifosfamide, tamoxifen and cyclosporine on the metabolism of methoxymorpholinodoxorubicin in human liver microsomes. Author(s): Service de pharmacologie et Centre regional de pharmacovigilance, CHU de la Cavale Blanche, Bd Tanguy Prigent, 29609 Brest cedex, France. Source: Beulz Riche, Dominique Robert, Jacques Riche, Christian Ratanasavanh, Damrong Cancer-Chemother-Pharmacol. 2002 April; 49(4): 274-80 0344-5704
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Elevated blood drug levels obtained from indwelling silicon catheters during oral cyclosporine A administration. Author(s): Bone Marrow Transplant Unit, University of Kiel, Schwanenweg 20, 24105 Kiel, Germany. Source: Claviez, A Glass, B Dreger, P Suttorp, M Bone-Marrow-Transplant. 2002 Mar; 29(6): 535-6 0268-3369
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Expression of apoptosis-related genes in chronic cyclosporine nephrotoxicity in mice. Author(s): Division of Nephrology, Catholic University of Korea, Seoul, Korea.
[email protected] Source: Yang, C W Faulkner, G R Wahba, I M Christianson, T A Bagby, G C Jin, D C Abboud, H E Andoh, T F Bennett, W M Am-J-Transplant. 2002 May; 2(5): 391-9 16006135
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Melatonin antagonises the cyclosporine A immunosuppressive effects in rat thymuses. Author(s): Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy. Source: Rezzani, R Rodella, L Bianchi, R Int-Immunopharmacol. 2001 August; 1(8): 16159 1567-5769
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Mycophenolic acid and mycophenolic acid glucuronide pharmacokinetics in pediatric liver transplant recipients: effect of cyclosporine and tacrolimus comedication. Author(s): Institute of Liver Studies and School of Medicine, London, United Kingdom.
[email protected]
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Source: Brown, N W Aw, M M Mieli Vergani, G Dhawan, A Tredger, J M Ther-DrugMonit. 2002 October; 24(5): 598-606 0163-4356 •
Nephrotoxicity of cyclosporine A and amphotericin B-deoxycholate as continuous infusion in allogenic stem cell transplantation. Author(s): Department of Medicine, University Hospital of Zurich, Switzerland. Source: Furrer, K Schaffner, A Vavricka, S R Halter, J Imhof, A Schanz, U Swiss-MedWkly. 2002 June 15; 132(23-24): 316-20 1424-7860
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Paclitaxel and cyclosporine A show supra-additive antiproliferative effects on smooth muscle cells by activation of protein kinase C. Author(s): Institute for Arteriosclerosis Research and Department of Cardiology and Angiology, University of Munster, Germany.
[email protected] Source: Sindermann, J R Skaletz Rorowski, A Bartels, A Hohage, H Plenz, G Schmidt, A Breithardt, G Basic-Res-Cardiol. 2002 March; 97(2): 125-31 0300-8428
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Phase II and pharmacologic study of weekly oral paclitaxel plus cyclosporine in patients with advanced non-small-cell lung cancer. Author(s): Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Source: Kruijtzer, C M Schellens, J H Mezger, J Scheulen, M E Keilholz, U Beijnen, J H Rosing, H Mathot, R A Marcus, S van Tinteren, H Baas, P J-Clin-Oncol. 2002 December 1; 20(23): 4508-16 0732-183X
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Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. Author(s): Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, USA.
[email protected] Source: Shihab, F S Bennett, W M Yi, H Andoh, T F Am-J-Transplant. 2002 February; 2(2): 111-9 1600-6135
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Quercetin, a bioflavonoid, protects against oxidative stress-related renal dysfunction by cyclosporine in rats. Author(s): Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Source: Satyanarayana, P S Singh, D Chopra, K Methods-Find-Exp-Clin-Pharmacol. 2001 May; 23(4): 175-81 0379-0355
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Subclinical renal injury induced by transient cyclosporine exposure is associated with salt-sensitive hypertension. Author(s): Solid Organ Transplant Service, Legacy Good Samaritan Hospital, Portland, OR 97232, USA.
[email protected] Source: Andoh, T F Johnson, R J Lam, T Bennett, W M Am-J-Transplant. 2001 September; 1(3): 222-7 1600-6135
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMD®Health: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
The following is a specific Web list relating to cyclosporine; 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: •
Vitamins Ascorbic Acid Source: Integrative Medicine Communications; www.drkoop.com Vitamin C (Ascorbic Acid) Source: Integrative Medicine Communications; www.drkoop.com
Nutrition
Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Alternative names: Alpha-Tocopherol, Beta-Tocopherol, D-Alpha-Tocopherol, Delta-Tocopherol, Gamma-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com •
Minerals Alpha-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Beta-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com D-Alpha-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Delta-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Gamma-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Magnesium Source: Healthnotes, Inc.; www.healthnotes.com Potassium Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: Integrative Medicine Communications; www.drkoop.com
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Food and Diet Omega-3 Fatty Acids Source: Integrative Medicine Communications; www.drkoop.com Omega-6 Fatty Acids Source: Integrative Medicine Communications; www.drkoop.com
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CHAPTER 3. ALTERNATIVE MEDICINE AND CYCLOSPORINE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to cyclosporine. At the conclusion of this chapter, we will provide additional sources.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to cyclosporine and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “cyclosporine” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to cyclosporine: •
A phase I study of carboplatin and etoposide administered in conjunction with dipyridamole, prochlorperazine and cyclosporine A. Author(s): Raschko JW, Synold TW, Chow W, Coluzzi P, Hamasaki V, Leong LA, Margolin KA, Morgan RJ, Shibata SI, Somlo G, Tetef ML, Yen Y, ter Veer A, Doroshow JH. Source: Cancer Chemotherapy and Pharmacology. 2000; 46(5): 403-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11127945
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A randomized study comparing three cyclosporine-based regimens in cadaveric renal transplantation. Italian Multicentre Study Group for Renal Transplantation (SIMTRe). Author(s): Ponticelli C, Tarantino A, Segoloni GP, Cambi V, Rizzo G, Altieri P, Mastrangelo F, Castagneto M, Salvadori M, Valente U, Cossu M, Federico S, Pisani F, Montagnino G, Messina M, Arisi L, Carmellini M, Piredda G, Corbetta G.
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Source: Journal of the American Society of Nephrology : Jasn. 1997 April; 8(4): 638-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10495794 •
A trial of oral magnesium supplementation in renal transplant recipients receiving cyclosporine. Author(s): Nguyen T, Steiner RW. Source: Transplantation Proceedings. 1998 December; 30(8): 4317-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9865371
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Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation. Author(s): Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, Komiya T, Okamura M, Kim S, Iwao H, Miura K. Source: Transplantation. 2003 April 15; 75(7): 1040-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12698095
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Acute toxic myopathy due to pyrazinamide in a patient with renal transplantation and cyclosporine therapy. Author(s): Fernandez-Sola J, Campistol JM, Miro O, Garces N, Soy D, Grau JM. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 1996 September; 11(9): 1850-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8918638
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Arginine modulated cyclosporine-induced immune suppression in rats transplanted with gastric cancer cells. Author(s): Kung SP, Wu CW, Lui WY. Source: In Vivo. 2001 January-February; 15(1): 39-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11286127
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Assessment of systemic toxicity in children receiving chemotherapy with cyclosporine for sarcoma. Author(s): Theis JG, Chan HS, Greenberg ML, Malkin D, Karaskov V, Moncica I, Koren G, Doyle J. Source: Medical and Pediatric Oncology. 2000 April; 34(4): 242-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10742059
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Attenuation of cyclosporine-induced renal dysfunction by catechin: possible antioxidant mechanism. Author(s): Anjaneyulu M, Tirkey N, Chopra K. Source: Renal Failure. 2003 September; 25(5): 691-707. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14575278
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Beneficial effects of a diet rich in a mixture of n - 6/n - 3 essential fatty acids and of their metabolites on cyclosporine - nephrotoxicity. Author(s): Tsipas G, Morphake P. Source: The Journal of Nutritional Biochemistry. 2003 November; 14(11): 626-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14629893
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Beneficial effects of a diet rich in a mixture of n - 6/n - 3 essential fatty acids and of their metabolites on cyclosporine - nephrotoxicity. Author(s): Tsipas G, Morphake P. Source: The Journal of Nutritional Biochemistry. 2003 August; 14(8): 480-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12948879
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Clinical interaction between grapefruit juice and cyclosporine: is there any interest for the hematologists? Author(s): Emilia G, Longo G, Bertesi M, Gandini G, Ferrara L, Valenti C. Source: Blood. 1998 January 1; 91(1): 362-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9414309
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Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. Author(s): Malingre MM, Richel DJ, Beijnen JH, Rosing H, Koopman FJ, Ten Bokkel Huinink WW, Schot ME, Schellens JH. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2001 February 15; 19(4): 1160-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11181682
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Comparison of 'sequential' versus 'standard' chemotherapy as re-induction treatment, with or without cyclosporine, in refractory/relapsed acute myeloid leukaemia (AML): results of the UK Medical Research Council AML-R trial. Author(s): Liu Yin JA, Wheatley K, Rees JK, Burnett AK; UK MRC Adult Leukemia Working Party. Source: British Journal of Haematology. 2001 June; 113(3): 713-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11380463
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Curcumin blocks cyclosporine A-resistant CD28 costimulatory pathway of human Tcell proliferation. Author(s): Ranjan D, Johnston TD, Wu G, Elliott L, Bondada S, Nagabhushan M. Source: The Journal of Surgical Research. 1998 July 1; 77(2): 174-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9733605
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Curcumin enhances the immunosuppressive activity of cyclosporine in rat cardiac allografts and in mixed lymphocyte reactions. Author(s): Chueh SC, Lai MK, Liu IS, Teng FC, Chen J.
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Source: Transplantation Proceedings. 2003 June; 35(4): 1603-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12826232 •
Cyclosporine inhibited calcium-mediated apoptosis of HL-60 cells. Author(s): Huang QQ, Fang M, Zhang HQ, Xue SB. Source: Zhongguo Yao Li Xue Bao. 1997 May; 18(3): 262-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10072947
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Cyclosporine transfer from low- and high-density lipoproteins is partially influenced by lipid transfer protein I triglyceride transfer activity. Author(s): Wasan KM, Subramanian R, Chou JW, Ramaswamy M, Pritchard PH. Source: Pharmaceutical Research. 1999 July; 16(7): 1067-73. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10450932
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Cyclosporine-induced anaphylaxis. Author(s): Kuiper RA, Malingre MM, Beijnen JH, Schellens JH. Source: The Annals of Pharmacotherapy. 2000 July-August; 34(7-8): 858-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10928395
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Cyclosporine-induced autologous graft-versus-host disease in patients with acute myeloid leukemia undergoing non-myeloablative chemotherapy without progenitor cell reinfusion. Author(s): Stein M, Feldman E, Seiter K, Chiao JW, Goff H, Baskind P, Beer M, Ahmed T. Source: Bone Marrow Transplantation. 1999 November; 24(10): 1073-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10578157
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Cyclosporine-insensitive partial signaling and multiple roles of Ca2+ in Fas ligandinduced lysis. Author(s): Rogers AM, Thilenius AR, Russell JH. Source: Journal of Immunology (Baltimore, Md. : 1950). 1997 October 1; 159(7): 3140-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9317111
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Daily variations of amino acid concentration in mediobasal hypothalamus, in rats injected with Freund's adjuvant. Effect of cyclosporine. Author(s): Duvilanski BH, Selgas L, Garcia-Bonacho M, Esquifino AI. Source: Journal of Neuroimmunology. 1998 July 1; 87(1-2): 189-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9670862
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Decrease of erythrocyte deformability in cyclosporine-treated renal transplant patients: correction with fish oil as well as corn oil. Author(s): Schut NH, Hardeman MR, Wilmink JM.
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Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 1992; 5 Suppl 1: S536-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14621869 •
Dietary omega-3 and omega-9 fatty acids uniquely enhance allograft survival in cyclosporine-treated and donor-specific transfusion-treated rats. Author(s): Alexander JW, Valente JF, Greenberg NA, Custer DA, Ogle CK, Gibson SW, Babcock GF. Source: Transplantation. 1998 May 27; 65(10): 1304-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9625010
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Dietary potassium and magnesium supplementation in cyclosporine-induced hypertension and nephrotoxicity. Author(s): Pere AK, Lindgren L, Tuomainen P, Krogerus L, Rauhala P, Laakso J, Karppanen H, Vapaatalo H, Ahonen J, Mervaala EM. Source: Kidney International. 2000 December; 58(6): 2462-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11115079
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Divergent effects of calcium channel and angiotensin converting enzyme blockade on glomerulotubular function in cyclosporine-treated renal allograft recipients. Author(s): Sennesael JJ, Lamote JG, Violet I, Tasse S, Verbeelen DL. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 1996 May; 27(5): 701-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8629631
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Drug interaction between St. John's wort and cyclosporine. Author(s): Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR. Source: The Annals of Pharmacotherapy. 2000 September; 34(9): 1013-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10981246
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Drug interaction of herbal tea containing St. John's wort with cyclosporine. Author(s): Alscher DM, Klotz U. Source: Transplant International : Official Journal of the European Society for Organ Transplantation. 2003 July; 16(7): 543-4. Epub 2003 April 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12677367
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Effect of dietary lipids on hepatic Na+,K(+)-ATPase in cyclosporine A-treated rats: immunocytochemical analysis of alpha1 subunit by confocal laser scanning microscopy imaging. Author(s): Benkoel L, Chanussot F, Dodero F, de la Maisonneuve C, Lambert R, Brisse J, Chamlian A.
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Source: Digestive Diseases and Sciences. 1999 August; 44(8): 1643-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10492147 •
Effect of dietary supplementation with fish oil on cyclosporine A-induced vascular toxicity. Author(s): Berkenboom G, Brekine D, Unger P, Richelle M, Carpentier Y, Fontaine J. Source: Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy. 1996 July; 10(3): 379-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8877082
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Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients. Author(s): Min DI, Ku YM, Perry PJ, Ukah FO, Ashton K, Martin MF, Hunsicker LG. Source: Transplantation. 1996 July 15; 62(1): 123-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8693526
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Effect of grapefruit juice on serum concentration of cyclosporine in Iranian renal transplant patients. Author(s): Mehrsai AR, Pourmand G, Mansour D, Zand S, Rezaali A. Source: Transplantation Proceedings. 2003 November; 35(7): 2739-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14612100
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Effect of high-dose cyclosporine on etoposide pharmacodynamics in a trial to reverse P-glycoprotein (MDR1 gene) mediated drug resistance. Author(s): Lum BL, Kaubisch S, Fisher GA, Brown BW, Sikic BI. Source: Cancer Chemotherapy and Pharmacology. 2000; 45(4): 305-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10755319
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Effect of iron and ascorbate on cyclosporine-induced oxidative damage of kidney mitochondria and microsomes. Author(s): Lee SH, Yoon YC, Jang YY, Song JH, Han ES, Lee CS. Source: Pharmacological Research : the Official Journal of the Italian Pharmacological Society. 2001 February; 43(2): 161-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11243718
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Effect of n-3 polyunsaturated fatty acids on cyclosporine pharmacokinetics in kidney graft recipients: a randomized placebo-controlled study. Author(s): Busnach G, Stragliotto E, Minetti E, Perego A, Brando B, Broggi ML, Civati G. Source: Journal of Nephrology. 1998 March-April; 11(2): 87-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9589380
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Effectiveness and safety of azithromycin on the treatment of cyclosporine-induced gingival overgrowth. Author(s): Palomar R, Belart M, Soy D, Oppenheimer F, Campistol JM. Source: Nephron. 1998; 79(1): 101-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9609470
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Effects of curcumin on cyclosporine-induced cholestasis and hypercholesterolemia and on cyclosporine metabolism in the rat. Author(s): Deters M, Klabunde T, Meyer H, Resch K, Kaever V. Source: Planta Medica. 2003 April; 69(4): 337-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12709901
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Effects of OKY-046 and nifedipine in cyclosporine-induced renal dysfunction in rats. Author(s): Papanikolaou N, Darlametsos I, Tsipas G, Morphake P, Bokas S, Gkikas G, Hornych A, Bariety J, Gkika EL, Karageorgou I, Patsialos K. Source: Prostaglandins, Leukotrienes, and Essential Fatty Acids. 1996 October; 55(4): 249-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8951993
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Effects of paclitaxel, cyclophosphamide, ifosfamide, tamoxifen and cyclosporine on the metabolism of methoxymorpholinodoxorubicin in human liver microsomes. Author(s): Beulz-Riche D, Robert J, Riche C, Ratanasavanh D. Source: Cancer Chemotherapy and Pharmacology. 2002 April; 49(4): 274-80. Epub 2002 January 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11914905
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Enhanced oral bioavailability of docetaxel by coadministration of cyclosporine: quantitation and role of P-glycoprotein. Author(s): Chiou WL, Wu TC, Ma C, Jeong HY. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2002 April 1; 20(7): 1951-2; Author Reply 1952. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11919259
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Evaluation of renal function in low-dose cyclosporine-treated patients using technetium-99m diaminocyclohexane: a cationic tubular excretion agent. Author(s): Sonmezoglu K, Erdil TY, Demir M, Sayman HB, Kabasakal L, Yardi OF, Ozkara H, Cem Mat M, Solanki K, Britton KE. Source: European Journal of Nuclear Medicine. 1998 December; 25(12): 1630-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9871094
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Hyperbaric oxygen and cyclosporine as a combined treatment regimen to prevent skin allograft rejection in immunohistoincompatible mice. Author(s): Erdmann D, Roth AC, Hussmann J, Lyons SF, Mody NJ, Brown RE, Kucan JO.
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Source: Annals of Plastic Surgery. 1996 March; 36(3): 304-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8659956 •
Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii. I. Prolongation of rat cardiac and renal allograft survival by the PG27 extract and immunosuppressive synergy in combination therapy with cyclosporine. Author(s): Wang J, Xu R, Jin R, Chen Z, Fidler JM. Source: Transplantation. 2000 August 15; 70(3): 447-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10949186
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Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii. II. Prolongation of hamster-to-rat cardiac xenograft survival by combination therapy with the PG27 extract and cyclosporine. Author(s): Wang J, Xu R, Jin R, Chen Z, Fidler JM. Source: Transplantation. 2000 August 15; 70(3): 456-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10949187
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In vitro effects of docosahexaenoic and eicosapentaenoic acids in association with cyclosporine A on human lymphocyte proliferation. Author(s): Khalfoun B, Gruel Y, Bardos P, Lebranchu Y. Source: Transplantation Proceedings. 1997 February-March; 29(1-2): 1286-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9123309
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In vitro induction of apoptosis for nasal angiocentric natural killer cell lymphomaderived cell line, NK-YS, by etoposide and cyclosporine A. Author(s): Uno M, Tsuchiyama J, Moriwaki A, Noguchi T, Mizoguchi K, Ogino T, Yoshino T, Okada S, Harada M. Source: British Journal of Haematology. 2001 June; 113(4): 1009-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11442496
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Increased incidence of acute graft-versus-host disease with the continuous infusion of cyclosporine A compared to twice-daily infusion. Author(s): Ogawa N, Kanda Y, Matsubara M, Asano Y, Nakagawa M, SakataYanagimoto M, Kandabashi K, Izutsu K, Imai Y, Hangaishi A, Kurokawa M, Tsujino S, Ogawa S, Aoki K, Chiba S, Motokura T, Hirai H. Source: Bone Marrow Transplantation. 2004 March; 33(5): 549-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14716350
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Inhibition of ex vivo-expanded cytotoxic T-lymphocyte function by high-dose cyclosporine. Author(s): Zhan X, Brown B, Slobod KS, Hurwitz JL.
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Source: Transplantation. 2003 August 27; 76(4): 739-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12973121 •
Inhibitory effect of tea polyphenols on renal cell apoptosis in rat test subjects suffering from cyclosporine-induced chronic nephrotoxicity. Author(s): Shi S, Zheng S, Zhu Y, Jia C, Xie H. Source: Chinese Medical Journal. 2003 September; 116(9): 1345-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14527363
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Interaction between cyclosporine and grapefruit juice requires long-term ingestion in stable renal transplant recipients. Author(s): Brunner LJ, Munar MY, Vallian J, Wolfson M, Stennett DJ, Meyer MM, Bennett WM. Source: Pharmacotherapy. 1998 January-February; 18(1): 23-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9469677
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Interaction between cyclosporine and Hypericum perforatum (St. John's wort) after organ transplantation. Author(s): Moschella C, Jaber BL. Source: American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 2001 November; 38(5): 1105-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11684566
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Kidney function and morphology after short-term combination therapy with cyclosporine A, tacrolimus and sirolimus in the rat. Author(s): Nielsen FT, Ottosen P, Starklint H, Dieperink H. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2003 March; 18(3): 491-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12584269
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Kidney function in cyclosporine-treated pediatric heart transplant recipients. Author(s): Laine J, Jalanko H, Leijala M, Sairanen H, Holmberg C. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1997 December; 16(12): 1217-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9436133
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Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Author(s): Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, Okamura M, Kim S, Iwao H, Miura K.
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Source: Transplantation. 2002 September 27; 74(6): 784-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12364856 •
Microdialysis assessment of microfibrous collagen containing a P-glycoproteinmediated transport inhibitor, cyclosporine A, for local delivery of etoposide. Author(s): Sato H, Kitazawa H, Adachi I, Horikoshi I. Source: Pharmaceutical Research. 1996 October; 13(10): 1565-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8899852
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Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia. Author(s): Dahl GV, Lacayo NJ, Brophy N, Dunussi-Joannopoulos K, Weinstein HJ, Chang M, Sikic BI, Arceci RJ. Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2000 May; 18(9): 1867-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10784627
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Mitoxantrone, etoposide, and cytarabine plus cyclosporine for patients with relapsed or refractory acute myeloid leukemia: an Eastern Cooperative Oncology Group pilot study. Author(s): Tallman MS, Lee S, Sikic BI, Paietta E, Wiernik PH, Bennett JM, Rowe JM. Source: Cancer. 1999 January 15; 85(2): 358-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10023703
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Modulation effects of cyclosporine on etoposide pharmacokinetics and CNS distribution in the rat utilizing microdialysis. Author(s): Burgio DE, Gosland MP, McNamara PJ. Source: Biochemical Pharmacology. 1996 April 12; 51(7): 987-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8651950
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Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen: a cancer and leukemia group B study. Author(s): Samuels BL, Hollis DR, Rosner GL, Trump DL, Shapiro CL, Vogelzang NJ, Schilsky RL. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 1997 November; 3(11): 1977-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9815587
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Non-immunosuppressive cyclosporine derivative PSC 833 abolishes resistance of human multidrug-resistant ovarian carcinoma cells in vitro to paclitaxel and paclitaxel-induced radiosensitization. Author(s): Chorvath B, Sedlak J, Novotny L, Hunakova L, Boljesikova E, Sevcikova L, Chorvath M.
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Source: International Journal of Cancer. Journal International Du Cancer. 1997 September 4; 72(5): 916-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9311614 •
Nutritional immunomodulation leads to enhanced allograft survival in combination with cyclosporine A and rapamycin, but not FK506. Author(s): Gibson SW, Valente JF, Alexander JW, Custer DA, Li BG, Frede S, Babcock GF, Ogle CK. Source: Transplantation. 2000 May 27; 69(10): 2034-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10852592
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Oral supplementation of L-arginine prevents chronic cyclosporine nephrotoxicity in rats. Author(s): Yang CW, Kim YS, Kim J, Kim YO, Min SY, Choi EJ, Bang BK. Source: Experimental Nephrology. 1998 January-February; 6(1): 50-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9523173
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Paclitaxel and cyclosporine A show supra-additive antiproliferative effects on smooth muscle cells by activation of protein kinase C. Author(s): Sindermann JR, Skaletz-Rorowski A, Bartels A, Hohage H, Plenz G, Schmidt A, Breithardt G. Source: Basic Research in Cardiology. 2002 March; 97(2): 125-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12002259
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Peppermint oil enhances cyclosporine oral bioavailability in rats: comparison with Dalpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS) and ketoconazole. Author(s): Wacher VJ, Wong S, Wong HT. Source: Journal of Pharmaceutical Sciences. 2002 January; 91(1): 77-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11782899
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Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia. Author(s): Lacayo NJ, Lum BL, Becton DL, Weinstein H, Ravindranath Y, Chang MN, Bomgaars L, Lauer SJ, Sikic BI, Dahl GV. Source: Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2002 May; 16(5): 920-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11986955
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Phase II and pharmacologic study of weekly oral paclitaxel plus cyclosporine in patients with advanced non-small-cell lung cancer. Author(s): Kruijtzer CM, Schellens JH, Mezger J, Scheulen ME, Keilholz U, Beijnen JH, Rosing H, Mathot RA, Marcus S, van Tinteren H, Baas P.
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Source: Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2002 December 1; 20(23): 4508-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12454106 •
Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity. Author(s): Andoh TF, Gardner MP, Bennett WM. Source: Transplantation. 1997 November 15; 64(9): 1236-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9371662
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Quercetin, a bioflavonoid, protects against oxidative stress-related renal dysfunction by cyclosporine in rats. Author(s): Satyanarayana PS, Singh D, Chopra K. Source: Methods Find Exp Clin Pharmacol. 2001 May; 23(4): 175-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11676225
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Red wine decreases cyclosporine bioavailability. Author(s): Tsunoda SM, Harris RZ, Christians U, Velez RL, Freeman RB, Benet LZ, Warshaw A. Source: Clinical Pharmacology and Therapeutics. 2001 November; 70(5): 462-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11719733
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Resistance of human multidrug-resistant neoplastic cell lines to paclitaxel-inducedradiosensitization is reduced by the non-immunosuppressive cyclosporine analog SDZ PSC 833. Author(s): Sedlak J, Hunakova L, Chorvath M, Sulikova M, Novotny L, Boljesikova E, Zeillinger R, Chorvath B. Source: Anticancer Res. 1998 July-August; 18(4C): 3099-105. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9713517
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Role of prostanoids and endothelins in the prevention of cyclosporine-induced nephrotoxicity. Author(s): Darlametsos IE, Varonos DD. Source: Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2001 April-May; 64(45): 231-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11418017
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SDZ PSC 833, the cyclosporine A analogue and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitive and drug-resistant cancer cells. Author(s): Cabot MC, Giuliano AE, Han TY, Liu YY.
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Source: Cancer Research. 1999 February 15; 59(4): 880-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10029079 •
Significant decrease of cyclosporine bioavailability in rats caused by a decoction of the roots of Scutellaria baicalensis. Author(s): Lai MY, Hsiu SL, Hou YC, Tsai SY, Chao PD. Source: Planta Medica. 2004 February; 70(2): 132-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14994190
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Successful use of cyclosporine A in the treatment of refractory thrombotic thrombocytopenic purpura. Author(s): Hand JP, Lawlor ER, Yong CK, Davis JH. Source: British Journal of Haematology. 1998 March; 100(3): 597-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9504648
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The effect of cyclosporine concentration on the labeling efficiency of an in vitro technetium-99m red blood cell labeling procedure. Author(s): Spicer JA, Hladik WB 3rd. Source: Journal of Nuclear Medicine Technology. 1997 March; 25(1): 70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9239609
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The effect of diphenyl-dimethyl-dicarboxylate on cyclosporine-A blood level in kidney transplants with chronic hepatitis. Author(s): Kim YS, Kim DH, Kim DO, Lee BK, Kim KW, Park JN, Lee JC, Choi YS, Rim H. Source: Korean J Intern Med. 1997 January; 12(1): 67-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9159041
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The effect of nutritional immunomodulation on cardiac allograft survival in rats receiving mycophenolate mofetil, cyclosporine A, and donor-specific transfusion. Author(s): Gibson SW, Valente JF, Alexander JW, Custer DA, Babcock GF, Ogle CK. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 1999 March; 18(3): 185-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10328142
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The effect of silibinin on experimental cyclosporine nephrotoxicity. Author(s): Zima T, Kamenikova L, Janebova M, Buchar E, Crkovska J, Tesar V. Source: Renal Failure. 1998 May; 20(3): 471-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9606735
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Treatment of psoriasis by cyclosporine and grapefruit juice. Author(s): Taniguchi S, Kobayashi H, Ishii M.
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Source: Archives of Dermatology. 1996 October; 132(10): 1249. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8859044 •
Treatment with high-dose folic acid effectively lowers plasma homocysteine concentration in cyclosporine-treated renal transplant recipients. Author(s): Arnadottir M, Hultberg B. Source: Transplantation. 1997 October 15; 64(7): 1087. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9381536
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Trough concentrations of cyclosporine in blood following administration with grapefruit juice. Author(s): Ducharme MP, Provenzano R, Dehoorne-Smith M, Edwards DJ. Source: British Journal of Clinical Pharmacology. 1993 November; 36(5): 457-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12959294
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Use of vincristine and cyclosporine in childhood thrombotic thrombocytopenic purpura. Author(s): Jayabose S, Levendoglu-Tugal O, Ozkayanak MF, Chao CP, Cuccovia B, Sandoval C. Source: Journal of Pediatric Hematology/Oncology : Official Journal of the American Society of Pediatric Hematology/Oncology. 2003 May; 25(5): 421-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759633
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com®: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMD®Health: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to cyclosporine; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Depression Source: Integrative Medicine Communications; www.drkoop.com Depression (Mild to Moderate) Source: Prima Communications, Inc.www.personalhealthzone.com Hirsuitism Source: Integrative Medicine Communications; www.drkoop.com Inflammatory Bowel Disease Source: Integrative Medicine Communications; www.drkoop.com Psoriasis Source: Healthnotes, Inc.; www.healthnotes.com Rheumatoid Arthritis Source: Healthnotes, Inc.; www.healthnotes.com Systemic Lupus Erythematosus Source: Healthnotes, Inc.; www.healthnotes.com Ulcerative Colitis Source: Healthnotes, Inc.; www.healthnotes.com Ulcerative Colitis Source: Integrative Medicine Communications; www.drkoop.com
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Herbs and Supplements Cyclosporine Source: Healthnotes, Inc.; www.healthnotes.com Cyclosporine Alternative names: Neoral, Sandimmune Source: Prima Communications, Inc.www.personalhealthzone.com DHA Source: Integrative Medicine Communications; www.drkoop.com
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Docosahexaenoic Acid (DHA) Source: Integrative Medicine Communications; www.drkoop.com Eicosapentaenoic Acid (EPA) Source: Integrative Medicine Communications; www.drkoop.com EPA Source: Integrative Medicine Communications; www.drkoop.com Evening Primrose Alternative names: Oenothera biennis, Sun Drop Source: Integrative Medicine Communications; www.drkoop.com Gamma-Linolenic Acid (GLA) Source: Integrative Medicine Communications; www.drkoop.com Ginkgo Biloba Source: Healthnotes, Inc.; www.healthnotes.com Ginkgo Biloba Source: Integrative Medicine Communications; www.drkoop.com GLA Source: Integrative Medicine Communications; www.drkoop.com Hypericum Perforatum Source: Integrative Medicine Communications; www.drkoop.com Klamathweed Source: Integrative Medicine Communications; www.drkoop.com Maidenhair Tree Alternative names: Ginkgo Biloba Source: Integrative Medicine Communications; www.drkoop.com Milk Thistle Alternative names: Silybum marianum Source: Integrative Medicine Communications; www.drkoop.com Oenothera Biennis Source: Integrative Medicine Communications; www.drkoop.com Silybum Marianum Source: Integrative Medicine Communications; www.drkoop.com St. John's Wort Alternative names: Hypericum perforatum, Klamathweed Source: Integrative Medicine Communications; www.drkoop.com St. John's Wort Source: Prima Communications, Inc.www.personalhealthzone.com
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St. Mary's Thistle Source: Integrative Medicine Communications; www.drkoop.com Sun Drop Source: Integrative Medicine Communications; www.drkoop.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON CYCLOSPORINE Overview In this chapter, we will give you a bibliography on recent dissertations relating to cyclosporine. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “cyclosporine” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cyclosporine, we have not necessarily excluded nonmedical dissertations in this bibliography.
Dissertations on Cyclosporine ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to cyclosporine. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
Studies on cyclosporine analogs, asymmetric synthesis of alpha-hydrazinocarboxylic acids and biosynthetic studies using stable isotope NMR techniques by Trimble, Laird Alexander; PhD from UNIVERSITY OF ALBERTA (CANADA), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL32527
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Supercritical carbon dioxide extraction of cyclosporine from the fungus Beauvaria nivea by Te Bokkel, Derk Willem; PhD from THE UNIVERSITY OF WESTERN ONTARIO (CANADA), 1990 http://wwwlib.umi.com/dissertations/fullcit/NL55265
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The effect of cyclosporine and other immunosuppressive agents on systemic MHC expression in the mouse by Autenried, Peter; PhD from UNIVERSITY OF TORONTO (CANADA), 1988 http://wwwlib.umi.com/dissertations/fullcit/NL46309
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Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. PATENTS ON CYCLOSPORINE Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “cyclosporine” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on cyclosporine, we have not necessarily excluded nonmedical patents in this bibliography.
Patents on Cyclosporine By performing a patent search focusing on cyclosporine, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 8Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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example of the type of information that you can expect to obtain from a patent search on cyclosporine: •
Antibodies to specific regions of cyclosporine related compounds Inventor(s): Malcolm; Andrew J. (Alberta, CA), Naicker; S. Selvaraj (Alberta, CA), Yatscoff; Randall W. (Alberta, CA) Assignee(s): Isotechnika, Inc. (Edmonton, CA) Patent Number: 6,686,454 Date filed: September 3, 1999 Abstract: This invention relates to the production of polyclonal and monoclonal antibodies to specific regions of cyclosporine (CSA) and/or CSA metabolites/derivatives. The reactivity of these polyclonal and monoclonal antibodies make them particularly useful for immunoassays for therapeutic drug monitoring (TDM). These immunoassays or TDM kits may include polyclonal or monoclonal antibodies to specific sites of CSA and/or CSA metabolites. These kits may also include various combinations of polyclonal antibodies, polyclonal and monoclonal antibodies or a panel of monoclonal antibodies. Cyclosporine or CSA metabolite conjugate immunogens are prepared for the immunization of a host animal to produce antibodies directed against specific regions of the CSA or CSA metabolite molecule. By determining the specific binding region of a particular antibody, immunoassays which are capable of distinguishing between the parent molecule, active metabolites, inactive metabolites and other structurally similar immunosuppressant compounds are developed. The use of divinyl sulfone (DVS) as the linker arm molecule for forming cyclosporine and cyclosporine metabolite protein conjugate immunogens is described. Excerpt(s): This invention relates to the production of polyclonal and monoclonal antibodies to specific sites of cyclosporine and/or cyclosporine metabolites, derivatives and analogues. The reactivity of these polyclonal and monoclonal antibodies makes them particularly useful for immunoassays for therapeutic drug monitoring (TDM). These immunoassays or TDM kits may include polyclonal or monoclonal antibodies to specific sites of cyclosporine (CSA) and/or metabolites, derivatives and analogues of cyclosporine. These kits may also include various combinations of polyclonal antibodies, polyclonal and monoclonal antibodies or a panel of monoclonal antibodies. Currently, the two immunosuppressive drugs administered most often to prevent organ rejection in transplant patients are cyclosporine (CSA) and tacrolimus (FK-506 or FK). Rapamycin (Rapa) is another known immunnosuppressant. Cyclosporine's primary target appears to be the helper T lymphocytes. Cyclosporine acts early in the process of T cell activation, it has secondary effects on other cell types that are normally activated by factors produced by the T cells. Cyclosporine inhibits the production of interleukin 2 (IL-2) by helper T cells, thereby blocking T cell activation and proliferation (amplification of immune response). It is effective both in the prevention and in the treatment of ongoing acute rejection. The current model for the mechanism of action of CSA suggests that, in the T cell cytoplasm, CSA binds to a specific binding protein called immunophilin. The CSA-immunophilin complex in turn binds to and blocks a phosphatase called calcineurin. The latter is required for the translocation of an activation factor (NF-ATc) from the cytosol to the nucleus, where it would normally bind to and activate enhancers/promoters of certain genes. In the presence of CSA, the cytosolic activation factor is unable to reach the nucleus, and the transcription of IL-2 (and other early activation factors) is strongly inhibited. As a result of this inhibition, T
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cells do not proliferate, secretion of gamma-interferon is inhibited, no MHC class II antigens are induced, and no further activation of the macrophages occurs. Various side effects are associated with cyclosporine therapy, including nephrotoxicity, hypertension, hyperkalemia, hypomagnesemia and hyperuricemia. Neuro- or nephrotoxicity has been correlated with certain cyclosporine metabolites. A necessary requirement of cyclosporine drug monitoring assays is to measure the levels of parent cyclosporine drug and metabolite with immunosuppressive and toxic activity. There is a need for improved methods of monitoring levels of CSA and/or CSA metabolites and derivatives. Web site: http://www.delphion.com/details?pn=US06686454__ •
Camptothecin drug combinations and methods with reduced side effects Inventor(s): Gupta; Elora (Chicago, IL), Ratain; Mark J. (Chicago, IL) Assignee(s): Arch Development Corporation (Chicago, IL) Patent Number: 5,786,344 Date filed: April 17, 1995 Abstract: This invention provides methods and combination formulations and kits to reduce the toxicity of camptothecin drugs, such as irinotecan (CPT-11). Disclosed are therapeutics and treatment methods employing such drugs in combination with agents that increase conjugative enzyme activity or glucuronosyltransferase activity, and agents that decrease biliary transport protein activity, such as cyclosporine A, the resultant effects of which are to decrease the significant side effects previously associated with treatment using these drugs. Excerpt(s): The present invention relates generally to the fields of reducing drug toxicity and enhancing drug efficacy. More particularly, it concerns new treatment methods, compositions and kits comprising camptothecin drugs, such as irinotecan (CPT-11) and topotecan, in combination with agents that reduce excretion of active camptothecin species through the bile. Agents that increase conjugative enzyme activity, such as glucuronosyltransferase activity, and agents that decrease p-glycoprotein activity, such as cyclosporine A, are particularly provided. Camptothecin was identified as the active component of the crude extract from the stem wood of Camptotheca acuminata that showed promising in vitro anti-neoplastic activities by inhibiting topoisomerase 1 (Wall et al., 1966). Camptothecin entered clinical trials in the early 1970s, but these were suspended (Muggia et al., 1972; Gottlieb et al., 1970). The drug exhibited marginal to partial responses to gastrointestinal malignancies and melanoma but resulted in severe dose-limiting hemorrhagic cystitis and unpredictable myelosuppression. In these trials, the sodium salt of the alkaloid was used which improved its water solubility but which also resulted in about 10 fold reduction of antitumor activity and an enhancement of toxicity (Wani et al., 1980; Giovanella et al., 1991). The reduced activity was due to the fact that camptothecins require a closed lactone ring structure for optimal activity. Formulation as the sodium salt resulted in opening of the ring to a hydroxy acid form that exhibited poor topoisomerase 1 inhibition. Efforts have thus been directed towards synthesis of water-soluble derivatives of camptothecin that would have high antitumor activity and low toxicity. Topotecan was synthesized by the introduction of a basic side chain at the 9-position of the 10-hydroxycamptothecin ring. This enabled topotecan to retain its water solubility in the lactone form (Kingsbury et al., 1991). CPT-11 was synthesized by the introduction of an ethyl group at the 7-position of camptothecin and a hydroxyl group at the 10-position which formed an ester linkage with a
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piperidinopiperidino carbonyl group (Kunimoto et al., 1987). The ester linkage enhanced the polarity of the compound. Web site: http://www.delphion.com/details?pn=US05786344__ •
Cyclosporine assay Inventor(s): Fischer; Gunter (Halle, DD), Kullertz; Namen G. (Brandenburg, DD) Assignee(s): Arzneimittelwerk Dresden GmbH (Radebeul, DE) Patent Number: 5,480,779 Date filed: January 12, 1993 Abstract: A process for determining the concentration of cyclosporine in a sample, which comprises adding to the sample a predetermined amount of an isomerase which isomerizes N-terminal peptide to proline, then measuring the enzyme-catalyzed inhibition of the isomerization of a proline-containing substrate, and determining the concentration or cyclosporine from a calibration curve. Excerpt(s): The present invention relates to a process for determining the concentration of cyclosporine and its biologically active derivatives. Determination of cyclosporine concentration in the body is important for supervision of therapy in patients treated with drugs which contain the therapeutically significant stripstance group of cyclosporines. Cyclosporine is it cyclic polypeptide immunosuppressant agent consisting of eleven amino acids. It is usually produced as metabolite by the fungus species Tolypocladium inflatum Gams. Chemically cyclosporine is [R-{R*, R*-(E)}]cyclic-(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-m ethyl-L-valyl-3hydroxy-N-,4-dimethyl-L-2-amino-6-octenoyl-L-.alpha.-amino- butyryl-N-methylglycylN-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl). Cyclosporine generally prolongs survival of allogencic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestines, and lungs. It generally also suppresses some humoral immunity and to a greater extent cell-medicated reaction such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis and graft vs. host disease in many animal species for a variety of organs. Web site: http://www.delphion.com/details?pn=US05480779__
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Cyclosporine derivatives and uses thereof Inventor(s): Wang; Chengrong (Hockessin, DE) Assignee(s): Dade Behring Inc. (Deerfield, IL) Patent Number: 5,990,274 Date filed: November 25, 1997 Abstract: The present invention provides novel cyclosporine C (CsC) derivatives having improved protein conjugatibility and hydrolytic stability. The present invention further provides a CsC derivative conjugated to a carrier, e.g., a solid support. Preferably, the solid support is a latex or magnetic particle. Excerpt(s): 1. Field of the Invention. The present invention relates to novel cyclosporine derivatives that have improved protein and solid surface conjugatibility and hydrolytic stability. The cyclosporine derivatives of the present invention are useful in assays
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measurement of cyclosporin A levels, as well as in the production of cyclosporine immunogens and capture conjugates. Cyclosporine A (cyclosporine) is a potent immuno-suppressant that has been widely used in the United States and other countries to prevent the rejection of transplanted organs such as kidney, heart, bone marrow and liver, in humans. Web site: http://www.delphion.com/details?pn=US05990274__ •
Derivatives of cyclosporina A, antibodies directed thereto and uses thereof Inventor(s): Cacalano; Nicholas A. (Irvington, NY), Cleveland; William L. (New York, NY), Erlanger; Bernard F. (Whitestone, NY) Assignee(s): The Trustees of Columbia University in the City of New York (NY) Patent Number: 5,350,574 Date filed: May 13, 1991 Abstract: This invention provides a molecule comprising cyclosporine A or a congener of cyclosporine A which is photochemically attached to a ligand containing a reactive group. This invention also provides a composition of matter which comprises a conjugate of a compound and the aforementioned molecule wherein the compound is bound to the molecule through the reactive group. This invention further provides an antibody directed to the aforementioned composition of matter specific for cyclosporine A or congener of cyclosporine A. This invention also provides methods for detecting the presence of cyclosporine A or congener thereof, methods for detecting the concentration of cyclosporine A or congener thereof, as well as a method of monitoring levels of cyclosporine A or congener of cyclosporine A in a subject. Finally, this invention provides a method of reducing the amount of endogenous immunoregulatory substances, a method of testing the potential of a pharmalogical agent as an immunoactive agent, as well as a method of testing a pharmalogical agent for immunosuppressive activity. Excerpt(s): Throughout this application, various publications are referenced by arabic numerals within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed in this application. Cyclosporine A (CsA) is a cyclic undecapeptide of fun-gal origin which is a immunosuppressive agent useful in preventing organ rejection in transplant patients (1-3). CsA is now widely used in human recipients of kidney, liver, heart, combined heart-lung and bone marrow transplants, and most recently in the treatment of such autoimmune diseases uveitis and Type I diabetes (26,27). Web site: http://www.delphion.com/details?pn=US05350574__
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Drug screening and treatment for HIV thymocyte depletion Inventor(s): Bonyhadi; Mark L. (Belmont, CA), Kaneshima; Hideto (Palo Alto, CA), McCune; Joseph M. (San Francisco, CA), Namikawa; Reiko (Palo Alto, CA), Su; Lishan (Palo Alto, CA) Assignee(s): Systemix, Inc. (Palo Alto, CA) Patent Number: 5,612,018 Date filed: January 18, 1994 Abstract: A method is provided for screening compounds for the ability to supress thymocyte depletion in thymuses of HIV-infected individuals, particularly enhancing the CD4.sup.+ -expressing population as compared to an untreated individual. Particularly, drugs are provided which allow for this result, cyclosporine A being exemplary. Excerpt(s): The field of this invention is the screening of drugs and treatment for HIV. The Acquired Immunodeficiency Syndrome (AIDS) is a serious and expanding pandemic. While extraordinary efforts have been made to find ways to protect humans from its etiologic agent, the human immunodeficiency virus (HIV), to date there has been little other than palliative treatments available. For the most part, drugs have been directed to slowing the intractable course of the disease and to treating various of the opportunistic infections which often accompany it. It is recognized that a major consequence of infection with HIV is the substantial loss of "helper" T-cells, which are identified by the CD4 marker. In the normal ratio, helper T-cells are a substantially larger population than "suppressor/cytotoxic" T-cells, which are CD8+. During the course of the disease this ratio is reversed and ultimately there are substantially no helper T-cells in the external circulation. As a result, fullblown AIDS occurs as an inevitably fatal disease. Web site: http://www.delphion.com/details?pn=US05612018__
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Enhancement of transplant graft survival through nutritional immunomodulation with omega-9 fatty acid dietary supplement therapy Inventor(s): Alexander; J. Wesley (Cincinnati, OH), Greenberg; Norman A. (New Hope, MN), Ogle; Cora K. (Cincinnati, OH), Valente; John F. (Cincinnati, OH) Assignee(s): Novartis Nutrition AG (Berne, CH), University of Cincinnati (Cincinnati, OH) Patent Number: 6,210,700 Date filed: June 30, 1998 Abstract: An improved immunomodulatory therapy for enhancement of depressed host defense mechanisms and improving allograft survival rates comprising the use of omega-9 unsaturated fatty acids to alter the immune response associated with organ transplantation. It is administered optionally in conjunction with an immunomodulatory diet comprising arginine and its salts, or metabolic precursors of arginine, together with an immuno-suppressive treatment comprising the administration of cyclosporine or other immuno-suppressants and optionally, with or without a donor specific transfusion. An especially preferred source of the omega-9 unsaturated fatty acids is canola oil.
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Excerpt(s): The present invention relates generally to therapeutic regimens for immunologically impaired individuals recovering from surgery, infection, burns and other trauma. More specifically, the invention relates to an immunomodulatory diet and immunosuppressive therapy for the enhancement of host defense mechanisms and prolongation of allograft survival. The physiological trauma that besets the human body as a result of surgery, cancer, intensive burns, radiation therapy and the like has a deleterious effect on the health of the individual in more ways than one. It is well known that patients recovering from such trauma and who are being therapeutically treated often have compromised host defense mechanisms. A damaged or reduced immune system can often lead to increased morbidity and eventual death as a result of infection and/or organ failure through rejection. In a related case U.S. Pat. No 5,231,085 also to Alexander, the present applicants discovered novel immuno- modulatory compositions and methods which enhance host defense mechanisms which have been compromised and are deficient for one reason or another. The immunomodulatory compositions are composed of an amino acid such as arginine or ornithine that are used in the biosynthetic pathways of other polyamines, a nucleobase source and a combination of omega-3- and omega4-polyunsaturated fatty acids. The composition is administered enterally or modified for parenteral administration and is preferably used as a supplement to a complete nutritional diet meeting the complete daily caloric and vitamin requirements of the patient. The administration of these compositions restore damaged or compromised immune systems to their healthy state. The Alexander patent 5,231,085 is hereby incorporated by reference. Web site: http://www.delphion.com/details?pn=US06210700__ •
FK-506 cytosolic binding protein, FKBP12.6 Inventor(s): Sewell; Tonya J. (Edison, NJ), Wiederrecht; Gregory J. (Westfield, NJ) Assignee(s): Merck & Co., Inc. (Rahway, NJ) Patent Number: 5,457,182 Date filed: February 15, 1994 Abstract: A new homogeneous cytosolic binding protein (FKBP12.6), having a specific binding activity of about 4.8 mg FK-506 per mg protein and a molecular weight of about 10-12 kilodaltons, reversibly binds the immunosuppressant FK-506, but not cyclosporine A (CSA). The protein is unstable to heating at 56.degree. C. for 30 minutes losing its FK-506 binding affinity. The FKBP12.6 protein is isolated from the cytosol of mammalian tissues, preferably bovine or human brain tissue, and can be used in diagnostic and purification procedures involving FK-506-type macrolide immunosuppressants. The FKBP12.6 protein also has peptidyl-proline isomerase enzymatic activity, catalyzing the cis-trans isomerization of proline-containing peptide bonds. In addition, FKBP12.6 binds to and inhibits the phosphatase calcineurin in the presence of FK-506. Excerpt(s): The present invention relates to a new homogeneous cytosolic binding protein (entitled "FKBP12.6") which binds FK-506 but not cyclosporine A, is unstable to heating at 56.degree. C. for 30 minutes, and has a molecular weight of about 10-12 kilodaltons. The FKBP12.6 protein has peptidyl-proline isomerase enzymatic activity. Moreover, FKBP12.6 binds to and inhibits the phosphatase calcineurin in the presence of FK-506. Immunoregulatory abnormalities have been shown to exist in a wide variety of "autoimmune" and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type 1 diabetes mellitus, type 2 adult onset
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diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, and Graves ophthalmopathy. Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and self-reactive lymphocytes. Such selfreactivity may be due, in pan, to a loss of the homeostatic controls under which the normal immune system operates. Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft rejection. Web site: http://www.delphion.com/details?pn=US05457182__ •
Hydrophilic binary systems for the administration of lipophilic compounds Inventor(s): Abdullah; Bashar Y. (Veron Hill, IL), Al-Razzak; Laman A. (Highland Park, IL), Constantinides; Panayiotis Pericleous (Gurnee, IL), Kaul; Dilip (Gurnee, IL), Lipari; John M. (Racine, WI), McChesney-Harris; Lisa L. (Veron Hill, IL) Assignee(s): Abbott Laboratories (Abbott Park, IL) Patent Number: 6,008,192 Date filed: March 12, 1998 Abstract: Binary pharmaceutical compositions comprising (i) a cyclosporine compound, (ii) a hydrophilic phase and (iii) a surfactant provide bioavailability of the active ingredient which is equivalent to that provided by ternary compositions, but without the need for a lipophilic phase. Excerpt(s): The present invention relates to pharmaceutical compositions containing lipophilic medicinal compounds, suitable for oral as well as topical, local and other routes of administration. In particular, the invention relates to binary formulations of cyclosporines which comprise a hydrophilic phase and one or more surfactants, but which lack a lipophilic phase. Pharmaceutical compounds which are highly lipophilic present considerable formulation challenges. Because of their low solubility in aqueous media, including the contents of the mammalian digestive tract, they often suffer from poor or variable bioavailability when given orally or via other routes that require transmembrane absorption. Examples of such medicinal compounds include the immunosuppressants cyclosporine and FK506 (tacrolimus); protease inhibitors such as ritonavir; central nervous system drugs such as tiagabine; and anti-inflammatory agents such as zileuton and other 5-lipoxygenase inhibitors. One method of formulating lipophilic compounds is to combine them with glyceride carriers which form emulsions upon mixing with water. Emulsions are described, for example, in U.S. Pat. No. 4,388,307 issued to Cavanak, a commercial example of which is the cyclosporinecontaining product SANDIMMUNE.RTM. oral solution. This product comprises the emulsifier LABRAFIL.RTM. (a polyoxyethylated kernel oil), olive oil and alcohol, with the compound cyclosporin A present at a concentration of 100 mg/ml. Cavanak suggests that such glyceride carriers may assist in alleviating problems of physical instability such as precipitation of the drug from solution, and may also enable higher plasma concentrations. Web site: http://www.delphion.com/details?pn=US06008192__
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Immunoassay reagents and method for determining cyclosporine Inventor(s): Lunetta; Steven E. (Waukegan, IL), Meucci; Victoria P. (Chicago, IL), Morrison; Marjorie A. (Grayslake, IL), Simpson; Elizabeth A. (Skokie, IL), Zajac; Mariola B. (Chicago, IL) Assignee(s): Abbott Laboratories (Abbott Park, IL) Patent Number: 5,489,668 Date filed: November 4, 1993 Abstract: Cyclosporine derivatives useful as detectable tracer compounds for the immunoassay determination of cyclosporine are disclosed. The cyclosporine derivatives comprise a detectable moiety coupled to the amino acid at the first position (MeBmt) in cyclosporine, the second position (Abu) in cyclosporine, the third position (Sar) in cyclosporine, the eighth position (D-Ala) in cyclosporine, or the tenth position (MeLeu) in cyclosporine. A preferred cyclosporine derivative comprises a fluorescent moiety coupled to the hydroxyl group of the amino acid at the first position in cyclosporine, and is especially useful for the fluorescent polarization immunoassay deterimination of cyclosporine. A fluorescent polarization immunoassay method and test kit are also disclosed. Excerpt(s): The present invention relates to reagents for determining the presence or amount of cyclosporine in a test sample. In particular, the present invention relates to detectable tracer compounds for use in immunoassays, especially fluorescent polarization immunoassays, for detecting the presence or amount of cyclosporine and metabolites of cyclosporine in a test sample. Cyclosporine levels in whole blood, plasma and serum have been measured by high performance liquid chromatogaphy (HPLC) [Lensmeyer, et al., Clinical Chemistry, Vol. 31(2), pages 196-201 (1985)], radioimmunoassay (RIA) utilizing.sup.3 H [Donatsch et al., Journal of Immunoassay, Vol. 2(1), pages 19-32 (1981)] or.sup.125 I [U.S. Pat. No. 4,727,035and Mahoney, et al., Clinical Chemistry, Vol. 31(3), pages 459-462 (1985)], fluorescent immunoassays (U.S. Pat. No. 4,727,035), and by fluorescence polarization immunoassay (FPIA) [Marty, et al., Analytical Letters, Vol. 22(13 & 14), pages 2717-2736 (1989) and European Patent Application Publication No. 283,801]. While the metabolites of cyclosporine can be distinguished from cyclosporine itself according to such HPLC methods, HPLC is nevertheless time and labor intensive, requiring extensive sample preparation and at least thirty minutes to perform the assay. Similarly, RIA assays suffer from the disadvantages of using radioactive materials which require special storage, handling and disposal, and typically require a minimum of two hours to perform. While fluorescent polarization immunoassays are superior to the methods described above, particularly in ease of use, commercially available polyclonal antibody immunoassays display a lack of specificity for cyclosporine over its metabolites. In this regard, the specificity of immunoassays is dependent upon the antibody used, and the relative affinities of the antibody for cyclosporine, metabolites of cyclosporine, and the labeled form of cyclosporine. Recently, monoclonal antibodies specific for cyclosporine over its metabolites have been described [Quesniaux, et al., Immunology Letters, Vol. 12(1), pages 120-126 (1985), Clinical Chemistry, Vol. 33(1), pages 32-37 (1987), and Molecular Immunology, Vol. 24(11), pages 1159-1168 (1987)], and RIA assays using these antibodies have been found to correlate well with HPLC. Web site: http://www.delphion.com/details?pn=US05489668__
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Immunosuppressive drug binding proteins and use Inventor(s): Soldin; Steven J. (6335 31st St., NW., Washington, DC 20015) Assignee(s): none reported Patent Number: 5,698,448 Date filed: April 8, 1994 Abstract: Purified immunosuppressive drug binding proteins (immunophilins) of molecular mass 2.4-3.0 kDa, 4.5 kDa, 34-37 kDa, 50-54 kDa, 80-100 kDa, and greater than about 120 kDa are described. The 34-37 kDa immunophilin specifically binds FK-506 and rapamycin. The 50-54 kDa immunophilin specifically binds FK-506, rapamycin and cyclosporine A, but with binding site distinctions. The 50-54 kDa immunophilin is devoid of significant rotomase activity, but inhibits cAMP-activated protein kinase activity. The amino acid composition, and the sequences of a dodecameric amino acid Cterminus partial sequence and of two heptameric internal partial amino acid sequences, of the 50-54 kDa immunophilin are described; the deduced molecular weight is 52,171. Recombinant about 52 kDa immunophilin is also described. These novel immunophilins can be used as reagents for the detection, quantification and capture of immunosuppressive drugs and their biologically active metabolites, derivatives and analogues in fluid samples, and for the capture of potential immunosuppressive drugs from microbial extracts or culture media or from mammalian body fluids and tissues. Excerpt(s): This invention relates to drug binding proteins and their use in methods for the quantitation of such drugs in biological fluids. More particularly, this invention relates to purified cytosolic, non-immunoglobulin binding proteins ("immunophilins") for macrocyclic and cyclicpeptide immunosuppressive drugs and their use in the quantitation of such drugs and their biologically active metabolites, analoguss and derivatives in fluid samples by means of protein binding assays. All of the metabolites characterized to date have retained the cyclic aspect of the molecule, and, as with the parent CsA, the metabolites are extensively bound to target tissues. Ryffel et al., Transplant. Proc., 20:575 (1988). The immunosuppressive cyclosporines and their metabolites are known to interfere with T-lymphocyte helper and effector cell proliferation, and CsA, selectively inhibits lymphokine production by stimulated T cells. Nonetheless, the mechanism of action of cyclosporines remains unclear. See, generally, Drugge et al., Transplant. Proc., 20:301 (1988), a review. Web site: http://www.delphion.com/details?pn=US05698448__
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Method for evaluating immunosuppressive regimens Inventor(s): Murray; John J. (Brentwood, TN), Stein; Charles M. (Nashville, TN), Wood; Alastair J. J. (Brentwood, TN) Assignee(s): Vanderbilt University (Nashville, TN) Patent Number: 6,329,153 Date filed: June 22, 1999 Abstract: The present invention describes a simple technique that provides a biologically relevant measure of the inhibitory effect of cyclosporine in vivo. This ability to measure response to cyclosporine may improve prediction of the efficacy of immunosuppressive treatment in patients and may allow optimal immunosuppression in individual patients.
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Excerpt(s): The present invention relates generally to immunosuppression and the use of cyclosporin. More specifically, the present invention relates to a method of evaluating an immunosuppressive regimen on a patient-by-patient basis. The addition of cyclosporine (CSA) to the immunosuppressive regimens following organ transplantation has resulted in a marked improvement in graft survival (1,2). Cyclosporine, which remains an important component of most anti-rejection immunosuppressive regimens is, however, a problematic drug to use. The optimal clinical use of cyclosporine aims to both maximize efficacy, thus maintaining graft survival and to minimize drug-related toxicity. Optimal clinical use has remained controversial, not only because of a poorly defined relationship between the dose of cyclosporine administered and the concentration of cyclosporine achieved, but also because both cyclosporine dose and concentration are poor predictors of clinical efficacy and toxicity (3-6). Thus, as detailed in recent reviews (4-6), numerous studies have examined the relationship between clinical efficacy and various pharmacokinetic parameters of cyclosporine disposition, such as trough concentrations, area-under-the-concentration-time curve (AUC), average cyclosporine concentrations and clearance. Some studies have shown a relationship between each of these pharmacokinetic measures and efficacy, but the correlation between any measure of cyclosporine disposition and efficacy is poor. This is reflected by a wide range of clinical practice, as demonstrated in the most recent consensus guidelines on the monitoring of cyclosporine concentrations after organ transplantation, where a wide range of cyclosporine trough concentrations was designated as "therapeutic" by different institutions (7). Web site: http://www.delphion.com/details?pn=US06329153__ •
Method of inhibiting side effects of solvents containing ricinoleic acid or castor oil or derivatives thereof employing a thromboxane A.sub.2 receptor antagonist and pharmaceutical compositions containing such solvents Inventor(s): Lodge; Nicholas J. (Hamilton Square, NJ) Assignee(s): Bristol-Myers Squibb Company (Princeton, NJ) Patent Number: 5,462,726 Date filed: December 17, 1993 Abstract: A method is provided for inhibiting or preventing toxicity and other unwanted effects (a) caused by solvents for pharmaceuticals which solvents contain castor oil or ricinoleic acid or derivatives thereof, such as Cremophor, or (b) caused by a drug, such as cyclosporine A, dissolved or suspended in solvents such as ricinoleic acid or castor oil or derivative thereof, employing a thromboxane A.sub.2 receptor antagonist. Solvent compositions containing ricinoleic acid or castor oil or derivatives thereof and a thromboxane A.sub.2 receptor antagonist, and pharmaceutical compositions including a drug, solvent containing ricinoleic acid or castor oil or derivative thereof, and a thromboxane A.sub.2 receptor antagonist are also provided. Excerpt(s): The present invention relates to a method for inhibiting or preventing toxicity and other unwanted side effects caused by pharmaceutical solvents containing ricinoleic acid or castor oil or a derivative thereof, such as Cremophor EL, and by pharmaceuticals dissolved or suspended in such solvents, employing a thromboxane A.sub.2 receptor antagonist, and to solvent compositions containing a thromboxane A.sub.2 receptor antagonist, and to pharmaceutical compositions including a drug, solvents containing ricinoleic acid or castor oil or a derivative thereof and a thromboxane A.sub.2 receptor antagonist. Ricinoleic acid, castor oil or derivatives
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thereof have been employed as effective solvents or carriers for pharmaceuticals. Unfortunately such solvents have been found to have untoward side effects. For example, ricinoleic acid and castor oil and solvents containing these substances, such as Cremophor, cause vasoconstriction. It has been found that Cremophor (a derivative of castor oil and ethylene oxide) evokes a concentration-dependent increase in force development in vascular tissues, such as the jugular vein and aorta. Cremophor EL is known for its use with an extensive array of pharmaceuticals including taxol (Rowinsky et al "Taxol: The First of the Taxanes, an Important New Class of Antitumor Agents, Seminars in Oncology, Vol. 19, No. 6 (December) 1992, 646-662), miconazole (Handbook on Injectable Drugs), echinomycin (Handbook on Injectable Drugs), teniposide (Rowinsky et al supra), vitamin K (Rowinsky et al supra), didemnin B (Rowinsky et al supra), diazepam (Lau et al, "Absorption of diazepam and lorazepam following intranasal administration", Int. J. Pharm. 54:171-174 (Sep. 1) 1989), althesin (Dye et al, Br. Med. J. 280:1353 (Jun. 7) 1980). Web site: http://www.delphion.com/details?pn=US05462726__ •
Method of treating ocular diseases by periocular administration of cyclosporine A or G Inventor(s): Nussenblatt; Robert B. (Bethesda, MD), Palestine; Alan G. (Potomac, MD) Assignee(s): The Government of the United States of America as represented by the (Washington, DC) Patent Number: 5,294,604 Date filed: December 20, 1989 Abstract: The present invention provides a method of treating ocular diseases by the administration of cyclosporine A or G by periocular injection in a pharmaceutically acceptable carrier. Excerpt(s): The present invention relates to a method for treating ocular disease and, more specifically, to a method for treating ocular disease by administration of cyclosporine A or G to a patient through a periocular injection pharmaceutically acceptable carrier to a patient. Cyclosporines A and G belong to a class of structurally distinct, cyclic, poly-N-methylated undecapeptides having valuable pharmacological, in particular immunosuppressive, anti-inflammatory and anti-protozoal activity. The first to be isolated and the "parent" compound of this class is the naturally occurring fungal metabolite "cyclosporine," also known as cyclosporine A, the production and properties of which are described for example in U.S. Pat. No. 4,117,118. Note that use of the term "cyclosporin(e)" alone is generally recognized in the art to refer only to cyclosporine A unless otherwise stated. Since the original discovery of cyclosporine A, a wide variety of a naturally occurring cyclosporines have been isolated and identified and many further non-natural cyclosporines have been prepared by synthetic or semisynthetic means or by the application of modified cultured techniques. The class comprised by the cyclosporines is thus now substantial and includes, for example, the naturally occurring cyclosporines A, C, D and G, as well as various semisynthetic derivatives thereof, such as their dihydroderivatives, as disclosed, e.g., in U.S. Pat. Nos. 4,108,985; 4,210,581 and 4,220,641, and other natural and artificial cyclosporines such as those disclosed in European Patent Publication No. 0058,134 B1. Cyclosporine A has been used in the treatment of ocular disease mediated by immune processes. Lately, cyclosporine A has been used locally in the form of ophthalmic drops for the treatment of disorders involving the anterior portion of the eye and conjunctiva with good results as reported
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at Holland et al, ("Immunohistologic Findings and Results of Treatment With Cyclosporine in Ligneous Conjunctivitis," Amer. J. of Ophthalmology, 107:160-166, Feb. 1989). Cyclosporin A has also been used in an ophthalmic treatment by topical administration thereof to the eye (U.S. Pat. No. 4,649,047 to Kaswan), as well as for increasing tear production by topical administration thereof (U.S. Pat. No. 4,839,342 to Kaswan). Web site: http://www.delphion.com/details?pn=US05294604__ •
Methods for inducing site-specific immunosuppression and compositions of site specific immunosuppressants Inventor(s): Black; Kirby S. (13401 Sussex Pl., Santa Ana, CA 92705), Hewitt; Charles W. (698 Tranquility Turn, Marlton, NJ 08053) Assignee(s): Black; Kirby S. (Acworth, GA), Hewitt; Charles W. (Marlton, NJ) Patent Number: 5,540,931 Date filed: June 24, 1994 Abstract: The present invention provides methods and formulations for site-specific immune suppression of immune/inflammatory responses with localized or topical application of immunosuppressants including cyclosporines, rapamycins (RPM), or combinations of immunosuppressants and anti-inflammatory compounds. Methods for the use of said formulations to effect site-specific immune suppression of local inflammatory/immune responses in mammalian tissue and for treatment of autoimmune, T-cell mediated immune disease, inflammatory conditions, inhibition of contact hypersensitivity, and for producing prolonged skin allograft survival, and wound healing are presented. In addition, methods for use of said formulations--in tandem with systemic applications of immunosuppressant such as cyclosporine or without same--are presented. The present invention also relates to alternative formulations and delivery systems for the efficacious treatment of the aforementioned conditions. Excerpt(s): Cyclosporine (CsA), a selective immunosuppressant and a potent antiinflammatory agent, has demonstrated great clinical success in inhibiting T-cell mediated immune processes such as allograft rejection, graft-versus-host disease, and autoimmune disease when administered systemically. (See, e.g., A. D. Hess al., Transpl. Proc. 20: 29 (1988).) As to the latter, systemic CsA has been proven efficacious for treating psoriasis, an autoimmune disorder of the skin. (See, e.g., C. N. Ellis, et al., JAMA 256: 3110 (1986).). However, the induction of immunosuppression at the tissue site and focal responding immunocytes could result in surprisingly greater efficacy, and could have significant immunologic and clinical ramifications. As an example of the aforementioned ramifications, within the specialty of dermatology, it would be desirable to treat putative autoimmune conditions and related diseases of the skin, including, for example, eczema, contact hypersensitivity, alopecia areata and psoriasis. Few if any models for testing the disease mechanism and the efficacy of various treatment modalities have been available in this field, however. Moreover, due to the variability of expression of most skin conditions, and the inherent differences between epidermal tissues in various locations on the body, a single treatment methodology or pharmaceutical composition is rarely effective for all disease conditions presented. A basic understanding of the immune response involved will facilitate the understanding and appreciation of the present invention. T-cell mediated immune events play an important role in eliciting allograft rejection and other inflammatory reactions. The
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immunological cascade that follows alloengraftment includes: (1) recognition of antigen; (2) lymphocyte activation; (3) development of specific cellular and molecular lines of communication between responding immunocytes via lymphokine release and induced expression of major histocompatibility complex ("MHC") antigens; and (4) mononuclear inflammatory cell infiltration into the target tissue which leads to eventual graft destruction (rejection). Systemic administration of CsA, a novel fungal metabolite, is well known to block this inflammatory cascade and to facilitate permanent allograft acceptance (actively-acquired immunological tolerance) in various experimental animal models, probably by inhibitory effects upon T-helper cells with sparing of T-suppressor cell expression. (See, e.g., A. D. Hess, et al., Transpl. Proc. 29 (1988).) Cyclosporines and other similar immunosuppressants such as rapamycins, FK-506 derivatives and immunophilin binding agent have novel immunosuppressive properties compared to conventional agents: they are selective in their mechanism of action, demonstrate superior graft survival times, and are potent anti-inflammatory compounds. Cyclosporines are well-recognized for their powerful ability to permanently alter immune responsiveness, in comparison with conventional agents, so that some degree of selective immunologic tolerance (graft acceptance) can be achieved in various models. Therefore, it would be extremely advantageous and desirable to develop topical formulations of cyclosporines, rapamycins and other immunosuppressants for localized tissue site-specific action. Web site: http://www.delphion.com/details?pn=US05540931__ •
Minimally invasive bioactivated endoprosthesis for vessel repair Inventor(s): Dayton; Michael P. (14802 Hadleigh Way, Tampa, FL 33624) Assignee(s): none reported Patent Number: 5,449,382 Date filed: March 2, 1994 Abstract: A minimally invasive bioactivated endoprosthesis device for vessel repair. The device comprises a stent which is formed from metal or polymers into a predetermined shape which includes a plurality of holes patterned with a desired size, shape and number to provide a desired bending modulus. The stent is then coated with a polymer or is formed from a polymer which contains a bioactive substance which achieves an equilibrium with the surrounding body tissues or fluids, with the equilibrium being controlled by charge distribution, concentration and molecular weight of the bioactive substance in relation to the pore size of the polymeric carrier for controlled prolonged release of said bioactive substance. The bioactive substance may be selected from the group of heparin, hirudin, prostacyclenes and analogs thereof, antithrombogenic agents, steroids, ibuprofen, antimicrobials, antibiotics, tissue plasma activators, rifamicin, monoclonal antibodies, snake venom protein by-products, antifibrosis agents, cyclosporine and mixtures of these bioactive substances for simultaneous multiple treatments. The stent itself may take several distinct configurations, all of which have a predetermined biasing force acting on the diameter of the stent. Preferred is a rolled stent which is provided with a coiled shape to which it tends to return when expanded. Locking tabs are provided to engage the some of the plurality of holes at the maximum expanded size to prevent return to the smaller diameter coiled shape. Alternatively the predetermined bias of the stent may be the expanded size so that the stent is coiled against this bias during insertion.
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Excerpt(s): The present invention relates to an improved percutaneously inserted endoprosthesis device which is permanently or temporarily implanted within a body vessel, typically a blood vessel. More particularly, the present invention relates to a new procedure for administering localized bioactive substances via prostheses designs which are adapted to resist problems associated with restenosis, thrombosis, infection calcification and/or fibrosis after implantation. In certain medical treatment procedures, a type of endoprosthesis device known as a stent is placed or implanted within a blood vessel for treating various problems such as stenonses, strictures, or aneurysms in the blood vessel. These devices are implanted within the vascular system to reinforce collapsing, partially occluded, weakened or abnormally dilated sections of the blood vessel. Stents may also be implanted in the ureter, urethra, bile duct, or any body vessel which has been narrowed, weakened or in any of the other ways which requires reinforcement. A common approach for implanting stents in peripheral or coronary arteries is to first open the constricted region of the vessel via a percutaneous transluminally inserted angioplasty balloon catheter. The uninflated balloon at the tip of the catheter is advanced into the narrowed portion of the vessel lumen. The balloon is inflated so as to push the stenotic plaque outward, thereby enlarging the luminal diameter. Thereafter another catheter containing the stent is advanced to the region just enlarged by the balloon catheter and the stent is deployed. The catheter is withdrawn leaving the stent within the vessel. Web site: http://www.delphion.com/details?pn=US05449382__ •
Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions Inventor(s): Bosch; H. William (Bryn Mawr, PA), Hovey; Douglas C. (Collegeville, PA), Ostrander; Kevin D. (Reading, PA) Assignee(s): Elan Pharma International Ltd. (Shannon, IE) Patent Number: 6,656,504 Date filed: September 9, 1999 Abstract: Nanoparticulate amorphous cyclosporine formulations, and nanoparticulate cyclosporine formulations comprising a mixture of amorphous and crystalline cyclosporine, having effective average particle sizes of less than about 2000 nm are described. The compositions exhibit increased bioavailability and increased consistency of bioavailability as compared to prior macro-sized cyclosporine and formulations. Methods of making and using the compositions are also described. Excerpt(s): The present invention is directed to nanoparticulate compositions comprising amorphous cyclosporine, or a mixture of amorphous and crystalline cyclosporine, and methods of making and using such compositions. Cyclosporine is a hydrophobic, cyclic, undecapeptide that exerts immunosuppressive, antiinflammatory, antifungal, and antiparasitic activities. Immunosuppressive medications play a large part of the management of many pediatric illnesses. Cyclosporine is the primary tool used to prevent rejection following solid organ and bone marrow transplantation; the drug helped revolutionize transplantation by improving transplant survival, reducing hospitalization, and reducing patient morbidity. It has been estimated that cyclosporine is given to more than 90% of children who have received a kidney transplant in the United States. Cyclosporine also has been effective in various other autoimmune conditions such as uveitis, psoriasis, type I diabetes mellitus, rheumatoid arthritis, inflammatory bowel disease, certain nephropathies, refractory Crohn's disease,
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ulcerative colitis, biliary cirrhosis, aplastic anemia, rheumatoid arthritis, myasthenia gravis, and dermatomyositis. Cyclosporine is in clinical use worldwide under the trade names SANDIMMUNE.RTM. (Novartis), NEORAL.RTM. (Novartis), and SANGCYA.RTM. (SangStat). SANDIMMUNE.RTM., introduced in 1983, suffered from poor and widely variable absorption rates. This prompted development of a second generation cyclosporine formulation, NEORAL.RTM., which is a microemulsion formulation having better absorption than SANDIMUNE.RTM.-both in quantity and consistency. Since 1995, when NEORAL.RTM. was introduced, about 70% of patients have switched from SANDIMMUNE.RTM. to NEORAL.RTM., indicating the severity of poor and inconsistent absorption of cyclosporine. SANGCYA.RTM., which is a modified oral solution bioequivalent to NEORAL.RTM., was introduced in 1998. Web site: http://www.delphion.com/details?pn=US06656504__ •
Nephro protective infusion solutions Inventor(s): Bertermann; Hagen (Flensburger Strasse 83, D-2300 Kiel, DE) Assignee(s): none reported Patent Number: 5,290,538 Date filed: April 21, 1992 Abstract: The invention herein is a method of protecting against renal damage in a patient receiving carboplatin, cyclosporine A or cisplatin comprising administering to said patient the following mixture of amino acids consisting of glycine, L-alanine, Lserine, L-threonine, L-valine, L-leucine, L-isoleucine and L-proline. Excerpt(s): This invention relates to nephroprotective infusion solutions. More particularly, it relates to the use of a mixture of L-amino acids in solutions to protect patients from nephrotoxic cytostatic and immunosuppressive agents. Toxic renal damage constitutes a substantial side effect of cytostatic treatment of malignant tumors, while also excluding approximately one-third of patients from treatment. If renal elimination of cytostatic or immunosuppressive agents is delayed, further toxic damages may arise in other organs, particularly in the bore marrow, as a secondary result of nephrotoxicity. Efforts to reduce toxicity by increasing diuresis and/or urine flow do not prevent the occurrence of serious renal function impairment resulting from the administration of cytostatic or immunosuppressive agents. Thus, a reduction in kidney function often remains clinically undiscovered, as serum creatinine levels do not rise until more severe loss of renal function is reached. It is a well-known procedure to treat renally insufficient patients from a nutritive standpoint with amino acid mixtures containing mainly essential L-amino acids. The mixtures of L-amino acids developed for this purpose, one of which is presented in DE 34 14 491 Al, however, may also have a detrimental effect on the kidneys. In individual cases they may induce acute renal failure or potentiate a preexisting acute renal failure. Web site: http://www.delphion.com/details?pn=US05290538__
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Ocular cyclosporine composition Inventor(s): Kaswan; Renee (Athens, GA) Assignee(s): University of Georgia Research Foundation, Inc. (Atlanta, GA) Patent Number: 5,411,952 Date filed: February 6, 1990 Abstract: Cyclosporine compositions for topical ophthalmic use for treatment of immune disorders, to enhance or restore tear production, and to enhance or effect normal healing of the surface of the eye, containing cyclosporine dissolved in corn oil. The composition may further include antioxidants, lubricants, antibiotics, antifungals, antivirals, pilocarpine, vasoconstrictors, surfactants, wetting agents, anti-inflammatory agents (i.e. corticosteroids), preservatives, mucolytic agents (i.e. bromhexine, acetylcysteine), as well as other compounds.The preferred composition is 2% cyclosporine, 1 mole % alpha tocopherol and 0.005% methyl paraben in corn oil. Excerpt(s): Cyclosporine is a metabolite isolated from the culture broths of the fungal species Tolypocladium inflatum Gams. A neutral, hydrophobic cyclic peptide composed of eleven amino acid residues, cyclosporine includes a previously unknown Nmethylated amino acid composed of nine carbon atoms. A number of additional cyclosporines (B, C, D, E, and G) have been reported since the first cyclosporine was isolated (CsA). As described in U.S. Pat. No. 4,117,118 issued Sep. 26, 1978 to Harriet al, cyclosporine is readily soluble in most of the usual organic solvents and practically insoluble in petroleum ether and water. As distributed by Sandoz Ltd, Basel, Switzerland, under the tradename Sandimmune, cyclosporine for oral administration is dissolved in olive oil for further dilution with food and in polyoxyethylated castor oil and ethanol for intravenous injection. Cyclosporine is a potent immunosuppressive agent used to prolong survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine and lung. The exact mechanism of action is not known but experimental evidence suggests that the effectiveness of cyclosporine is due to specific and reversible inhibition of immunocompetent cells, primarily T-helper cells. Lymphokine production, gamma interferon production and release of interleukin-2 or T-cell growth factor are also inhibited by cyclosporine. Cyclosporine is primarily administered orally or by injection. Unfortunately, parenteral administration of the drug has been associated with renal toxicity, hepatotoxicity, and increased incidence of opportunistic infection. The quantity of drug required for systemic administration is also prohibitively expensive. Web site: http://www.delphion.com/details?pn=US05411952__
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Pharmaceutical composition for cyclosporines Inventor(s): Bhalani; Vinayak T. (Livingston, NJ), Patel; Satishchandra P. (Livingston, NJ) Assignee(s): Sidmak Laboratories, Inc. (East Hanover, NJ) Patent Number: 5,858,401 Date filed: January 22, 1997 Abstract: The invention comprises a stable solution of cyclosporine forming a polar lipid self-emulsifying drug delivery system ("PLSEDDS"). The composition typically consists of cyclosporine dissolved in a polar lipid, such as a medium chain
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monoglyceride of C.sub.6 -C.sub.12 fatty acids having a monoglyceride content of at least 50% and a surfactant. The composition provided here instantly forms a fine emulsion on exposure to water. The encapsulated dosage form of this composition needs neither a hydrophilic component nor air-tight blister packaging, and is particularly suitable for oral administration. Excerpt(s): This application claims the benefit of U.S. Provisional application Ser. No. 60/010,410, filed Jan. 22, 1996, the disclosure of which is incorporated by reference in its entirety. Cyclosporines form a class of polypeptides commonly possessing immunosuppressive and anti-inflammatory activity. The most commonly known cyclosporine is cyclosporine-A. It is commercially available as Sandimmune.RTM. in a soft gelatin capsule dosage form. Other forms of cyclosporines include cyclosporine-B, C, -D, and their derivatives. It should be understood that in this specification the terms "cyclosporine" or "cyclosporines" refer to any of the several cyclosporines or to any mixture of the several cyclosporines. Cyclosporine is a hydrophobic material exhibiting poor bioavailability. The liquid oral formulations containing oils, ethanol and a transesterification product of a triglyceride and a polyol as a surfactant (U.S. Pat. No. 4,388,307) have a variety of difficulties, such as unpleasant taste, which is unacceptable for long-term therapy. The use of the soft gelatin capsule dosage to mask the taste of the solution entails specialized packaging of the encapsulated product in an air tight blister or aluminum foil blister package. This renders the product more bulky and more expensive. The storage conditions are far from ideal. Web site: http://www.delphion.com/details?pn=US05858401__ •
Pharmaceutical compositions containing cyclosporine and a carrier comprising at least an ester of.alpha.-glycerophosphoric acid Inventor(s): Salini; Alberto (Lugano, CH) Assignee(s): Flarer S.A. (Lugano, CH) Patent Number: 6,194,401 Date filed: November 18, 1998 Abstract: A description is given of new pharmaceutical compositions containing cyclosporine, combined with a carrier comprising at least a derivative of.alpha.glycerophosphoric acid, such as.alpha.-glycerophosphorylcholine,.alpha.glycerophosphorylserine,.alpha.-glycerophosphorylethanolamine and.alpha.glycerophosphoryl-myo-inositol, which allow cyclosporine bioavailability to significantly increase. Excerpt(s): The following description sets forth new pharmaceutical compositions containing cyclosporine as active ingredient, combined with a carrier comprising an ester of.alpha.-glycerophosphoric acid, esterified on the phosphoric group with a choline, serine, ethanolamine or inositol hydroxyl group, which allow cyclosporine bioavailability to be significantly increased. The claimed compositions are useful for the curative and symptomatic treatment of human and animal diseases wherefor cyclosporine is efficacious, e.g. inflammatory--especially chronic--states, rejection of transplanted organs or bone marrow, autoimmune diseases, tumours immunotherapy, parasitosis. Cyclosporines are compounds having a peptide-cyclic chemical structure. Among cyclosporines, cyclosporin A is not only therapeutically important, but also commercially significant due to its high cost. Web site: http://www.delphion.com/details?pn=US06194401__
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Pharmaceutical cyclosporin formulation with improved biopharmaceutical properties, improved physical quality and greater stability, and method for producing said formulation Inventor(s): Muller; Rainer Helmut (Berlin, DE), Penkler; Lawrence John (Port Elizabeth, ZA), Ravelli; Vittorino (Milan, IT), Runge; Stephan Anton (Eckernfoerde, DE) Assignee(s): Pharmatec International S.R.L. (Milane, IT) Patent Number: 6,551,619 Date filed: January 22, 2001 Abstract: The invention relates to solid, particulate lipid-based excipients which are loaded with cyclosporine. Said excipients have improved biopharmaceutical properties for cyclosporines in vivo, are of a better quality (in terms of fineness, homogeneity of the particles, inclusion of the medicament) and are more physically stable in the particulate formulation (no aggregation or gel formation). The invention also relates to a therapeutic treatment with cyclosporine formulations which produce an average blood level concentration in the steady state range of 300 ng/ml to over 1000 ng/ml, preferably over 800 ng/ml, especially up to 900 ng/ml, preferably 400 ng/ml to 800 ng/ml in the absence of high initial blood level concentrations essentially over 1500 ng/ml, especially over 1200 ng/ml. This blood level concentration is preferably maintained for an extended period of at least 5 hours, preferably at least 7 hours. Excerpt(s): The invention relates to particulate systems loaded with cyclosporin (also spelled "cyclosporine") or cyclosporin derivatives of natural and/or synthetic origin, which said systems have improved biopharmaceutical properties for cyclosporins in vivo, improved quality (fineness and homogeneity of the particles, drug inclusion) and improved physical stability of the particulate formulation (no aggregation or gel formation). Cyclosporins are cyclic oligopeptides. They are a group of natural oligopeptides ranging from cyclosporin A to cyclosporin Z. Synthetic derivatives have also been described (SDZ IMM 125, the hydroxyethyl derivative of D-serine-8cyclosporin). Cyclosporin A is a lipophilic molecule consisting of 11 aminoacids. It is obtained by fermenting mushrooms. Its molecular weight is 1203. Web site: http://www.delphion.com/details?pn=US06551619__
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Pharmaceutical preparation containing cyclosporine(s) for intravenous administration and a process for its production Inventor(s): Dietl; Hans (Eichendorffstrasse 33, Bad Aibling, DE) Assignee(s): none reported Patent Number: 5,527,537 Date filed: May 12, 1993 Abstract: A pharmaceutical preparation is disclosed which contains one or several cyclosporine(s), one or several natural oils, 3-sn-phosphatidyl choline and/or phosphatidyl ethanol amine and water. Excerpt(s): The invention relates to a new pharmaceutical preparation containing cyclosporine(s), a production process for this pharmaceutical preparation and its use for intravenous administration. Cyclosporines are cyclic oligopeptides from lower fungi, which were discovered by scientists of Sandoz AG, Basel. Particularly, cyclosporine A or cyclosporine B are used as immunosuppressants, in particular in organ
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transplantations. Moreover, the cyclosporine derivative "SDZ IMM 125", a hydroxy ethyl derivative of D-serine-8-cyclosporine, is preferred. The application for other diseases, e.g. diabetes and psoriasis and numerous autoimmune diseases (e.g. rheumatoid arthritis, endogenous uveitis, etc.) has also been described. The most known cyclosporine is cyclosporine A (formula: C.sub.62 H.sub.111 N.sub.11 O.sub.12). Web site: http://www.delphion.com/details?pn=US05527537__ •
Screening methods for the identification of anti-HIV compounds employing a cyclosporine-specific monoclonal antibody that cross-reacts with HIV-1 p24 Inventor(s): Chen; Bi-Xing (New York, NY), Erlanger; Bernard F. (Whitestone, NY) Assignee(s): The Trustees of Columbia University in the City of New York (New York, NY) Patent Number: 6,177,253 Date filed: January 8, 1998 Abstract: The subject invention provides new uses for novel derivatives of cyclosporine A and antibodies directed thereto. Specifically, the derivatives and antibodies are useful in methods of treating AIDS, methods of purifying the Gag protein of HIV, methods of screening for anti-HIV compounds, and methods for detecting HIV in a subject. The derivatives and antibodies can also be incorporated into a kit useful for screening for anti-HIV compounds. Excerpt(s): Throughout this application, various publications are referenced by arabic numerals within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed in this application. Cyclosporine A (CsA) is a cyclic undecapeptide of fun-gal origin which is a immunosuppressive agent useful in preventing organ rejection in transplant patients (1-3). Because the therapeutic index of CsA is narrow, it is important to measure serum cyclosporine levels in patients treated with CsA (4). This can be accomplished by high performance liquid chromatography or by RIA, with the latter procedure being the more convenient one. Web site: http://www.delphion.com/details?pn=US06177253__
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Synergistic administration of cyclosporine and fructose diphosphate Inventor(s): Markov; Angel K. (5973 Hanging Moss Rd., Jackson, MS 39206) Assignee(s): none reported Patent Number: 5,747,461 Date filed: July 26, 1994 Abstract: This invention discloses a method of using fructose-1,6-diphosphate (FDP) to help suppress the rejection of internal organs such as kidneys, hearts, etc. At least three major advantages of FDP in conjunction with organ transplants have been identified: (1) FDP can help reduce the unwanted proliferation of certain types of stimulated lymphocytes which would otherwise pose a risk of attacking the non-self cells in the transplanted organ; (2) FDP can also potentiate the effectiveness of cyclosporine as a
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transplant-protecting immunosuppressant, thereby allowing a reduction in CSA dosages, which in turn can reduce the likelihood and the severity of toxic side effects and other dangers of CSA treatment; (3) FDP can also reduce the amount of damage inflicted on an organ during the removal and storage steps required in organ transplantation. Excerpt(s): This invention relates to the use of fructose-1,6-diphosphate, a naturallyoccurring mammalian metabolite, in the preservation and transplantation of internal organs such as hearts and kidneys. In subsequent steps which use FDP as a substrate and consume it in the process, an FDP molecule (which has 6 carbon atoms) is broken into two smaller molecules with three carbons each (glyceraldehyde and dihydroxyacetone), in a reaction catalyzed by an aldolase enzyme. These reactions, and various additional steps in aerobic and anaerobic glycolysis, are discussed in nearly any textbook on biochemistry or physiology; see, e.g., L. Stryer, Biochemistry, pp. 260-261 (second edition, 1981) or A. C. Guyton, Medical Physiology, pp. 841-842 (sixth edition, 1981). Web site: http://www.delphion.com/details?pn=US05747461__ •
Synthetic reconstructive implant device Inventor(s): Dayton; Michael P. (14802 Hadleigh Way, Tampa, FL 33624) Assignee(s): none reported Patent Number: 5,344,451 Date filed: May 5, 1993 Abstract: A synthetic reconstructive surgical implant device and method for making the same in which the device is suitable for implanting in a human. The device includes a sealed prosthesis envelope having a predetermined shape when filled, with the envelope being formed from an elastic polymer having a microporous structure with a texturized or non-texturized surface, such as silicone, polyurethane, polyvinylalcohol polyethylene, polyesters, hydrogels, tetrafluroethylene and polytetrafluroethylene, fluorosilicone and mixtures thereof. The envelope is filled with a biocompatible viscoelastic material in an amount sufficient to provide the predetermined shape. The biocompatible viscoelastic material is a sterile, non-pyrogenic solution which, in a preferred embodiment may be selected from salts of chondrotin sulfate, salts of hyaluronate, hydroxyproplymethylcellulose and mixtures thereof. In another preferred embodiment, the device includes a bioactive substance admixed in the polymer for elution from the microporous structure of the envelope after implantation. The bioactive substance may be selected from the group of heparin, prostacyclenes, steroids, ibuprofen, antimicrobials, antibiotics, tissue plasma activators, monoclonal antibodies, snake venom protein by-products, antifibrosis agents, cyclosporine and mixtures thereof. The rate of elution of the bioactive substance is controlled by selecting a pore size for the microporous structure in response to the concentration and molecular weight of the bioactive substance to achieve equilibrium between the envelope surface and the tissue proximate the envelope upon implant. Excerpt(s): The present invention relates to an improved reconstructive surgical implant device, and more particularly to a device useful as a prosthesis and a method for making the same which is biocompatible, natural in appearance and feel, and which is adapted to resist problems from fibrotic capsular contracture and/or post implant infection. The present invention also relates to a new procedure in which bioactive
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substances may be used. In recent years, the use of reconstructive surgical implant devices has become a commonly elected surgical procedure. In some instances, the procedure is done to correct the patient's appearance for cosmetic reasons. More important, of course, is the use of this procedure to restore the patient to an appearance that approximates that which existed before other surgery or injury. One major use is, of course. postmastectomy breast reconstruction. At the same time, as the procedure is more common, some of the disadvantages of the procedure are causing more concern. At the present time, there are three major types of mammary prostheses in use. These prostheses procedures include the autologous breast prosthesis, which is fashioned by grafting the patient's own abdominal fatty tissues, which are, of course, not synthetic. This procedure has the advantages of having a natural appearance and feel, and is completely biocompatible. Unfortunately, it is about three tinges as expensive as synthetic procedures, in part because of the need for two procedures. In addition, this procedure is a more involved surgical procedure with all of the attendant risks which that brings. Web site: http://www.delphion.com/details?pn=US05344451__ •
Use of essential oils to increase bioavailability of oral pharmaceutical compounds Inventor(s): Benet; Leslie Z. (Belvedere, CA), Benet; Reed M. (Belvedere, CA), Wacher; Vincent J. (San Francisco, CA) Assignee(s): AvMax, Inc. (Berkeley, CA) Patent Number: 5,665,386 Date filed: June 7, 1995 Abstract: A method for increasing bioavailability and reducing inter- and intraindividual variability of an orally administered hydrophobic pharmaceutical compound, which comprises orally administering the pharmaceutical compound to a mammal in need of treatment with the compound concurrently with an essential oil or essential oil component in an amount sufficient to provide bioavailability of the compound in the presence of the essential oil or essential oil component greater than bioavailability of the compound in the absence of the essential oil or essential oil component, wherein the essential oil or essential oil component has an activity of at least 10% inhibition at a concentration of 0.01 wt. % or less in an assay that measures conversion of cyclosporine to hydroxylated products using an assay system containing 250.mu.g rat liver microsomes, 1.mu.M cyclosporine, and 1 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH) in 1 ml of 0.1M sodium phosphate buffer, pH 7.4. Excerpt(s): This invention is directed to the field of pharmacology and particularly to the formulation of oral pharmaceutical compositions for increased bioavailability and reduced inter- and intra-individual variability. Pharmacokinetics is the study of the fate of pharmaceuticals from the time they are ingested until they are eliminated from the body. The sequence of events for an oral composition includes absorption through the various mucosal surfaces, distribution via the blood stream to various tissues, biotransformation in the liver and other tissues, action at the target site, and elimination of drug or metabolites in urine or bile. F.sub.oral is oral bioavailability fraction, which is the fraction of the oral dose that reaches the circulation in an active, unchanged form. F.sub.oral is less than 100% of the active ingredient in the oral dose for four reasons: (1) drug is not absorbed out of the gut lumen into the cells of the intestine and is eliminated in the feces; (2) drug is absorbed into the cells of the intestine but back-transported into
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the gut lumen; (3) drug is biotransformed by the cells of the intestine (to an inactive metabolite); or (4) drug is eliminated by the cells of the liver, either by biotransformation and/or by transport into the bile. Thus, oral bioavailability is the product of the fraction of the oral dose that is absorbed (F.sub.ABS), the fraction of the absorbed dose that successfully reaches the blood side of the gastrointestinal tract (F.sub.G), and the fraction of the drug in the GI blood supply that reaches the heart side of the liver (F.sub.H). The extent of gut wall absorption, back transport and metabolism, and liver elimination are all subject to wide inter- and intra-individual variability. Web site: http://www.delphion.com/details?pn=US05665386__ •
Use of leflunomide to control and reverse chronic allograft rejection Inventor(s): Williams; James (655 Superior, Oak Park, IL 60302) Assignee(s): none reported Patent Number: 5,624,946 Date filed: July 5, 1994 Abstract: The present invention relates to methods of controlling or reversing chronic rejection of allografts in a transplantation patient by administering leflunomide product alone, or in combination with one or more immunosuppressive agents selected from the group consisting of Cyclosporine A, FK506, rapamycin and corticosteroids. The invention also relates to methods of preventing or controlling acute and chronic rejection of xenografts in a transplantation patient by administering leflunomide product alone, or in combination with one or more immunosuppressive agents selected from the group consisting of Cyclosporine A, FK506, rapamycin and corticosteroids. Excerpt(s): Organ transplants of liver, kidney, heart and lung are now regularly performed as treatment for end-stage organ disease. Allograft (same species donor and recipient) as well as xenograft (different species donor and recipient) transplants have been performed. In 1989 over 14,000 patients received allografts in the United States alone. Transplant outcome has progressively improved with the development of refinements in tissue typing, surgical techniques, and more effective immunosuppressive treatments. However, because of problems with long-term chronic rejection, organ transplantation is not yet a permanent solution to irreversible organ disease. Chronic rejection, which manifests as progressive and irreversible damage to the graft from attack due to host immune responses, is the leading cause of organ transplant loss after the first postoperative year. A significant proportion of grafts, regardless of type, deteriorate and fail within the first several months or years after transplant despite administration of maintenance immunosuppression. Although the pace of graft destruction varies from patient to patient, essentially all heart or kidney transplants of cadaveric origin eventually succumb to chronic rejection. This persistent rate of decline of long-functioning grafts has remained constant over time, despite improvements in immunosuppressive therapy and in overall care for graft recipients. The half-life of a kidney transplant after the first year is seven years and has not changed with use of Cyclosporine A or anti-lymphocyte antibodies. In multicenter data from North America reported in 1988, less than half of the kidney cadaveric grafts continued to function at six years post-transplant although 80% behave satisfactorily at the end of the first year. There is a similar rate of decline for other types of organ grafts; the incidence of coronary arteriosclerosis in heart grafts reaches 50% before five years, resulting in a 25% mortality rate, and 40-50% of liver allografts no longer function at 5 years after transplant. This somewhat lower rate of chronic rejection for liver may be
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due to lower immunogenicity of liver tissue. The mechanism underlying chronic rejection is poorly understood. Various aspects of host immune responses have been implicated in the phenomenon, and its etiology may be multifaceted. Chronic rejection is inexorable and uncontrollable because there is no known effective treatment. Thus, there continues to exist a need for a treatment effective in preventing, controlling or reversing the chronic rejection of organ transplants. Web site: http://www.delphion.com/details?pn=US05624946__ •
Use of perillyl alcohol in organ transplantation Inventor(s): Imagawa; David K. (Orange, CA), Ming-Sing; Si (Santa Ana, CA) Assignee(s): The Regents of The University of California (Oakland, CA) Patent Number: 6,133,324 Date filed: May 6, 1999 Abstract: Perillyl alcohol and its monoterpene derivatives used alone or in combination with existing immunosuppressive agents, such as cyclosporine A and azathioprine, to provide methods and compositions which reduce allograft rejection in organ transplant patients. Excerpt(s): The present invention relates generally to the use of perillyl alcohol and derivatives thereof in organ transplantation. More particularly, the present invention involves the use of perillyl alcohol and/or derivatives thereof alone or in combination with other immunosuppressive agents to reduce allograft rejection in organ transplantation. A number of immunosuppressive agents are presently being used to prevent graft rejection. These agents include: cyclosporine A (CsA), tacrilomus (FK506), corticosteroids (e.g. prednisone), mycophenolate mofetil, mizoribine, brequinar sodium, 15-deoxyspergualin, rapamycin, azathioprine, cyclophosphamide, antilymphocyte and antithymocyte antibodies, and muromonab-CD3 (OKT3). Lymphocytes are the primary immune cells involved in the mammalian immune response. Therefore, inhibiting lymphocyte activation causes significant immunosuppression. Agents such as CsA, FK506 and rapamycin inhibit lymphocyte activation pathways and thus are immunosuppressive agents. Web site: http://www.delphion.com/details?pn=US06133324__
Patent Applications on Cyclosporine As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to cyclosporine:
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This has been a common practice outside the United States prior to December 2000.
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Cyclosporiine particles Inventor(s): Parikh, Indu; (Durham, NC), Snow, Robert A.; (West Chester, PA) Correspondence: Nixon & Vanderhye P.C.; 8th Floor; 1100 North Glebe Road; Arlington; VA; 22201; US Patent Application Number: 20020013271 Date filed: December 29, 2000 Abstract: Pharmaceutical compositions containing solid cyclic oligopeptide cyclosporine microparticles are prepared by applying energy input to solid cyclic oligopeptide cyclosporine in the presence of phospholipid and one or more non-ionic, anionic or cationic second surface modifiers. The microparticles consist essentially of a solid cyclic oligopeptide cyclosporine core coated with a combination of phospholipid and at least one second surface modifier. The combination of phospholipid and second surface modifier(s) provide volume-weighted mean particle size values of solid cyclic oligopeptide cyclosporine particles that are about 50% smaller than cyclic oligopeptide cyclosporine particles produced in the presence of the phospholipid and without the presence of the second surface modifier(s) using the same energy input. Excerpt(s): This invention relates to compositions and procedures that yield sub-micron and micron stable particles of solid water-insoluble or solid poorly soluble drugs such as cyclic oligopeptide cyclosporine or other industrially useful insoluble compounds. The compositions of this invention include combinations of natural or synthetic phospholipids, and one or more non-ionic, anionic or cationic second surfactants, which are also referred to interchangeably herein as second surface modifiers, coated or adhered onto the surfaces of the water insoluble-compound particles, each of which contains a core of solid compound. The combination of phospholipids and one or more second surfactants (or second surface modifiers) allows the formation and stabilization of the sub-micron and micron size compound particles via hydrophilic, lipophilic and electrostatic interactions and therefore prevents these particles from aggregation or flocculation. Cyclic oligopeptide cyclosporine, a drug, is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress some humoral immunity and to a greater extent, cellmediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft vs. host disease in many animal species for a variety of organs. Cyclosporin is useful in these and other indications. For example, cyclosporine is useful as an immunosuppressive agent in humans. Cyclosporine has been used in immunosuppressive therapy and management of organ transplant recipients to prevent rejection of transplanted organs (e.g., skin, pancreas, bone marrow, small intestine, lung, kidney, liver, heart), in immunosuppressive therapy and management of rheumatoid arthritis, and immunosuppressive therapy and management of psoriasis. The oral bioavailability of cyclosporine in human patients in available cyclosporine dosage forms is not complete, varies among patients in a patient population, and varies with the formulation, varies when food is taken by a patient proximal to the time of administration of a cyclosporine dosage form to or by the patient. When the level of cyclosporine received by a patient is not well controlled, the patient can experience undesired side effects that include organ rejection when concentrations achieved are too low. When the level of cyclosporine received by a patient is too high, renal dysfunction, nephrotoxicity, hepatotoxicity, and systemic hypertension can result.
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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Cyclosporine analogue mixtures and their use as immunomodulating agents Inventor(s): Foster, Robert T.; (Edmonton, CA), Naicker, Selvaraj; (Edmonton, CA), Yatscoff, Randall W.; (Edmonton, CA) Correspondence: Burns Doane Swecker & Mathis L L P; Post Office Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20030139326 Date filed: October 17, 2002 Abstract: The invention is directed to isomeric mixtures of cyclosporine analogues that are structurally similar to cyclosporine A. The mixtures possess enhanced efficacy and reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. Embodiments of the present invention are directed toward cis and trans-isomers of cyclosporin A analogs referred to as ISA.sub.TX247, and derivatives thereof. Mixtures of ISA.sub.TX247 isomers exhibit a combination of enhanced potency and reduced toxicity over the naturally occurring and presently known cyclosporins. ISA.sub.TX247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of stereoselectivity. The ratio of isomers in a mixture may range from about 10 to 90 percent by weight of the (E)-isomer to about 90 to 10 percent by weight of the (Z)isomer, based on the total weight of the mixture. Excerpt(s): This application claims the benefit of U.S. application Ser. Nos. 60/346,201 filed Oct. 19, 2001 and 60/370,596 filed Apr. 5, 2002. The disclosure of each of these applications is incorporated herein by reference in its entirety. The invention is directed to isomeric mixtures of cyclosporin analogues that are related to cyclosporine A. It is contemplated that the mixtures possess enhanced efficacy and/or reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. In addition, the present invention relates to synthetic pathways for producing isomers of cyclosporin A analogs, where such pathways vary in the degree of stereoselectivity depending on the specific reaction conditions. Bennett, W. M., "The nephrotoxicity of new and old immunosuppressive drugs," Renal Failure, Vol. 20, pp. 687-90 (1998). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Deuterated cyclosporine analogs and their use as immunomodulating agents Inventor(s): Foster, Robert T.; (Edmonton, CA), Naicker, Salvaraj; (Edmonton, CA), Yatscoff, Randall W.; (Edmonton, CA) Correspondence: Mary Ann Dillahunty, ESQ.; Burns, Doane, Swecker & Mathis, L.L.P.; P.O. Box 1404; Alexandria; VA; 22313-1404; US Patent Application Number: 20020132763 Date filed: November 7, 2001 Abstract: Cyclosporine derivatives are disclosed which possess enhanced efficacy and reduced toxicity over naturally occurring and other presently known cyclosporins and
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cyclosporine derivatives. The cyclosporine derivatives of the present invention are produced by chemical and isotopic substitution of the cyclosporine A (CsA) molecule by: (1) Chemical substitution and optionally deuterium substitution of amino acid 1; and (2) deuterium substitution at key sites of metabolism of the cyclosporine A molecule such as amino acids 1, 4, 9. Also disclosed are methods of producing the cyclosporine derivatives and method of producing immunosuppression with reduced toxicity with the disclosed cyclosporine derivatives. Excerpt(s): 2. Deuterium substitution at key sites of metabolism of the cyclosporine A molecule such as amino acids 1, 4, 9. The cyclosporins are a family of, neutral, hydrophobic cyclic undecapeptides, containing a novel nine-carbon amino acid (MeBmt) at position 1 of the ring that exhibit potent immunosuppressive, antiparasitic, fungicidal, and chronic anti-inflammatory properties. The naturally occurring members of this family of structurally related compounds are produced by various fungi imperfecti. Cyclosporines A and C, are the major components. Cyclosporine A, which is discussed further below, is a particularly important member of the cyclosporin family of compounds. Twenty four minor metabolites, also oligopeptides, have been identified: Lawen et al, J. Antibiotics 42, 1283 (1989); Traber et al, Helv. Chim. Acta 70, 13 (1987); Von Wartburg and Traber Prog. Med. Chem., 25, 1 (1988). Isolation of cyclosporines A and C, as well as the structure of A were reported by A. Ruegger et al., Helv. Chim. Acta 59, 1075(1976); M. Dreyfuss et al., J. Appl. Microbiol. 3, 125 ( 1976). Crystal and molecular structures of the iodo derivative of A have been reported by T. J. Petcher et al., Helv. Chim. Acta 59, 1480 (1976). The structure of C was reported by R. Traber et al., ibid. 60, 1247 (1977). Production of A and C has been reported by E. Harri et al., U.S. Pat. No. 4,117,118 (1978 to Sandoz). Isolation, characterization and antifungal activity of B, D, E, as well as the structures of A through D have been reported by R. Traber et al., Helv. Chim. Acta 60, 1568(1977). Isolation and structures of E, F, G, H, I: eidem, ibid. 65, 1655 (1982). Preparation of [2-Deutero-3-fluoro-D-Ala].sup.8-CsA is disclosed by Patchett et al in GB 2,206,199A which was published on Dec. 29, 1988. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Flavopiridol drug combinations and methods with reduced side effects Inventor(s): Innocenti, Federico; (Chicago, IL), Iyer, Lalitha; (Chicago, IL), Ratain, Mark J.; (Chicago, IL) Correspondence: Gina N. Shishima; Fulbright & Jaworski L.L.P.; Suite 2400; 600 Congress Avenue; Austin; TX; 78701; US Patent Application Number: 20020016293 Date filed: April 12, 2001 Abstract: This invention provides methods, formulations and kits to reduce the toxicity of flavopiridol and analogs thereof. Disclosed are therapeutics and treatment methods employing such drugs in combination with agents that increase conjugative enzyme activity or glucuronosyltransferase activity, and agents that decrease biliary transport protein activity, such as cyclosporine A, the resultant effects of which are to decrease the significant side effects previously associated with treatment using these drugs. The invention also characterizes specific isoforms of glucuronyltransferase enzymes involved in glucuronidation of flavopiridols and their analogs. Excerpt(s): The present application is a continuation-in-part of co-pending U.S. patent application Ser. No. 09/553,829, filed Apr. 21, 2000. The entire text of each of the above-
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referenced disclosures is specifically incorporated by reference herein without disclaimer. The present invention relates generally to the fields of cancer therapy. More particularly, it concerns new treatment methods and compositions for optimizing the treatment of cancer patients with flavopiridol. Flavopiridol (NSC 649890) is a novel semisynthetic flavone with direct inhibition of cyclin-dependent kinases, antiproliferative effects in vitro in a p53-independent manner, and activity in colon and prostate carcinoma animal models. Flavopiridol inhibits cell cycle progression in either G1 or G2 and is capable of killing noncycling as well as cycling cells (Bible et al., 1996). The drug is currently undergoing clinical evaluation, although dose-limiting toxicity results in moderate to severe diarrhea. Preclinical data on flavopiridol metabolism indicates that the drug undergoes hepatic glucuronidation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Hydrophobic active agent compositions and methods Inventor(s): Chen, Feng-Jing; (Salt Lake City, UT), Gutke, Kathryn; (Salt Lake City, UT), Patel, Mahesh V.; (Salt Lake City, UT), Venkateshwaran, Srinivasan; (Salt Lake City, UT) Correspondence: Thorpe North & Western, LLP.; 8180 South 700 East, Suite 200; P.O. Box 1219; Sandy; UT; 84070; US Patent Application Number: 20040115287 Date filed: December 17, 2002 Abstract: Compositions and methods for providing hydrophobic active agents in a bioavailable form, including cyclosporine are disclosed and described. In one aspect of the invention, a cyclosporine composition may be formulated that produces an aqueous dispersion containing cyclosporine in both dissolved and undissolved forms. In another aspect, the undissolved form of cyclosporine may be indicated by retention of cyclosporine particles on a 0.2 um membrane upon filtration of the aqueous dispersion therewith. In another aspect, the undissolved form of cyclosporine may be indicated by formation of a pellet upon centrifugation of the aqueous dispersion at about 12 K.times.G for about 10 minutes. Excerpt(s): The present invention relates to compositions containing a hydrophobic active agent, such as cyclosporine and methods associated therewith. Accordingly, the present invention involves the fields of chemistry, pharmaceutical sciences, and medicine. A number of hydrophobic drugs have been discovered to have a desirable, or potentially desirable effect in treating a variety of known conditions and maladies. For example, cyclosporine has been found to be very useful as an immune system suppressing agent, and is therefore indicated for administration to transplant patients in order to prevent the body from rejecting the newly received organ. However, the hydrophobic nature of such drugs causes significant challenges with administration and efficacy. Specifically, because the contents of the human digestive tract are aqueous, drugs that are highly hydrophobic generally cannot become sufficiently solubilized to allow significant absorption through the digestive tract. As a result, most hydrophobic drugs suffer from poor oral bioavailability. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel cyclosporine preparation forms for oral administration of simple composition and high bio-availability, and process for producing them Inventor(s): Olbrich, Matthias; (Reichenberg, DE), Potter, Heinrich; (Radebeul, DE) Correspondence: Thomas Hoxie; Novartis Corporation; Patent And Trademark Dept; 564 Morris Avenue; Summit; NJ; 079011027 Patent Application Number: 20020025927 Date filed: October 17, 2001 Abstract: The invention relates to formulations of cyclosporin with high bioavailability for oral administration, which contain about 1 part by weight of one or more cyclosporin(s), preferably cyclosporin A and/or cyclosporin G, 7.5 to 7.8 parts by weight of one or more polyethylene glycol esters of saturated C.sub.10-C.sub.22 hydroxy fatty acids, 0.7 to 0.85 part by weight of a monohydric alcohol as co-solvent, and 0.7 to 0.8 part by weight of a polyhydric alcohol as co-solvent. The drug form is produced by initially dissolving the cyclosporin in ethanol and, while stirring, adding propylene glycol and SOLUTOL.RTM. HS 15 until a clear, viscous solution results, bottled as drinkable solution or packed into capsules. Excerpt(s): This is a continuation of Ser. No. 09/605,512, Jun. 6, 2000, pending, which is a continuation of Ser. No. 09/134,298, Aug. 14, 1998, abandoned, which is a continuation of Ser. No. 08/806,106, Feb. 25, 1997, abandoned, which is a CIP of PCT/DE95/00951, Jul. 19, 1995. The invention relates to cyclosporin, especially cyclosporin A, containing liquid formulations and soft gelatin capsules for oral administration. Cyclosporins are neutral cyclic peptides produced by microbes. The most important representative of the cyclosporins is cyclosporin A, which is used in transplant therapy for suppressing organ rejection and in bone marrow transplantation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Oral dosage forms of water insoluble drugs and methods of making the same Inventor(s): Kerr, John E.; (Winterville, NC), Lawson, Allen L.; (Greenville, NC), Namburi, Ranga R.; (Greenville, NC) Correspondence: Myers Bigel Sibley & Sajovec; PO Box 37428; Raleigh; NC; 27627; US Patent Application Number: 20040052847 Date filed: July 11, 2003 Abstract: A method of making an oral dosage form of a water insoluble drug such as Saquinavir or Cyclosporine or Paclitaxel is carried out by: (a) providing a single phase working Solution comprising or consisting essentially of an active agent, water, a watersoluble polymer, and a solvent, said solvent selected from the group consisting of alcohol, acetone, and mixtures thereof; and may or may not contain a surfactant and pH of the said working solution may or may not be adjusted (b) providing particles formed from a pharmaceutically acceptable core material; (c) combining, preferably by spraying, said working solution with said particles to produce active agent-coated particles; such drug loaded particles may contain an external coat (d) drying said active agent-coated particles; and (e) forming said dried particles into an oral dosage form. Dried particles produced by the process, oral dosage forms containing such particles, and methods of treatment therewith are also described.
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Excerpt(s): This application claims the benefit of U.S. Provisional Patent Application serial No. 60/401,121, filed Aug. 5, 2002, and this application is a continuation-in-part of U.S. patent application Ser. No. 09/933,032, filed Aug. 20, 2001, the disclosures of both of which are incorporated by reference herein in their entirety. The present invention concerns methods of making oral formulations of water insoluble drugs, the oral dosage forms so made, and methods of use thereof. Increasing numbers of newly discovered drugs are insoluble (e.g., have a solubility of less than 100.mu.g per mL as per the definition of United States Pharmacopeia). For example, pharmaceutical compounds such as itraconazole, saquinavir, cyclosporine, paclitaxel, etoposide, etc. have an extremely low solubility in water. Indeed, the solubility of itraconazole in water and 0.1 N hydrochloric acid is less than 1 microgram and 6 micrograms per milliliter, respectively. Saquinavir, an antiviral compound, has approximately 10 microgram per mL solubility in water. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Pharmaceutical compositions of macrolides or cyclosporine with a polyethoxylated saturated hydroxy-fatty acid Inventor(s): Neuer, Klaus; (Schwendi, DE), Petszulat, Monika; (Ulm, DE), Walch, Hatto; (Laupheim, DE) Correspondence: Thomas Hoxie; Novartis Corporation; Patent And Trademark DEPT.; 564 Morris Avenue; Summit; NJ; 07901-1027; US Patent Application Number: 20010003589 Date filed: December 15, 2000 Abstract: Pharmaceutical compositions for oral administration comprising a cyclosporin or macrolide as active ingredient, and a polyethoxylated saturated hydroxy-fatty acid. Excerpt(s): This invention relates to medicinal preparations for peroral administration containing a cyclosporin, especially cyclosporin A, or a macrolide, e.g. a rapamycin or an ascomycin, as pharmaceutically active agent. Cyclosporins are cyclic oligopeptides of biological origin, which are used in particular as immunosuppressants. The cyclic polypeptide cyclosporin A consists of 11 amino acids. As a highly effective immunosuppressant, when tested on animals it prolongs the life of allografts, for example of skin, heart or kidneys. Research has shown that cyclosporin inhibits celllinked reactions, the delayed hypersensitivity of the skin, graft-versus-host disease and T-cell-dependent antibody production. For this reason, cyclosporins are employed in organ transplants to prevent rejection reactions. Since, in contrast to other immunosuppressants, these compounds have only very low bone marrow toxicity, they are also used in the case of bone marrow transplants. In addition, it is known that cyclosporins possess anti-inflammatory and anti-parasitic activity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Spontaneous emulsions containing cyclosporine Inventor(s): Egbaria, Kamel F.; (Gurnee, IL), Groves, Michael J.; (Deerfield, IL) Correspondence: Ratner And Prestia; Suite 301; One Westlakes, Berwyn; P.O. Box 980; Valley Forge; PA; 19482-0980; US Patent Application Number: 20030049280 Date filed: August 31, 2001 Abstract: A pharmaceutical composition contains cyclosporine as the active ingredient. More specifically, the composition is an orally administered pharmaceutical formulation in the form of a spontaneous emulsion comprising cyclosporine, ethanol ethyl oleate and polyoxyethylene glycerol trioleate. A method for preparing an orally administered pharmaceutical composition involves first dissolving cyclosporine in ethanol. Polyoxyethylene glycerol trioleate and an oil component are then added, mixed and diluted in an aqueous media to form a spontaneous emulsion. Excerpt(s): The invention relates to pharmaceutical compositions containing cyclosporine as the active ingredient. More specifically, the invention relates to orally administered pharmaceutical compositions in the form of a spontaneous emulsion comprising cyclosporine. Cyclosporines are a group of nonpolar cyclic oligopeptides, which have a broad spectrum of useful pharmacological activities, particularly immunosuppressive activity and anti-inflammatory activity. The major cyclosporine metabolite is cyclosporine A. Cyclosporine A is a neutral, lipophilic, cyclic endecapeptide with a low aqueous solubility and a molecular weight of 1200 daltons. Cyclosporine inhibits T cell activation and causes suppression of cell-mediated immune response. Cyclosporine has been used for suppression of immunological responses caused by tissue and organ transplantation, for example, transplantation of the heart, lung, liver, kidney, pancreas, bone marrow, skin and cornea, and especially the transplantation of foreign tissues and organs. In addition, cyclosporine is useful for the suppression of hematological disorders such as anemia, various autoimmune diseases such as systemic lupus erythematosus and idiopathic malabsorption syndrome, and inflammatory diseases such as arthritis and rheumatoid disorders. Cyclosporine is also useful in treatment of protozoal diseases such as malaria and schistosomiasis, and has recently been used in chemotherapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Therapeutic coating for an intravascular implant Inventor(s): Jayaraman, Swaminathan; (Fremont, CA) Correspondence: Paul D. Bianco; Fleit, Kain, Gibbons, Gutman & Bongini, P.L.; Suite A201; 520 Brickell Key Drive; Miami; FL; 33131; US Patent Application Number: 20030099712 Date filed: November 26, 2001 Abstract: The invention relates to a coating for an intravascular implant that prevents hyperproliferative vascular disease after a mechanical injury, such as angioplasty. The coating includes first and second agents, with the first agent acting on a calcium independent cellular pathway and the second agent acting on a calcium dependent cellular pathway. In an exemplary embodiment, the first agent is rapamycin and the second agent is cyclosporine A. The agents can be incorporated in a polymeric agent
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and can be applied either directly to the implant or on top of a primer layer placed on the implant. A top coat can be applied to the therapeutic coating, if desired. Excerpt(s): The present invention relates to a therapeutic coating for an intravascular implant, and in particular to a coating that prevents or treats hyperproliferative vascular disease including intimal smooth muscle cell hyperplasia, restenosis, and vascular occlusion. As discussed in more detail below, the prior art discloses many examples of therapeutic coatings that have been applied to intravascular devices. The objective behind applying the therapeutic coating is to either mediate or suppress a tissue response at the site of implantation. For example in intravascular situations, one of the obvious outcomes of implanting a foreign body is for an intense reaction at the site of implantation. This intense reaction can result from either the implantation itself or the stresses generated after implantation. Due to the reaction, there is an obvious interaction by the vessel wall to compensate for this injury by producing a host of tissue related responses that is generally called "healing due to injury." It is this healing process that the therapeutic coating attempts to mediate, suppress, or lessen. In some instances, this healing process is excessive in which it occludes the entire lumen providing for no blood flow in the vessel. This reoccluded vessel is also called a restenotic vessel. Therapeutic coatings can behave in different ways. For example, depending upon the kind of therapeutic agent used, the various cellular levels of mechanisms are tackled. Some of the therapeutic agents act on the growth factors that are generated at the site of implantation or intervention of the vessel. Some other therapeutic agents act on the tissues and suppress the proliferative response of the tissues. Others act on the collagen matrix that comprises the bulk of the smooth muscle cells. Some examples of prior art relating to therapeutic coatings follow. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
USE OF AEROSOLIZED CYCLOSPORINE FOR PREVENTION AND TREATMENT OF PULMONARY DISEASE Inventor(s): IACONO, ALDO T.; (PITTSBURGH, PA) Correspondence: Baker & Botts; 30 Rockefeller Plaza; New York; NY; 10112 Patent Application Number: 20020006901 Date filed: February 5, 1999 Excerpt(s): The present invention relates to methods and compositions for prevention of graft rejection in lung transplant recipients and for treatment of subjects with pulmonary disorders. Specifically, the methods and compositions of the invention provide a means for inhibiting immune response mediated inflammatory processes in the lungs. The method of the invention comprises the administration of aerosolized cyclosporine for prevention of acute and/or chronic refractory rejection in lung transplant patients. The invention is based on the observation that when aerosolized cyclosporine is administered shortly after lung transplantation, the preparation is well tolerated and the rate of acute rejection is substantially reduced, compared to controls that receive conventional oral or intravenous immunosuppression only. The invention further provides for the use of aerosolized cyclosporine to treat subjects having immunologically mediated inflammatory pulmonary disorders including, but not limited to, asthma, cystic fibrosis, idiopathic pulmonary fibrosis, chronic bronchitis and allergic rhinitis. The present invention, by enabling a method for the use of aerosolized cyclosporine for inhibiting pulmonary inflammation leading to prevention of graft rejection and treatment of pulmonary disorders, provides a safer and less toxic
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treatment than those methods that utilize systemic administration of cyclosporine. The long-term success of lung transplantation is currently limited by the high incidence of transplant-related lung disease (Glanville, A. R., et al., 1987, Ann Intern Med 107:300306; Trulock, E. P., 1993, Chest 103:1566-1576; Kesten, S., 1995, 152: 1321-1324; Paradis, I. et al., 1993, 14:751-763). This complication is related to the transplant recipients' ongoing immune response against donor major histocompatability antigens. Such an immune response generally leads to persistent acute rejection of the lung allograft which is a predominant risk factor for the subsequent development of chronic rejection and permanent allograft dysfunction and failure resulting in excessive morbidity and mortality. This is a tragic consequence of lung transplantation and for this reason, is a leading area of research in this field. Although the rates of short-term survival after lung transplantation have improved compared to most other solid organ transplants, the therapeutic benefit of lung transplantation is still limited by poor longer-term outcomes principally due to chronic rejection of the transplanted lung. Patients, whose lung allografts are in acute and/or chronic rejection, are currently treated by a variety of potent immunosuppressive agents, such as azathioprine, tacrolimus, mycophenolate mofetil and cyclosporine, generally given by the intravenous or oral route, that profoundly inhibit the T cell response to donor antigen within the transplanted allograft. Unfortunately, these immunosuppressive agents diminish the patient's ability to mount an effective response to viral, fungal and bacterial pathogens thereby predisposing the patient to life threatening opportunistic infections and other toxic events such as kidney toxicity. Despite usage of conventional systemic (oral or intravenous) immunosuppressive drugs, about 50% of the treated patients develop refractory chronic rejection, characterized histologically by bronchiolitis obliterans, followed by a progressive decline in pulmonary function and eventually respiratory failure and death. 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 cyclosporine, 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 “cyclosporine” (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 cyclosporine. You can also use this procedure to view pending patent applications concerning cyclosporine. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.
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CHAPTER 6. BOOKS ON CYCLOSPORINE Overview This chapter provides bibliographic book references relating to cyclosporine. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on cyclosporine include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.
Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “cyclosporine” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on cyclosporine: •
Stepping Into a New Life: A Transplant Recipient's Guide to Long-Term Care Source: East Hanover, NJ: Novartis Pharmaceuticals Corporation. 1997. 35 p. Contact: Available from Transplant Recipients International Organization, Inc. (TRIO). 1000 16th Street, NW, Suite 602, Washington, DC 20036-5705. (800) TRIO-386 or (202) 293-0980. Fax (202) 293-0873. E-mail:
[email protected]. PRICE: Single copy free. Summary: This booklet outlines a care plan for transplant patients who have reached the 6 month posttransplant mark. The first 6 months after transplant are characterized by a close connection with one's transplant team. The booklet emphasizes that this connection will evolve and that patients must make a commitment to their own health care and to keeping their new organ stable and functioning. Most important, patients must be committed to taking the prescribed dose of medication each and every day for the rest of their lives. The booklet describes the transfer of medical care from the transplant team to the community health professional, strategies to maintain stability
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and to avoid complications (such as transplant rejection), and ways to improve quality of life. The latter section discusses the importance of nutrition and exercise, the role of employment and health insurance, travel, romance and parenthood, and networking with other transplant recipients. The booklet includes a glossary of important terms, blank space for readers to record their questions and concerns, and the full prescribing information for Neoral (cyclosporine) capsules and oral solution. Throughout the booklet, the authors emphasize the importance of patient compliance to the medication regimens as the crucial factor for long term success with the transplant. •
Kidney Transplant Rejection: Diagnosis and Treatment. 2nd ed Source: New York, NY: Marcel Dekker, Inc. 1992. 773 p. Contact: Available from Marcel Dekker, Inc. P.O. Box 5005, Monticello, NY 12701. (800) 228-1160 or (212) 696-9000. Fax (914) 796-1772. E-mail:
[email protected]. PRICE: $275.00. ISBN: 0824784871. Summary: This medical text on the diagnosis and treatment of kidney transplant rejection presents 26 chapters in 4 sections: the biology of the allograft response; the diagnosis of rejection; new immunosuppressive agents; and systemic problems with immunosuppression. Specific topics include the mechanisms of cell-mediated rejection; the role of cytokines; suppressor cell regulation; antibody-mediated rejection; the pathology of acute tubular necrosis and acute rejection; fine needle aspiration biopsy; monitoring the components of the immune system; radionuclides in the evaluation of kidney transplant rejection; magnetic resonance imaging; antilymphocyte antibody therapy; cyclosporine; nephrotoxicity; cytomegalovirus infection; cancer in recipients of organ allografts; HIV infection and kidney transplantation; and molecular biology of transplant rejection. Each chapter, written by international experts in the field, includes numerous charts and diagrams, as well as extensive references. A detailed subject index concludes the volume.
•
Kidney Transplant Rejection: Diagnosis and Treatment. 3rd ed Source: New York, NY: Marcel Dekker, Inc. 1998. 680 p. Contact: Available from Marcel Dekker, Inc. Cimarron Road, P.O. Box 5005, Monticello, NY 12701. (800) 228-1160 or (845) 796-1919. Fax (845) 796-1772. E-mail:
[email protected]. International E-mail:
[email protected]. Website: www.dekker.com. PRICE: $225.00 plus shipping and handling. ISBN: 0824701399. Summary: This text on kidney transplant rejection is focused on basic immunological principles, mechanisms of rejection, diagnostic modalities, infections in the transplant setting, and clinical treatment of renal allograft rejection. All chapters have been contributed by recognized experts in the field of renal transplantation. Twenty-two chapters cover the molecular basis for transplantation immunity, the mechanisms of cell mediated rejection, cytokines (regulators and effectors of the immune response), regulation of allograft rejection by anti-idiotypic responses, clinical syndromes associated with antibody in allografts, renal injury and preservation in transplantation, mechanism of chronic rejection, xenotransplantation, histocompatibility and organ allocation, immunological tolerance and its relationship to clinical transplantation, pathology of kidney transplantation, fine needle aspiration cytology, the sonographic evaluation of acute renal transplant rejection, the history and prospects for antilymphocyte antibody therapy for tolerance induction, mechanisms of action of immunosuppressive agents (cyclosporine, FK506, rapamycin), the clinical use of cyclosporine in kidney transplantation, tacrolimus and mycophenolate mofetil as
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primary immunosuppression for renal allograft recipients, newer immunosuppressive agents and combination therapy, immune monitoring for transplant recipients, cancer in recipients of organ allografts, the impact of cytomegalovirus infection on renal transplantation, and hepatitis in the renal allograft recipient. Each chapter, written by experts in the field, includes lengthy references; a subject index concludes the text.
The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “cyclosporine” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:10 •
Proceedings of the First International Congress on Cyclosporine: May 16-19, 1983, Houston, Texas. Author: president and guest editor, Barry D. Kahan; honorary president, Jean F. Borel; Year: 1983
Chapters on Cyclosporine In order to find chapters that specifically relate to cyclosporine, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and cyclosporine using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “cyclosporine” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on cyclosporine: •
Cyclosporine Treatment of Glomerular Diseases Source: in Coggins, C.H., ed. Annual Review of Medicine: Selected Topics in the Clinical Sciences, Volume 50. Palo Alto, CA: Annual Reviews. 1999. p. 1-15. Contact: Available from Annual Reviews. 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303-0139. (650) 493-4400. E-mail:
[email protected]. Website: www.AnnualReviews.org. PRICE: $60.00 plus shipping and handling. ISBN: 0824305507. Summary: Cyclosporine A is primary therapy for organ transplantation. This article considers the potential role of cyclosporine's immunosuppressive effect as a therapy for
10
In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is currently adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a "Books" button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.
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autoimmune diseases, including several idiopathic and secondary glomerular conditions. Various forms of idiopathic nephrotic syndrome, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and membranous nephropathy (MN), may respond well to cyclosporine in selected patients. However, frequent relapse limits its use to those who have failed to respond to, or were intolerant of, steroids or cytotoxics. Cyclosporine's efficacy in other glomerulopathies, such as IgA nephropathy and membranoproliferative glomerulonephritis remains poorly studied and, given the risk of nephrotoxicity, cannot be recommended for treatment of these entities until further data are available. The authors note that cyclosporine demonstrates some efficacy in treating proliferative lupus nephritis and, based on pilot study data, membranous lupus as well. Again, given relapse rates and potential nephrotoxicity, it should be used only in combination with azathioprine and steroids, assuming cytotoxic therapy has failed. The authors conclude by briefly reviewing cyclosporine toxicity. 2 tables. 69 references. (AA-M). •
Cyclosporine in Crohn' Disease Source: in Bayless, T.M. and Hanauer, S.B. Advanced Therapy of Inflammatory Bowel Disease. Hamilton, Ontario: B.C. Decker Inc. 2001. p. 387-388. Contact: Available from B.C. Decker Inc. 20 Hughson Street South, P.O. Box 620, L.C.D. 1 Hamilton, Ontario L8N 3K7. (905) 522-7017 or (800) 568-7281. Fax (905) 522-7839. Email:
[email protected]. Website: www.bcdecker.com. PRICE: $129.00 plus shipping and handling. ISBN: 1550091220. Summary: This chapter on the use of the drug cyclosporine (CYSA) in treating Crohn's disease (CD) is from the second edition of a book devoted to the details of medical, surgical, and supportive management of patients with CD and ulcerative colitis (UC), together known as inflammatory bowel disease (IBD). Patients with Crohn's disease refractory to mesalamine, oral and topical products, and corticosteroids are candidates for immunomodulator therapy. CYSA, extracted from the soil fungus Tolypocladium inflatum, has been proposed as an alternative or adjunct to antimetabolite therapy, such as 6-mercaptopurine (6-MP) or azathioprine (AZA), for refractory (resistant to treatment)disease. Cyclosporine-associated nephrotoxicity, opportunistic infections, and possible oncogenesis (cancer development) suggest caution and the need for future controlled trials to evaluate its efficacy for Crohn's disease. Perhaps the best application for cyclosporine administration is use as a rapidly active agent for persistently active disease or fistulae that can serve as bridges to other immunosuppressive agents for maintenance of disease remission and fistula closure. 8 references.
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CHAPTER 7. PERIODICALS AND NEWS ON CYCLOSPORINE Overview In this chapter, we suggest a number of news sources and present various periodicals that cover cyclosporine.
News Services and Press Releases One of the simplest ways of tracking press releases on cyclosporine 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 “cyclosporine” (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 cyclosporine. 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 “cyclosporine” (or synonyms). The following was recently listed in this archive for cyclosporine: •
Aerosol cyclosporine improves lung function after transplant Source: Reuters Industry Breifing Date: April 10, 2003
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SangStat says Gengraf infringement ruling overturned, shares up Source: Reuters Industry Breifing Date: April 01, 2003
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FDA approves cyclosporine product for chronic dry eye therapy Source: Reuters Medical News Date: December 24, 2002
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Oral paclitaxel with cyclosporine active against non-small-cell lung cancer Source: Reuters Industry Breifing Date: December 18, 2002
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Methotrexate and cyclosporine have similar efficacy in severe psoriasis Source: Reuters Industry Breifing Date: August 18, 2003
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CellGate says topical cyclosporine effective for psoriasis in small study Source: Reuters Industry Breifing Date: May 02, 2003
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SangStat shares fall after jury ruling on cyclosporine patent Source: Reuters Industry Breifing Date: July 31, 2002
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Low-dose cyclosporine effective in treating severe aplastic anemia Source: Reuters Industry Breifing Date: October 25, 2001
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Sirolimus allows cyclosporine withdrawal in kidney transplant recipients Source: Reuters Industry Breifing Date: September 24, 2001
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CORRECTION: Intermittent cyclosporine improves safety of psoriasis therapy Source: Reuters Industry Breifing Date: April 12, 2001
•
Intermittent cyclosporine improves safety of psoriasis therapy Source: Reuters Industry Breifing Date: April 11, 2001 The NIH
Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name.
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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 “cyclosporine” (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 “cyclosporine” (or synonyms). If you know the name of a company that is relevant to cyclosporine, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/. BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “cyclosporine” (or synonyms).
Newsletters on Cyclosporine Find newsletters on cyclosporine using the Combined Health Information Database (CHID). You will need to use the “Detailed Search” option. To access CHID, go to the following hyperlink: http://chid.nih.gov/detail/detail.html. Limit your search to “Newsletter” and “cyclosporine.” Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter.” Type “cyclosporine” (or synonyms) into the “For these words:” box. The following list was generated using the options described above: •
Evolving Medical Therapies for Inflammatory Bowel Disease Source: Progress in Inflammatory Bowel Disease. 15(2): 1-5. Spring 1994. Contact: Available from Crohn's and Colitis Foundation of America, Inc. 386 Park Avenue South, 17th Floor, New York, NY 10016-8804. (800) 343-3637 or (800) 932-2423 or (212) 685-3440. Summary: This newsletter article reviews advances in medical approaches to treating ulcerative colitis and Crohn's disease (collectively, inflammatory bowel disease or IBD). Topics include the use of aminosalicylates, including 5-ASA, mesalamine, sulfasalazine, administration and dosage considerations, and the use of these agents specifically in Crohn's disease; steroid treatment of IBD, including the use of budesonide; immune
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modifiers, including azathioprine, 6-mercaptopurine, methotrexate, and cyclosporine; and miscellaneous therapies, including immunoinflammatory mediators, lipoxygenase inhibition, and short-chain fatty acids for ulcerative colitis. 22 references.
Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “cyclosporine” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on cyclosporine: •
Friendly Fire: Lifesaving Cyclosporine Takes Toll on Kidneys Source: UNOS Update. p. 18-20. Summer 1997. Contact: Available from United Network for Organ Sharing. 1100 Boulders Parkway, Suite 500, P.O. Box 13770, Richmond, VA 23225-8770. (888) 894-6361 or (804) 330-8541. Summary: This newsletter article describes the effects of cyclosporine, an immunosuppressive agent, on the kidneys. As transplant recipients are living longer, and thus receiving the drug for prolonged periods, cyclosporine-induced kidney damage has become a growing challenge. Researchers are now exploring explore ways to fight this potentially life-threatening condition. The long term effects of cyclosporine may cause some transplant patients without any prior kidney disease, particularly those receiving heart, liver, and lung transplants, to require dialysis or kidney transplantation. The article briefly reports on a research study that demonstrated that treatment with cyclosporine for more than 12 to 24 months can cause progressive injury to the kidney that is rarely reversible. The author then outlines the factors that play a role in the development of cyclosporine-induced kidney damage. The article notes a number of measures to help identify or delay the progress of kidney damage. Among the most important is earlier referral to a transplant nephrologist. Other suggested safety measures include a low protein diet, good blood pressure control, and the use of ACE inhibitors, when appropriate. 2 figures.
Academic Periodicals covering Cyclosporine Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to cyclosporine. In addition to these sources, you can search for articles covering cyclosporine 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.
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At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”
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CHAPTER 8. RESEARCHING MEDICATIONS Overview While a number of hard copy or CD-ROM resources are available for researching medications, a more flexible method is to use Internet-based databases. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.
U.S. Pharmacopeia Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications recommended for cyclosporine. 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 cyclosporine. 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 cyclosporine: Caffeine •
Systemic - U.S. Brands: Cafcit; Caffedrine Caplets; Dexitac Stay Alert Stimulant; Enerjets; Keep Alert; Maximum Strength SnapBack Stimulant Powders; NoDoz Maximum Strength Caplets; Pep-Back; Quick Pep; Ultra Pep-Back; Vivarin http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202105.html
Cyclosporine •
Ophthalmic - U.S. Brands: Restasis http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500453.html
•
Systemic - U.S. Brands: Neoral; Sandimmune; SangCya http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202176.html
Sirolimus •
Systemic - U.S. Brands: Rapamune http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500028.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.
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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
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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/
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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html
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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25
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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm
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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm
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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375
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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/
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
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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/
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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm
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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm
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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/
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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm
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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html
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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm
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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm
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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm
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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html
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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm
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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp
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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/
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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp
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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html
•
Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm
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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •
Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html
•
HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html
•
NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html
•
Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/
•
Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html
•
Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html
•
Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/
•
Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html
•
Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
•
Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html
•
MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html
12
Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.
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•
Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html
•
Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html
The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “cyclosporine” (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 27808 22 1151 62 78 29121
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 “cyclosporine” (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 cyclosporine 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 cyclosporine. 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 cyclosporine. 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 “cyclosporine”:
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Autoimmune Diseases http://www.nlm.nih.gov/medlineplus/autoimmunediseases.html Bleeding Disorders http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html Immune System and Disorders http://www.nlm.nih.gov/medlineplus/immunesystemanddisorders.html Kidney Transplantation http://www.nlm.nih.gov/medlineplus/kidneytransplantation.html Liver Transplantation http://www.nlm.nih.gov/medlineplus/livertransplantation.html Lupus http://www.nlm.nih.gov/medlineplus/lupus.html Psoriasis http://www.nlm.nih.gov/medlineplus/psoriasis.html Ulcerative Colitis http://www.nlm.nih.gov/medlineplus/ulcerativecolitis.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on cyclosporine. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •
Gout, and What to Do About It Source: American Family Physician. 59(7): 1810. April 1, 1999. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Also available at www.aafp.org. Summary: Gout is a kind of arthritis caused by too much uric acid in the joints. The acid causes joint pain. This patient education handout describes gout and offers suggestions for managing the disease. Written in a question and answer format, the handout first reviews the risk factors for gout, including eating a lot of foods that are rich in purines, being overweight, drinking alcohol, or having high cholesterol; certain medications may also cause gout, including some diuretics, aspirin, niacin (a B complex vitamin),
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cyclosporine, and some drugs used to treat cancer. The authors then describe a gout attack, which usually features an acute pain in a joint, particularly the joints of the toes and fingers. The authors emphasize that the sooner an attack is treated, the sooner the pain will go away. With treatment, the gout attack can go away in a few days. Without treatment, a gout attack can last for days or even weeks. If recurrent gout attacks are untreated, the patient may develop tophi, which are soft tissue swellings caused by uric acid crystals. Tophi usually form on the toes, fingers, hands, and elbows. Gout patients may also get kidney disease or kidney stones. The patient's physician can prescribe medicines to prevent future gout attacks. These drugs are used to wash the uric acid from the joints, reduce the swelling, or keep uric acid from forming. Readers are encouraged to lose weight if they need to, to reduce high blood pressure (hypertension) and high cholesterol, and to stay away from alcohol and foods that are high in purines (such as salmon, sardines, liver, and herring). Drinking lots of water (to help flush uric acid) is also recommended. The authors of the handout are also the authors of a lengthy article for physicians, published in the same journal issue. •
Your Child and Prednisone: Answers to Parents' Questions About Prednisone Source: Valencia, CA: Children's Liver Association for Support Services (C.L.A.S.S.). 1996. 18 p. Contact: Available from Children's Liver Association for Support Services (C.L.A.S.S.). 26444 Emerald Dove Drive, Valencia, CA 91355. (877) 679-8256 or (661) 255-0353. E-mail:
[email protected]. Website: www.classkids.org. PRICE: Single copy free; available on the Internet at http://www.classkids.org/library/pred.htm. Summary: Prednisone is one of the most universally prescribe immunosuppressant drugs. It is used to prevent rejection after organ transplantation, and also to treat autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, and others. This brochure educates parents about the use of prednisone in children. Written in question and answer format, the brochure covers the uses of prednisone, how the drug works, the use of newer immunosuppressant drugs such as cyclosporine and tacrolimus, administration and dosage of prednisone, the side effects, and weaning the patient off of it. Prednisone works by doing many things to the immune cells that fight infection and cause rejection; the result is that all inflammatory processes are slowed and weakened. By turning down the body's ability to produce inflammation, an organ transplant can survive longer. Prednisone is used to supplement the use of other anti-rejection drugs. Pretension is given orally, or by intravenous (IV) route. Side effects can include ulcers and abdominal pain, high blood pressure, weight gain, acne, cataracts, difficulty sleeping, brittle (easily broken) bones, high blood sugar and a tendency to develop diabetes, muscular weakness, excess hair growth, mood swings and personality changes, and slowed growth in children. The booklet concludes with a glossary of related terms. The brochure also offers a brief description of Children's Liver Association for Support Services (CLASS), a nonprofit organization dedicated to addressing the emotional, educational, and financial needs of families coping with childhood liver disease and transplantation.
•
Keeping Your New Liver Healthy: Facts About Transplant Medications Source: Mount Laurel, NJ: American Society of Transplantation. 200x. 25 p. Contact: Available from American Society of Transplantation, Ptient Care and Education. 17000 Commerce Parkway, Suite C, Mount Laurel, NJ 08054. (856) 439-9986.
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Fax (856) 439-9982. E-mail:
[email protected]. Website: http://www.a-s-t.org. PRICE: Single copy free. Summary: This booklet offers detailed information about medications for people who have just received a liver transplant. The booklet introduction reminds readers how important transplant medications are (in order to retain the transplanted liver) and cautions readers that many transplant medications have side effects, even side effects that can be difficult enough to warrant taking other medications to cope with those side effects. The booklet also reminds readers that their medications will be changed often and they must work in close tandem with their health care providers. The booklet then discusses medicines for infections, medicines that help to control side effects, the importance of taking medications the right way (timing, dosage, with or without meals, etc.), financial considerations, and specific medications. The booklet categorizes individual drugs and offers fact sheets on each drug or drug group, including: steroids, cyclosporine, azathioprine, sirolimus and rapamycin, tacrolimus, mycophenolate mofetil, trimethoprim-sulfamethoxazole, acyclovir, ganciclovir, nystatin or clotrimazole, medicines for ulcers, diuretics ('water pills'), vitamins and minerals, and blood pressure medications. The fact sheets cover how each drug works, common side effects, dosages, and how to store the drug. Final sections discuss which medications are safe to take together and new research (clinical studies) on drugs for transplant patients. 1 table. •
Drug Cost Share Program Source: New Fairfield, CT: NORD/Sandoz. 1994. 2 p. Contact: Available from NORD/Sandoz. Drug Cost Share Program, P.O. Box 8923, New Fairfield, CT 06812. (203) 746-6518 or (800) 447-NORD. PRICE: Single copy free. Summary: This brochure describes the NORD/Sandoz Drug Cost Share (DCS) Program, a program to assist financially needy patients in obtaining pharmaceutical drugs manufactured by Sandoz Pharmaceuticals Corporation to treat several rare diseases. Drugs currently subsidized under the program are Sandoglobulin (immune globulin intravenous, human), Sandimmune (cyclosporine), Sandostatin (octreotide acetate), Parlodel (bromocriptine mesylate), and Eldepryl (selegiline hydrochloride). The brochure describes how the DCS program works, DCS program benefits, who is eligible, how to apply, and off-label indication.
•
Nutrition and Transplantation Source: New York: National Kidney Foundation. 2001. 9 p. Contact: Available from National Kidney Foundation, Inc. 30 East 33rd Street, New York, NY 10016. (800) 622-9010. PRICE: Single copy free. Summary: This brochure explains dietary changes that are recommended for patients who have had kidney transplants. Written in a question and answer format, the brochure presents guidelines for maintaining adequate levels of protein, potassium, sodium, fluid, phosphorus, calories, and vitamins and minerals in the diet. The interrelationship between some medicines, notably steroids and cyclosporine, and diet are explored. Other topics discussed include cholesterol levels, weight control, and special considerations for the patient with diabetes mellitus. The brochure emphasizes the importance of close cooperation between the hemodialysis patient, the physician, and the renal dietitian in planning and following a healthy diet.
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Facts About Lichen Planus Source: Detroit, MI: American Autoimmune Related Diseases Association. 1997. 2 p. Contact: Available from American Autoimmune Related Diseases Association. Michigan National Bank Building, 15475 Gratiot Avenue, Detroit, MI 48205. (313) 371-8600. Website: www.aarda.org. PRICE: Single copy free; send self-addressed, stamped envelope. Summary: This brochure provides information on lichen planus, an inflammatory autoimmune skin disease which can affect the eyes, the skin, and mucosa lining of the mouth and genitalia. Lichen planus is not uncommon, accounting for approximately 5 percent of patients seen in an oral medicine clinic. In most patients, the disease is selflimited and usually remits within one or two years. The brochure reviews the affected population, the symptoms of lichen planus, diagnosis, treatment options, and a definition and description of autoimmunity. Treatment for lichen planus is usually patient specific and depends on the extent of the involvement of the disease and the frequency of reoccurrence of lesions or inflammation. Oral rinses with cyclosporine mouthwash have been used by some physicians to suppress disease activity and control inflammatory lesions in the mouth. The brochure concludes with a discussion of the work of the American Autoimmune Related Diseases Association (AARDA).
•
Transplantation-Facts. Optimal Drug Use: Be a Team Player Source: New York, NY: National Kidney Foundation. 200x. [2 p.]. Contact: Available from National Kidney Foundation of Southern California. 5777 West Century Boulevard, Suite 1450, Los Angeles, CA 90045-7404. (310) 641-8152. Fax (310) 641-5246. Website: www.kidneysocal.org. PRICE: Single copy free; bulk copies available. Summary: This fact sheet from the National Kidney Foundation (NKF) reviews the use of immunosuppressive medications for people who have received a kidney transplant. The fact sheet focuses on three types of immunosuppressants: cyclosporine (Sandimmune or Neoral) or tacrolimus (Prograf), steroids such as prednisone (Deltasone) or prednisolone (Medrol), and a third type of immunosuppressant, such as mycophenolate mofetil (Cellcept) or azathioprine (Imuran). These medications are crucial because they suppress the recipient's immune system's ability to recognize the new organ as foreign, thereby preventing rejection. The fact sheet encourages patients to educate themselves about their medications, making sure that they understand what each one is used for, what it looks like, what common side effects may be encountered, and how it should be taken. One section of the fact sheet considers generic substitutes for brand name drugs, cautioning that patients should not switch back and forth between different immunosuppressants. Patients are also cautioned about drug interactions (the immunosuppressant may interact with other drugs, including over the counter drugs and vitamins) and about food interactions. Patients are encouraged to ask their transplant team about which medications should be taken on an empty stomach, which medications should be taken with food, what foods should be avoided (grapefruit and grapefruit juice are especially cautioned against), and what time of day medications should be taken. The fact sheet concludes with a brief description of the role of the pharmacist and how to obtain the best pharmacy care. The contact information for the NKF is on the fact sheet (800-622-9010, www.kidney.org).
•
Immunosuppressants Source: New York, NY: National Kidney Foundation. 1993. [3 p.].
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Contact: Available from National Kidney Foundation of Southern California. 5777 West Century Boulevard, Suite 1450, Los Angeles, CA 90045-7404. (310) 641-8152. Fax (310) 641-5246. Website: www.kidneysocal.org. PRICE: Single copy free; bulk copies available. Summary: This fact sheet offers kidney disease patients an overview of immunosuppressants, a group of drugs or medicines that suppress or lower the body's ability to reject a transplanted organ. These drugs are also called antirejection drugs. Examples of immunosuppressants used for kidney transplants are cyclosporine, azathioprine, prednisone, and FK506. The fact sheet, written in question and answer format, explains the use of immunosuppressants, what to do if a scheduled dose is missed, different drugs and dosages used for different patients, signs or symptoms of rejection (even while on immunosuppressants), the problem of increased risk of infection while on these drugs, specific recommendations for different drugs, the possible side effects of these drugs, and how to get additional information. Prednisone should be taken with meals or food because it can be irritating to the stomach. Side effects can include weight gain, muscle weakness, acne, trouble sleeping, stomach ulcers, diabetes, and cataracts. Azathioprine should be taken once a day. Side effects can include low white blood cell count, liver problems, anemia, and nightmares. Cyclosporine comes in liquid and capsule form; it is usually taken twice a day, but the dose can be adjusted based on the amount in the patient's blood. Side effects can include kidney damage (nephrotoxicity), overgrowth of gums (gingival hyperplasia), hair growth, hair darkening, high blood pressure, tremors of the hands, and liver problems. FK506 is a drug whose actions and side effects are similar to cyclosporine. The fact sheet concludes with a brief description of the National Kidney Foundation (NKF) and its activities. 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 cyclosporine. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/specific.htm
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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/
•
Med Help International: http://www.medhelp.org/HealthTopics/A.html
•
Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/
Patient Resources
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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/
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WebMD®Health: http://my.webmd.com/health_topics
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Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to cyclosporine. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with cyclosporine. 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 cyclosporine. 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 “cyclosporine” (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 “cyclosporine”. 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 “cyclosporine” (or synonyms) into the “For
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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 “cyclosporine” (or a synonym) into the search box, and click “Submit Query.”
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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.
Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.22
Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.
Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of
22
Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.
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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)23: •
Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/
•
Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)
•
Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm
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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html
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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html
•
California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html
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California: Gateway Health Library (Sutter Gould Medical Foundation)
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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/
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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp
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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html
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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/
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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/
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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/
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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html
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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/
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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/
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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/
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Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/
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/
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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/
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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm
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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html
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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm
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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/
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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/
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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10
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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/
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Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html
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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp
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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp
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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/
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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html
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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm
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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp
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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/
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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html
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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/
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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm
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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/
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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html
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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm
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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330
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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)
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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html
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National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/
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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/
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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm
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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/
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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm
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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm
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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/
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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html
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New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/
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New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html
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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/
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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm
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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp
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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/
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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/
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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml
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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html
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Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html
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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml
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Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp
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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm
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Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/
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South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp
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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/
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Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/
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Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72
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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •
ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html
•
MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp
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Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/
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Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html
•
On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/
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Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp
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Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm
Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).
Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •
Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical
•
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
219
CYCLOSPORINE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 6-Mercaptopurine: An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal fat: Fat (adipose tissue) that is centrally distributed between the thorax and pelvis and that induces greater health risk. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Ablation: The removal of an organ by surgery. [NIH] Abscess: A localized, circumscribed collection of pus. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetone: A colorless liquid used as a solvent and an antiseptic. It is one of the ketone bodies produced during ketoacidosis. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acetylcysteine: The N-acetyl derivative of cysteine. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acute leukemia: A rapidly progressing cancer of the blood-forming tissue (bone marrow). [NIH]
Acute lymphoblastic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphocytic leukemia. [NIH] Acute lymphocytic leukemia: ALL. A quickly progressing disease in which too many immature white blood cells called lymphoblasts are found in the blood and bone marrow. Also called acute lymphoblastic leukemia. [NIH] Acute myelogenous leukemia: AML. A quickly progressing disease in which too many
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immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute nonlymphocytic leukemia. [NIH] Acute myeloid leukemia: AML. A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myelogenous leukemia or acute nonlymphocytic leukemia. [NIH] Acute nonlymphocytic leukemia: A quickly progressing disease in which too many immature blood-forming cells are found in the blood and bone marrow. Also called acute myeloid leukemia or acute myelogenous leukemia. [NIH] Acute renal: A condition in which the kidneys suddenly stop working. In most cases, kidneys can recover from almost complete loss of function. [NIH] Acute tubular: A severe form of acute renal failure that develops in people with severe illnesses like infections or with low blood pressure. Patients may need dialysis. Kidney function often improves if the underlying disease is successfully treated. [NIH] Acyclovir: Functional analog of the nucleoside guanosine. It acts as an antimetabolite, especially in viruses. It is used as an antiviral agent, especially in herpes infections. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjuvant: A substance which aids another, such as an auxiliary remedy; in immunology, nonspecific stimulator (e.g., BCG vaccine) of the immune response. [EU] Adolescence: The period of life beginning with the appearance of secondary sex 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] Adoptive Transfer: Form of passive immunization where previously sensitized immunologic agents (cells or serum) are transferred to non-immune recipients. When transfer of cells is used as a therapy for the treatment of neoplasms, it is called adoptive immunotherapy (immunotherapy, adoptive). [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal Medulla: The inner part of the adrenal gland; it synthesizes, stores and releases catecholamines. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a
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synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adrenoleukodystrophy: A chromosome X-linked disease. [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] 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] Agar: A complex sulfated polymer of galactose units, extracted from Gelidium cartilagineum, Gracilaria confervoides, and related red algae. It is used as a gel in the preparation of solid culture media for microorganisms, as a bulk laxative, in making emulsions, and as a supporting medium for immunodiffusion and immunoelectrophoresis. [NIH]
Age Groups: Persons classified by age from birth (infant, newborn) to octogenarians and older (aged, 80 and over). [NIH] Aged, 80 and Over: A person 80 years of age and older. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airways: Tubes that carry air into and out of the lungs. [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] 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
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nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. [NIH]
Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allergic Rhinitis: Inflammation of the nasal mucous membrane associated with hay fever; fits may be provoked by substances in the working environment. [NIH] Allo: A female hormone. [NIH] Allogeneic: Taken from different individuals of the same species. [NIH] Allogeneic bone marrow transplantation: A procedure in which a person receives stem cells, the cells from which all blood cells develop, from a compatible, though not genetically identical, donor. [NIH] Allograft: An organ or tissue transplant between two humans. [NIH] Allylamine: Possesses an unusual and selective cytotoxicity for vascular smooth muscle cells in dogs and rats. Useful for experiments dealing with arterial injury, myocardial fibrosis or cardiac decompensation. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha Cell: A type of cell in the pancreas (in areas called the islets of Langerhans). Alpha cells make and release a hormone called glucagon, which raises the level of glucose (sugar) in the blood. [NIH] Alpha Particles: Positively charged particles composed of two protons and two neutrons, i.e., helium nuclei, emitted during disintegration of very heavy isotopes; a beam of alpha particles or an alpha ray has very strong ionizing power, but weak penetrability. [NIH] 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] Aluminum: A metallic element that has the atomic number 13, atomic symbol Al, and atomic weight 26.98. [NIH] Ambulatory Care: Health care services provided to patients on an ambulatory basis, rather than by admission to a hospital or other health care facility. The services may be a part of a hospital, augmenting its inpatient services, or may be provided at a free-standing facility. [NIH]
Amebiasis: Infection with any of various amebae. It is an asymptomatic carrier state in most individuals, but diseases ranging from chronic, mild diarrhea to fulminant dysentery may occur. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amine: An organic compound containing nitrogen; any member of a group of chemical compounds formed from ammonia by replacement of one or more of the hydrogen atoms by organic (hydrocarbon) radicals. The amines are distinguished as primary, secondary, and
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tertiary, according to whether one, two, or three hydrogen atoms are replaced. The amines include allylamine, amylamine, ethylamine, methylamine, phenylamine, propylamine, and many other compounds. [EU] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnestic: Nominal aphasia; a difficulty in finding the right name for an object. [NIH] Amplification: The production of additional copies of a chromosomal DNA sequence, found as either intrachromosomal or extrachromosomal DNA. [NIH] Ampulla: A sac-like enlargement of a canal or duct. [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] Anaemia: A reduction below normal in the number of erythrocytes per cu. mm., in the quantity of haemoglobin, or in the volume of packed red cells per 100 ml. of blood which occurs when the equilibrium between blood loss (through bleeding or destruction) and blood production is disturbed. [EU] Anaerobic: 1. Lacking molecular oxygen. 2. Growing, living, or occurring in the absence of molecular oxygen; pertaining to an anaerobe. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] 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
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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] Anaphylaxis: An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. [NIH] Anaplasia: Loss of structural differentiation and useful function of neoplastic cells. [NIH] Anastomosis: A procedure to connect healthy sections of tubular structures in the body after the diseased portion has been surgically removed. [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] Anergic: 1. Characterized by abnormal inactivity; inactive. 2. Marked by asthenia or lack of energy. 3. Pertaining to anergy. [EU] Anergy: Absence of immune response to particular substances. [NIH] Anesthesia: A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. [NIH] Anesthetics: Agents that are capable of inducing a total or partial loss of sensation, especially tactile sensation and pain. They may act to induce general anesthesia, in which an unconscious state is achieved, or may act locally to induce numbness or lack of sensation at a targeted site. [NIH] Angina: Chest pain that originates in the heart. [NIH] 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] Angioplasty: Endovascular reconstruction of an artery, which may include the removal of atheromatous plaque and/or the endothelial lining as well as simple dilatation. These are procedures performed by catheterization. When reconstruction of an artery is performed surgically, it is called endarterectomy. [NIH] 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] Anionic: Pertaining to or containing an anion. [EU] Anisotropy: A physical property showing different values in relation to the direction in or along which the measurement is made. The physical property may be with regard to thermal or electric conductivity or light refraction. In crystallography, it describes crystals whose index of refraction varies with the direction of the incident light. It is also called acolotropy and colotropy. The opposite of anisotropy is isotropy wherein the same values characterize the object when measured along axes in all directions. [NIH]
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Anomalies: Birth defects; abnormalities. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Antecedent: Existing or occurring before in time or order often with consequential effects. [EU]
Anthracycline: A member of a family of anticancer drugs that are also antibiotics. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]
Antibiotics, Antifungal: Antibiotics inhibiting the growth of or killing fungi and used in the treatment of various fungal diseases. [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] Antibody therapy: Treatment with an antibody, a substance that can directly kill specific tumor cells or stimulate the immune system to kill tumor cells. [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] Antidepressant: A drug used to treat depression. [NIH] Antifungal: Destructive to fungi, or suppressing their reproduction or growth; effective against fungal infections. [EU] Antifungal Agents: Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from fungicides, industrial because they defend against fungi present in human or animal tissues. [NIH] 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] Antigen-presenting cell: APC. A cell that shows antigen on its surface to other cells of the immune system. This is an important part of an immune response. [NIH] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-infective: An agent that so acts. [EU]
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Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antimicrobial: Killing microorganisms, or suppressing their multiplication or growth. [EU] Antimitotic: Inhibiting or preventing mitosis. [EU] Antimycotic: Suppressing the growth of fungi. [EU] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antineoplastic Agents: Substances that inhibit or prevent the proliferation of neoplasms. [NIH]
Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antiproliferative: Counteracting a process of proliferation. [EU] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiseptic: A substance that inhibits the growth and development of microorganisms without necessarily killing them. [EU] Antithrombotic: Preventing or interfering with the formation of thrombi; an agent that so acts. [EU] Antithymocyte globulin: A protein used to reduce the risk of or to treat graft-versus-host disease. [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] Aplasia: Lack of development of an organ or tissue, or of the cellular products from an organ or tissue. [EU] Aplastic anaemia: A form of anaemia generally unresponsive to specific antianaemia therapy, often accompanied by granulocytopenia and thrombocytopenia, in which the bone marrow may not necessarily be acellular or hypoplastic but fails to produce adequate numbers of peripheral blood elements. The term actually is all-inclusive and most probably encompasses several clinical syndromes. [EU] Aplastic anemia: A condition in which the bone marrow is unable to produce blood cells. [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] Aponeurosis: Tendinous expansion consisting of a fibrous or membranous sheath which serves as a fascia to enclose or bind a group of muscles. [NIH]
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Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Applicability: A list of the commodities to which the candidate method can be applied as presented or with minor modifications. [NIH] Aqueous: Having to do with water. [NIH] 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] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arteriolar: Pertaining to or resembling arterioles. [EU] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Arteriosus: Circle composed of anastomosing arteries derived from two long posterior ciliary and seven anterior ciliary arteries, located in the ciliary body about the root of the iris. [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] Aspiration: The act of inhaling. [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Asthenia: Clinical sign or symptom manifested as debility, or lack or loss of strength and energy. [NIH] Atopic: Pertaining to an atopen or to atopy; allergic. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH]
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Attenuated: Strain with weakened or reduced virulence. [NIH] Auditory: Pertaining to the sense of hearing. [EU] 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] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autologous: Taken from an individual's own tissues, cells, or DNA. [NIH] Autologous bone marrow transplantation: A procedure in which bone marrow is removed from a person, stored, and then given back to the person after intensive treatment. [NIH] Autoradiography: A process in which radioactive material within an object produces an image when it is in close proximity to a radiation sensitive emulsion. [NIH] Avian: A plasmodial infection in birds. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Azithromycin: A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriostatic: 1. Inhibiting the growth or multiplication of bacteria. 2. An agent that inhibits the growth or multiplication of bacteria. [EU] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [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] Basophil: A type of white blood cell. Basophils are granulocytes. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]
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Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Acids: Acids made by the liver that work with bile to break down fats. [NIH] Bile Acids and Salts: Steroid acids and salts. The primary bile acids are derived from cholesterol in the liver and usually conjugated with glycine or taurine. The secondary bile acids are further modified by bacteria in the intestine. They play an important role in the digestion and absorption of fat. They have also been used pharmacologically, especially in the treatment of gallstones. [NIH] Bile duct: A tube through which bile passes in and out of the liver. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Binding agent: A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders. [NIH] Binding Sites: The reactive parts of a macromolecule that directly participate in its specific combination with another molecule. [NIH] Bioassay: Determination of the relative effective strength of a substance (as a vitamin, hormone, or drug) by comparing its effect on a test organism with that of a standard preparation. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Bioavailable: The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Bioequivalent: Having the same strength and similar bioavailability in the same dosage form as another specimen of a given drug substance. [EU] Biological Assay: A method of measuring the effects of a biologically active substance using an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc. [NIH] Biological response modifier: BRM. A substance that stimulates the body's response to infection and disease. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biological Transport: The movement of materials (including biochemical substances and drugs) across cell membranes and epithelial layers, usually by passive diffusion. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biomolecular: A scientific field at the interface between advanced computing and biotechnology. [NIH]
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Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biopsy specimen: Tissue removed from the body and examined under a microscope to determine whether disease is present. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] 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] Blast Crisis: Rapid increase in the proportion of blast cells in the blood and bone marrow. [NIH]
Blast phase: The phase of chronic myelogenous leukemia in which the number of immature, abnormal white blood cells in the bone marrow and blood is extremely high. Also called blast crisis. [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] Blasts: Immature blood cells. [NIH] Blister: Visible accumulations of fluid within or beneath the epidermis. [NIH] Blister pack: A package consisting of a clear plastic overlay affixed to a cardboard backing for protecting and displaying a product. [EU] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood Preservation: The process by which blood or its components are kept viable outside of the organism from which they are derived (i.e., kept from decay by means of a chemical agent, cooling, or a fluid substitute that mimics the natural state within the organism). [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH]
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Blood transfusion: The administration of blood or blood products into a blood vessel. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Blood-Brain Barrier: Specialized non-fenestrated tightly-joined endothelial cells (tight junctions) that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. [NIH] Blot: To transfer DNA, RNA, or proteins to an immobilizing matrix such as nitrocellulose. [NIH]
Body Fluids: Liquid components of living organisms. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone Remodeling: The continuous turnover of bone matrix and mineral that involves first, an increase in resorption (osteoclastic activity) and later, reactive bone formation (osteoblastic activity). The process of bone remodeling takes place in the adult skeleton at discrete foci. The process ensures the mechanical integrity of the skeleton throughout life and plays an important role in calcium homeostasis. An imbalance in the regulation of bone remodeling's two contrasting events, bone resorption and bone formation, results in many of the metabolic bone diseases, such as osteoporosis. [NIH] Bone Resorption: Bone loss due to osteoclastic activity. [NIH] Boron: A trace element with the atomic symbol B, atomic number 5, and atomic weight 10.81. Boron-10, an isotope of boron, is used as a neutron absorber in boron neutron capture therapy. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Brachytherapy: A collective term for interstitial, intracavity, and surface radiotherapy. It uses small sealed or partly-sealed sources that may be placed on or near the body surface or within a natural body cavity or implanted directly into the tissues. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Breast reconstruction: Surgery to rebuild a breast's shape after a mastectomy. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU]
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Bromocriptine: A semisynthetic ergot alkaloid that is a dopamine D2 agonist. It suppresses prolactin secretion and is used to treat amenorrhea, galactorrhea, and female infertility, and has been proposed for Parkinson disease. [NIH] Bronchi: The larger air passages of the lungs arising from the terminal bifurcation of the trachea. [NIH] Bronchial: Pertaining to one or more bronchi. [EU] Bronchioles: The tiny branches of air tubes in the lungs. [NIH] Bronchiolitis: Inflammation of the bronchioles. [NIH] Bronchiolitis Obliterans: Inflammation of the bronchioles with obstruction by fibrous granulation tissue or bronchial exudate. It may follow inhalation of irritating gases or foreign bodies and it complicates pneumonia. [NIH] Bronchitis: Inflammation (swelling and reddening) of the bronchi. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Budesonide: A glucocorticoid used in the management of asthma, the treatment of various skin disorders, and allergic rhinitis. [NIH] Bullous: Pertaining to or characterized by bullae. [EU] Busulfan: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH]
Bypass: A surgical procedure in which the doctor creates a new pathway for the flow of body fluids. [NIH] Caffeine: A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcineurin: A calcium- and calmodulin-binding protein present in highest concentrations in the central nervous system. Calcineurin is composed of two subunits. A catalytic subunit, calcineurin A, and a regulatory subunit, calcineurin B, with molecular weights of about 60 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] Calcinosis: Pathologic deposition of calcium salts in tissues. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with
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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] Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Calibration: Determination, by measurement or comparison with a standard, of the correct value of each scale reading on a meter or other measuring instrument; or determination of the settings of a control device that correspond to particular values of voltage, current, frequency, or other output. [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] Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA topoisomerase. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity. [NIH] Candidiasis: Infection with a fungus of the genus Candida. It is usually a superficial infection of the moist cutaneous areas of the body, and is generally caused by C. albicans; it most commonly involves the skin (dermatocandidiasis), oral mucous membranes (thrush, def. 1), respiratory tract (bronchocandidiasis), and vagina (vaginitis). Rarely there is a systemic infection or endocarditis. Called also moniliasis, candidosis, oidiomycosis, and formerly blastodendriosis. [EU] Candidosis: An infection caused by an opportunistic yeasts that tends to proliferate and become pathologic when the environment is favorable and the host resistance is weakened. [NIH]
Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capillary Fragility: The lack of resistance, or susceptibility, of capillaries to damage or disruption under conditions of increased stress. [NIH] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carboplatin: An organoplatinum compound that possesses antineoplastic activity. [NIH] Carcinogen: Any substance that causes cancer. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]
Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume
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(volume per beat). [NIH] Cardiac Surgical Procedures: Surgery performed on the heart. [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardioselective: Having greater activity on heart tissue than on other tissue. [EU] Cardiovascular: Having to do with the heart and blood vessels. [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] Caspase: Enzyme released by the cell at a crucial stage in apoptosis in order to shred all cellular proteins. [NIH] Castor Oil: Oil obtained from seeds of Ricinus communis that is used as a cathartic and as a plasticizer. [NIH] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catechin: Extracted from Uncaria gambier, Acacia catechu and other plants; it stabilizes collagen and is therefore used in tanning and dyeing; it prevents capillary fragility and abnormal permeability, but was formerly used as an antidiarrheal. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheter: A flexible tube used to deliver fluids into or withdraw fluids from the body. [NIH] Catheterization: Use or insertion of a tubular device into a duct, blood vessel, hollow organ, or body cavity for injecting or withdrawing fluids for diagnostic or therapeutic purposes. It differs from intubation in that the tube here is used to restore or maintain patency in obstructions. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] 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 Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing
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specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [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] Cell Transplantation: Transference of cells within an individual, between individuals of the same species, or between individuals of different species. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centrifugation: A method of separating organelles or large molecules that relies upon differential sedimentation through a preformed density gradient under the influence of a gravitational field generated in a centrifuge. [NIH] Ceramide: A type of fat produced in the body. It may cause some types of cells to die, and is being studied in cancer treatment. [NIH] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] 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] Chemokines: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C (chemokines, C), CC (chemokines, CC), and CXC (chemokines, CXC), according to variations in a shared cysteine motif. [NIH] Chemotactic Factors: Chemical substances that attract or repel cells or organisms. The concept denotes especially those factors released as a result of tissue injury, invasion, or immunologic activity, that attract leukocytes, macrophages, or other cells to the site of infection or insult. [NIH] Chemotherapeutic agent: A drug used to treat cancer. [NIH] Chemotherapy: Treatment with anticancer drugs. [NIH]
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Chlorambucil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Chlorophyll: Porphyrin derivatives containing magnesium that act to convert light energy in photosynthetic organisms. [NIH] Cholera: An acute diarrheal disease endemic in India and Southeast Asia whose causative agent is vibrio cholerae. This condition can lead to severe dehydration in a matter of hours unless quickly treated. [NIH] Cholestasis: Impairment of biliary flow at any level from the hepatocyte to Vater's ampulla. [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] Choline: A basic constituent of lecithin that is found in many plants and animal organs. It is important as a precursor of acetylcholine, as a methyl donor in various metabolic processes, and in lipid metabolism. [NIH] 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] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic granulocytic leukemia: A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myelogenous leukemia or chronic myeloid leukemia. [NIH] Chronic myelogenous leukemia: CML. A slowly progressing disease in which too many white blood cells are made in the bone marrow. Also called chronic myeloid leukemia or chronic granulocytic leukemia. [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] Ciprofloxacin: A carboxyfluoroquinoline antimicrobial agent that is effective against a wide range of microorganisms. It has been successfully and safely used in the treatment of resistant respiratory, skin, bone, joint, gastrointestinal, urinary, and genital infections. [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] Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with
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cellular arrest in the G2 phase of the cell cycle. [NIH] Citalopram: A selective neuronal serotonin reuptake inhibitor and a clinically effective antidepressant with tolerable side effects. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia (TD) in preference to tricyclic antidepressants, which aggravate this condition. [NIH]
Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]
Clinical Protocols: Precise and detailed plans for the study of a medical or biomedical problem and/or plans for a regimen of therapy. [NIH] Clinical 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] Clotrimazole: An imidazole derivative with a broad spectrum of antimycotic activity. It inhibits biosynthesis of the sterol ergostol, an important component of fungal cell membranes. Its action leads to increased membrane permeability and apparent disruption of enzyme systems bound to the membrane. [NIH] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]
Coculture: The culturing of normal cells or tissues with infected or latently infected cells or tissues of the same kind (From Dorland, 28th ed, entry for cocultivation). It also includes culturing of normal cells or tissues with other normal cells or tissues. [NIH] Codeine: An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [NIH] Coenzyme: An organic nonprotein molecule, frequently a phosphorylated derivative of a water-soluble vitamin, that binds with the protein molecule (apoenzyme) to form the active enzyme (holoenzyme). [EU] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (periodic disease). [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] 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] Colon: The long, coiled, tubelike organ that removes water from digested food. The
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remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Combinatorial: A cut-and-paste process that churns out thousands of potentially valuable compounds at once. [NIH] Common Bile Duct: The largest biliary duct. It is formed by the junction of the cystic duct and the hepatic duct. [NIH] Communis: Common tendon of the rectus group of muscles that surrounds the optic foramen and a portion of the superior orbital fissure, to the anterior margin of which it is attached at the spina recti lateralis. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Complementary and alternative medicine: CAM. Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices are not considered standard medical approaches. CAM includes dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complementary medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used to enhance or complement the standard treatments. Complementary medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Complete remission: The disappearance of all signs of cancer. Also called a complete
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response. [NIH] Complete response: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. [NIH] Compliance: Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. [NIH] Compulsions: In psychology, an irresistible urge, sometimes amounting to obsession to perform a particular act which usually is carried out against the performer's will or better judgment. [NIH] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Concomitant: Accompanying; accessory; joined with another. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Conjugated: Acting or operating as if joined; simultaneous. [EU] Conjugation: 1. The act of joining together or the state of being conjugated. 2. A sexual process seen in bacteria, ciliate protozoa, and certain fungi in which nuclear material is exchanged during the temporary fusion of two cells (conjugants). In bacterial genetics a form of sexual reproduction in which a donor bacterium (male) contributes some, or all, of its DNA (in the form of a replicated set) to a recipient (female) which then incorporates differing genetic information into its own chromosome by recombination and passes the recombined set on to its progeny by replication. In ciliate protozoa, two conjugants of separate mating types exchange micronuclear material and then separate, each now being a fertilized cell. In certain fungi, the process involves fusion of two gametes, resulting in union of their nuclei and formation of a zygote. 3. In chemistry, the joining together of two compounds to produce another compound, such as the combination of a toxic product with some substance in the body to form a detoxified product, which is then eliminated. [EU] Conjunctiva: The mucous membrane that lines the inner surface of the eyelids and the anterior part of the sclera. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] 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] Contracture: A condition of fixed high resistance to passive stretch of a muscle, resulting
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from fibrosis of the tissues supporting the muscles or the joints, or from disorders of the muscle fibres. [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] Contralateral: Having to do with the opposite side of the body. [NIH] Contrast Media: Substances used in radiography that allow visualization of certain tissues. [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 study: An experiment or clinical trial that includes a comparison (control) group. [NIH]
Contusion: A bruise; an injury of a part without a break in the skin. [EU] Conus: A large, circular, white patch around the optic disk due to the exposing of the sclera as a result of degenerative change or congenital abnormality in the choroid and retina. [NIH] Convulsion: A violent involuntary contraction or series of contractions of the voluntary muscles. [EU] Cooperative group: A group of physicians, hospitals, or both formed to treat a large number of persons in the same way so that new treatment can be evaluated quickly. Clinical trials of new cancer treatments often require many more people than a single physician or hospital can care for. [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Corn Oil: Oil from corn or corn plant. [NIH] Cornea: The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary
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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] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Cortical: Pertaining to or of the nature of a cortex or bark. [EU] 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] Cortisone: A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Creatinine: A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function. [NIH] Crossing-over: The exchange of corresponding segments between chromatids of homologous chromosomes during meiosia, forming a chiasma. [NIH] Croton Oil: Viscous, nauseating oil obtained from the shrub Croton tiglium (Euphorbaceae). It is a vesicant and skin irritant used as pharmacologic standard for skin inflammation and allergy and causes skin cancer. It was formerly used as an emetic and cathartic with frequent mortality. [NIH] Cryptococcosis: Infection with a fungus of the species Cryptococcus neoformans. [NIH] Cryptosporidiosis: Parasitic intestinal infection with severe diarrhea caused by a protozoan, Cryptosporidium. It occurs in both animals and humans. [NIH] Culture Media: Any liquid or solid preparation made specifically for the growth, storage, or transport of microorganisms or other types of cells. The variety of media that exist allow for the culturing of specific microorganisms and cell types, such as differential media, selective media, test media, and defined media. Solid media consist of liquid media that have been solidified with an agent such as agar or gelatin. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Curcumin: A dye obtained from tumeric, the powdered root of Curcuma longa Linn. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. [NIH] Cutaneous: Having to do with the skin. [NIH] 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]
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Cyclin: Molecule that regulates the cell cycle. [NIH] Cyclin-Dependent Kinases: Protein kinases that control cell cycle progression in all eukaryotes and require physical association with cyclins to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events. [NIH]
Cyclodextrins: A homologous group of cyclic glucans consisting of alpha-1,4 bound glucose units obtained by the action of cyclodextrin glucanotransferase on starch or similar substrates. The enzyme is produced by certain species of Bacillus. Cyclodextrins form inclusion complexes with a wide variety of substances. [NIH] Cyclophilins: A family of peptidyl-prolyl cis-trans isomerases that bind to cyclosporins and regulate the immune system. EC 5.2.1.- [NIH] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cycloserine: Antibiotic substance produced by Streptomyces garyphalus. It may be used in the treatment of resistant tuberculosis as part of a multi-drug regimen. It has also been used in urinary tract infections. [NIH] Cyclosporins: A group of closely related cyclic undecapeptides from the fungi Trichoderma polysporum and Cylindocarpon lucidum. They have some antineoplastic and antifungal action and significant immunosuppressive effects. Cyclosporins have been proposed as adjuvants in tissue and organ transplantation to suppress graft rejection. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystitis: Inflammation of the urinary bladder. [EU] Cytarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [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] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytomegalovirus: A genus of the family Herpesviridae, subfamily Betaherpesvirinae, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS. [NIH] Cytomegalovirus Infections: Infection with Cytomegalovirus, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary
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glands are the most common site in children, as are the lungs in adults. [NIH] Cytopenia: A reduction in the number of blood cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytostatic: An agent that suppresses cell growth and multiplication. [EU] Cytotoxic: Cell-killing. [NIH] Cytotoxicity: Quality of being capable of producing a specific toxic action upon cells of special organs. [NIH] Cytotoxins: Substances elaborated by microorganisms, plants or animals that are specifically toxic to individual cells; they may be involved in immunity or may be contained in venoms. [NIH]
Daclizumab: A monoclonal antibody that is being studied for treatment of adult T-cell leukemia. Also called dacliximab. Monoclonal antibodies are laboratory-produced substances that can locate and bind to cancer cells. [NIH] Daunorubicin: Very toxic anthracycline aminoglycoside antibiotic isolated from Streptomyces peucetius and others, used in treatment of leukemias and other neoplasms. [NIH]
De novo: In cancer, the first occurrence of cancer in the body. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Defense Mechanisms: Unconscious process used by an individual or a group of individuals in order to cope with impulses, feelings or ideas which are not acceptable at their conscious level; various types include reaction formation, projection and self reversal. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Delivery of Health Care: The concept concerned with all aspects of providing and distributing health services to a patient population. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Demethylation: Process that releases substantial amounts of carbon dioxide in the liver. [NIH]
Dendrites: Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Dendritic cell: A special type of antigen-presenting cell (APC) that activates T lymphocytes. [NIH]
Dentures: An appliance used as an artificial or prosthetic replacement for missing teeth and adjacent tissues. It does not include crowns, dental abutments, nor artificial teeth. [NIH]
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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] Dermatitis: Any inflammation of the skin. [NIH] Dermatology: A medical specialty concerned with the skin, its structure, functions, diseases, and treatment. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Detoxification: Treatment designed to free an addict from his drug habit. [EU] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Dexamethasone: (11 beta,16 alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4diene-3,20-dione. An anti-inflammatory glucocorticoid used either in the free alcohol or esterified form in treatment of conditions that respond generally to cortisone. [NIH] Dexterity: Ability to move the hands easily and skillfully. [NIH] Dextromethorphan: The d-isomer of the codeine analog of levorphanol. Dextromethorphan shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is a NMDA receptor antagonist (receptors, N-methyl-D-aspartate) and acts as a non-competitive channel blocker. It is used widely as an antitussive agent, and is also used to study the involvement of glutamate receptors in neurotoxicity. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU] Diathesis: A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the person more than usually susceptible to certain diseases. [EU] Dietitian: An expert in nutrition who helps people plan what and how much food to eat. [NIH]
Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive tract: The organs through which food passes when food is eaten. These organs are the mouth, esophagus, stomach, small and large intestines, and rectum. [NIH] Dihydroxy: AMPA/Kainate antagonist. [NIH] Dihydroxyacetone: A ketotriose compound. Its addition to blood preservation solutions results in better maintenance of 2,3-diphosphoglycerate levels during storage. It is readily phosphorylated to dihydroxyacetone phosphate by triokinase in erythrocytes. In combination with naphthoquinones it acts as a sunscreening agent. [NIH]
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Dihydroxyacetone Phosphate: An important intermediate in lipid biosynthesis and in glycolysis. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Diltiazem: A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of the calcium ion in membrane functions. It is also teratogenic. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Dimethyl: A volatile metabolite of the amino acid methionine. [NIH] Dipeptides: Peptides composed of two amino acid units. [NIH] Diploid: Having two sets of chromosomes. [NIH] Dipyridamole: A drug that prevents blood cell clumping and enhances the effectiveness of fluorouracil and other chemotherapeutic agents. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Disease-Free Survival: Period after successful treatment in which there is no appearance of the symptoms or effects of the disease. [NIH] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [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] Docetaxel: An anticancer drug that belongs to the family of drugs called mitotic inhibitors. [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] 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]
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Dorsum: A plate of bone which forms the posterior boundary of the sella turcica. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. [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] Doxazosin: A selective alpha-1-adrenergic blocker that lowers serum cholesterol. It is also effective in the treatment of hypertension. [NIH] Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetics. It is a hydroxy derivative of daunorubicin and is used in treatment of both leukemia and solid tumors. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Carriers: Substances that facilitate time-controlled delivery, organ-specific targeting, protection, prolonged in vivo function, and decrease of toxicity of drugs. Liposomes, albumin microspheres, soluble synthetic polymers, DNA complexes, protein-drug conjugates, and carrier erythrocytes among others have been employed as biodegradable drug carriers. [NIH] Drug Combinations: Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. It is differentiated from combination drug therapy in which two or more drugs are administered separately for a combined effect. [NIH] Drug Design: The molecular designing of drugs for specific purposes (such as DNAbinding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis. [NIH] Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug. [NIH] Drug Monitoring: The process of observing, recording, or detecting the effects of a chemical substance administered to an individual therapeutically or diagnostically. [NIH] Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from drug tolerance which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated
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dose and no-observed-adverse-effect level. [NIH] Drug Toxicity: Manifestations of the adverse effects of drugs administered therapeutically or in the course of diagnostic techniques. It does not include accidental or intentional poisoning for which specific headings are available. [NIH] Dry Eye Syndrome: A common condition that occurs when the eyes do not produce enough tears to keep the eye moist and comfortable. Common symptoms of dry eye include pain, stinging, burning, scratchiness, and intermittent blurring of vision. [NIH] Duct: A tube through which body fluids pass. [NIH] Duodenum: The first part of the small intestine. [NIH] Dura mater: The outermost, toughest, and most fibrous of the three membranes (meninges) covering the brain and spinal cord; called also pachymeninx. [EU] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] Dysmenorrhea: Painful menstruation. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Echinomycin: A toxic polypeptide quinoxaline antibiotic isolated from Streptomyces echinatus that binds to DNA and inhibits RNA synthesis. It has antitumor and antibacterial activity. [NIH] Eczema: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents (Dorland, 27th ed). [NIH] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Efferent: Nerve fibers which conduct impulses from the central nervous system to muscles and glands. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in
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all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] 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] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emollient: Softening or soothing; called also malactic. [EU] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Enalapril: An angiotensin-converting enzyme inhibitor that is used to treat hypertension. [NIH]
Encapsulated: Confined to a specific, localized area and surrounded by a thin layer of tissue. [NIH]
Encephalitis: Inflammation of the brain due to infection, autoimmune processes, toxins, and other conditions. Viral infections (see encephalitis, viral) are a relatively frequent cause of this condition. [NIH] Encephalomyelitis: A general term indicating inflammation of the brain and spinal cord, often used to indicate an infectious process, but also applicable to a variety of autoimmune and toxic-metabolic conditions. There is significant overlap regarding the usage of this term and encephalitis in the literature. [NIH] Endarterectomy: Surgical excision, performed under general anesthesia, of the atheromatous tunica intima of an artery. When reconstruction of an artery is performed as an endovascular procedure through a catheter, it is called atherectomy. [NIH] Endemic: Present or usually prevalent in a population or geographical area at all times; said of a disease or agent. Called also endemial. [EU] Endocarditis: Exudative and proliferative inflammatory alterations of the endocardium, characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary disorder or as a complication of or in association with another disease. [EU] Endogenous: Produced inside an organism or cell. The opposite is external (exogenous) production. [NIH] Endoscopic: A technique where a lateral-view endoscope is passed orally to the duodenum for visualization of the ampulla of Vater. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelins: 21-Amino-acid peptides produced by vascular endothelial cells and
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functioning as potent vasoconstrictors. The endothelin family consists of three members, endothelin-1, endothelin-2, and endothelin-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH] Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Enhancer: Transcriptional element in the virus genome. [NIH] 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] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Ephedrine: An alpha- and beta-adrenergic agonist that may also enhance release of norepinephrine. It has been used in the treatment of several disorders including asthma, heart failure, rhinitis, and urinary incontinence, and for its central nervous system stimulatory effects in the treatment of narcolepsy and depression. It has become less extensively used with the advent of more selective agonists. [NIH] Epidermal: Pertaining to or resembling epidermis. Called also epidermic or epidermoid. [EU] 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] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic
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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] Epitope: A molecule or portion of a molecule capable of binding to the combining site of an antibody. For every given antigenic determinant, the body can construct a variety of antibody-combining sites, some of which fit almost perfectly, and others which barely fit. [NIH]
Ergot: Cataract due to ergot poisoning caused by eating of rye cereals contaminated by a fungus. [NIH] Erythrocyte Deformability: Ability of erythrocytes to change shape as they pass through narrow spaces, such as the microvasculature. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythromycin: A bacteriostatic antibiotic substance produced by Streptomyces erythreus. Erythromycin A is considered its major active component. In sensitive organisms, it inhibits protein synthesis by binding to 50S ribosomal subunits. This binding process inhibits peptidyl transferase activity and interferes with translocation of amino acids during translation and assembly of proteins. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]
Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estrogen: One of the two female sex hormones. [NIH] Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethanolamine: A viscous, hygroscopic amino alcohol with an ammoniacal odor. It is widely distributed in biological tissue and is a component of lecithin. It is used as a surfactant, fluorimetric reagent, and to remove CO2 and H2S from natural gas and other gases. [NIH] Ether: One of a class of organic compounds in which any two organic radicals are attached directly to a single oxygen atom. [NIH] Ethylene Glycol: A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins. [NIH]
Etoposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase
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of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. [NIH] Evaluable patients: Patients whose response to a treatment can be measured because enough information has been collected. [NIH] Evoke: The electric response recorded from the cerebral cortex after stimulation of a peripheral sense organ. [NIH] Excipient: Any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; a vehicle. [EU] Excitation: An act of irritation or stimulation or of responding to a stimulus; the addition of energy, as the excitation of a molecule by absorption of photons. [EU] Excrete: To get rid of waste from the body. [NIH] Exfoliation: A falling off in scales or layers. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Expiration: The act of breathing out, or expelling air from the lungs. [EU] Extensor: A muscle whose contraction tends to straighten a limb; the antagonist of a flexor. [NIH]
External-beam radiation: Radiation therapy that uses a machine to aim high-energy rays at the cancer. Also called external radiation. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Extrapyramidal: Outside of the pyramidal tracts. [EU] Exudate: Material, such as fluid, cells, or cellular debris, which has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation. An exudate, in contrast to a transudate, is characterized by a high content of protein, cells, or solid materials derived from cells. [EU] Facial: Of or pertaining to the face. [EU] Facial Paralysis: Severe or complete loss of facial muscle motor function. This condition may result from central or peripheral lesions. Damage to CNS motor pathways from the cerebral cortex to the facial nuclei in the pons leads to facial weakness that generally spares the forehead muscles. Facial nerve diseases generally results in generalized hemifacial weakness. Neuromuscular junction diseases and muscular diseases may also cause facial paralysis or paresis. [NIH] 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,
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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] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Femoral: Pertaining to the femur, or to the thigh. [EU] Femur: The longest and largest bone of the skeleton, it is situated between the hip and the knee. [NIH] Fentanyl: A narcotic opioid drug that is used in the treatment of pain. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Filtration: The passage of a liquid through a filter, accomplished by gravity, pressure, or vacuum (suction). [EU] Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Flavopiridol: Belongs to the family of anticancer drugs called flavinols. [NIH] Flexor: Muscles which flex a joint. [NIH] Flow Cytometry: Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. [NIH] Flucytosine: A fluorinated cytosine analog that is used as an antifungal agent. [NIH] Fludarabine: An anticancer drug that belongs to the family of drugs called antimetabolites. [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] Fluorescence Polarization: Measurement of the polarization of fluorescent light from solutions or microscopic specimens. It is used to provide information concerning molecular size, shape, and conformation, molecular anisotropy, electronic energy transfer, molecular interaction, including dye and coenzyme binding, and the antigen-antibody reaction. [NIH] Fluorescence Polarization Immunoassay: Fluoroimmunoassay where detection of the hapten-antibody reaction is based on measurement of the increased polarization of fluorescence-labeled hapten when it is combined with antibody. The assay is very useful for the measurement of small haptenic antigens such as drugs at low concentrations. [NIH] Fluorescent Dyes: Dyes that emit light when exposed to light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances
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that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. They are used as markers in biochemistry and immunology. [NIH] Fluorouracil: A pyrimidine analog that acts as an antineoplastic antimetabolite and also has immunosuppressant. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. [NIH] Fluoxetine: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. [NIH] Fluvoxamine: A selective serotonin reuptake inhibitor. It is effective in the treatment of depression, obsessive-compulsive disorders, anxiety, panic disorders, and alcohol amnestic disorders. [NIH] Folate: A B-complex vitamin that is being studied as a cancer prevention agent. Also called folic acid. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Folic Acid: N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-Lglutamic acid. A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Free Radicals: Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. [NIH] 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] Fungicides, Industrial: Chemicals that kill or inhibit the growth of fungi in agricultural applications, on wood, plastics, or other materials, in swimming pools, etc. [NIH] Fungus: A general term used to denote a group of eukaryotic protists, including mushrooms, yeasts, rusts, moulds, smuts, etc., which are characterized by the absence of chlorophyll and by the presence of a rigid cell wall composed of chitin, mannans, and sometimes cellulose. They are usually of simple morphological form or show some reversible cellular specialization, such as the formation of pseudoparenchymatous tissue in the fruiting body of a mushroom. The dimorphic fungi grow, according to environmental conditions, as moulds or yeasts. [EU] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallopamil: Coronary vasodilator that is an analog of iproveratril (verapamil) with one more methoxy group on the benzene ring. [NIH] Gamma Rays: Very powerful and penetrating, high-energy electromagnetic radiation of shorter wavelength than that of x-rays. They are emitted by a decaying nucleus, usually between 0.01 and 10 MeV. They are also called nuclear x-rays. [NIH] Gamma-interferon: Interferon produced by T-lymphocytes in response to various mitogens and antigens. Gamma interferon appears to have potent antineoplastic, immunoregulatory and antiviral activity. [NIH]
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Ganciclovir: Acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Ganglion: 1. A knot, or knotlike mass. 2. A general term for a group of nerve cell bodies located outside the central nervous system; occasionally applied to certain nuclear groups within the brain or spinal cord, e.g. basal ganglia. 3. A benign cystic tumour occurring on a aponeurosis or tendon, as in the wrist or dorsum of the foot; it consists of a thin fibrous capsule enclosing a clear mucinous fluid. [EU] Gangrenous: A circumscribed, deep-seated, suppurative inflammation of the subcutaneous tissue of the eyelid discharging pus from several points. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gas exchange: Primary function of the lungs; transfer of oxygen from inhaled air into the blood and of carbon dioxide from the blood into the lungs. [NIH] Gastrectomy: An operation to remove all or part of the stomach. [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] Gene Expression Profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH]
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Genital: Pertaining to the genitalia. [EU] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]
Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Giardiasis: An infection of the small intestine caused by the flagellated protozoan Giardia lamblia. It is spread via contaminated food and water and by direct person-to-person contact. [NIH] Gingival Hyperplasia: A pathological increase in the depth of the gingival crevice surrounding a tooth at the gum margin. [NIH] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] 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] Globus Pallidus: The representation of the phylogenetically oldest part of the corpus striatum called the paleostriatum. It forms the smaller, more medial part of the lentiform nucleus. [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] Glucans: Polysaccharides composed of repeating glucose units. They can consist of branched or unbranched chains in any linkages. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]
Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration
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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] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]
Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]
Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycolysis: The pathway by which glucose is catabolized into two molecules of pyruvic acid with the generation of ATP. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Gonadal: Pertaining to a gonad. [EU] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] 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 Rejection: An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient. [NIH] Graft Survival: The survival of a graft in a host, the factors responsible for the survival and the changes occurring within the graft during growth in the host. [NIH] Graft vs Host Reaction: An immunological attack mounted by a graft against the host because of tissue incompatibility when immunologically competent cells are transplanted to an immunologically incompetent host; the resulting clinical picture is that of graft vs host disease. [NIH]
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Grafting: The operation of transfer of tissue from one site to another. [NIH] Graft-versus-host disease: GVHD. A reaction of donated bone marrow or peripheral stem cells against a person's tissue. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Granulation Tissue: A vascular connective tissue formed on the surface of a healing wound, ulcer, or inflamed tissue. It consists of new capillaries and an infiltrate containing lymphoid cells, macrophages, and plasma cells. [NIH] Granulocyte: A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes. [NIH] Granulocytopenia: A deficiency in the number of granulocytes, a type of white blood cell. [NIH]
Grasses: A large family, Gramineae, of narrow-leaved herbaceous monocots. Many grasses produce highly allergenic pollens and are hosts to cattle parasites and toxic fungi. [NIH] Gravis: Eruption of watery blisters on the skin among those handling animals and animal products. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanine: One of the four DNA bases. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Haematological: Relating to haematology, that is that branch of medical science which treats of the morphology of the blood and blood-forming tissues. [EU] Haematology: The science of the blood, its nature, functions, and diseases. [NIH] Hair Cells: Mechanoreceptors located in the organ of Corti that are sensitive to auditory stimuli and in the vestibular apparatus that are sensitive to movement of the head. In each case the accessory sensory structures are arranged so that appropriate stimuli cause movement of the hair-like projections (stereocilia and kinocilia) which relay the information centrally in the nervous system. [NIH] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Haploid: An organism with one basic chromosome set, symbolized by n; the normal condition of gametes in diploids. [NIH] Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the major histocompatibility complex. [NIH] Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. [NIH] Hay Fever: A seasonal variety of allergic rhinitis, marked by acute conjunctivitis with lacrimation and itching, regarded as an allergic condition triggered by specific allergens. [NIH]
Health Care Costs: The actual costs of providing services related to the delivery of health
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care, including the costs of procedures, therapies, and medications. It is differentiated from health expenditures, which refers to the amount of money paid for the services, and from fees, which refers to the amount charged, regardless of cost. [NIH] Health Expenditures: The amounts spent by individuals, groups, nations, or private or public organizations for total health care and/or its various components. These amounts may or may not be equivalent to the actual costs (health care costs) and may or may not be shared among the patient, insurers, and/or employers. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heart Transplantation: The transference of a heart from one human or animal to another. [NIH]
Hematologic malignancies: Cancers of the blood or bone marrow, including leukemia and lymphoma. Also called hematologic cancers. [NIH] Hematopoiesis: The development and formation of various types of blood cells. [NIH] Hematopoietic growth factors: A group of proteins that cause blood cells to grow and mature. [NIH] Hematopoietic Stem Cell Transplantation: The transference of stem cells from one animal or human to another (allogeneic), or within the same individual (autologous). The source for the stem cells may be the bone marrow or peripheral blood. Stem cell transplantation has been used as an alternative to autologous bone marrow transplantation in the treatment of a variety of neoplasms. [NIH] Hematopoietic Stem Cells: Progenitor cells from which all blood cells derive. [NIH] Hematuria: Presence of blood in the urine. [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] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemolytic: A disease that affects the blood and blood vessels. It destroys red blood cells, cells that cause the blood to clot, and the lining of blood vessels. HUS is often caused by the Escherichia coli bacterium in contaminated food. People with HUS may develop acute renal failure. [NIH] Hemolytic-Uremic Syndrome: Syndrome of hemolytic anemia, thrombocytopenia, and acute renal failure, with pathological finding of thrombotic microangiopathy in kidney and renal cortical necrosis. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH]
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Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]
Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [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] Herpes: Any inflammatory skin disease caused by a herpesvirus and characterized by the formation of clusters of small vesicles. When used alone, the term may refer to herpes simplex or to herpes zoster. [EU] Herpes Zoster: Acute vesicular inflammation. [NIH] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]
High-density lipoproteins: Lipoproteins that contain a small amount of cholesterol and carry cholesterol away from body cells and tissues to the liver for excretion from the body. Low-level HDL increases the risk of heart disease, so the higher the HDL level, the better. The HDL component normally contains 20 to 30 percent of total cholesterol, and HDL levels are inversely correlated with coronary heart disease risk. [NIH] Hirsutism: Excess hair in females and children with an adult male pattern of distribution. The concept does not include hypertrichosis, which is localized or generalized excess hair. [NIH]
Hirudin: The active principle in the buccal gland secretion of leeches. It acts as an antithrombin and as an antithrombotic agent. [NIH] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histidine: An essential amino acid important in a number of metabolic processes. It is required for the production of histamine. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH]
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Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormonal: Pertaining to or of the nature of a hormone. [EU] 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] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [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] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [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] 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 Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. [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] Hydrophilic: Readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water. [EU] 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] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH]
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Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] 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] Hyperthermia: A type of treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs. [NIH] Hyperthyroidism: Excessive functional activity of the thyroid gland. [NIH] Hypertrichosis: Localized or generalized excess hair. The concept does not include hirsutism, which is excess hair in females and children with an adult male pattern of distribution. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [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 an increase in the number of cells. [NIH] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypnotic: A drug that acts to induce sleep. [EU] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]
Hypokinesia: Slow or diminished movement of body musculature. It may be associated with basal ganglia diseases; mental disorders; prolonged inactivity due to illness; experimental protocols used to evaluate the physiologic effects of immobility; and other conditions. [NIH] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxanthine: A purine and a reaction intermediate in the metabolism of adenosine and in the formation of nucleic acids by the salvage pathway. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU] Hypoxic: Having too little oxygen. [NIH] Ibuprofen: A nonsteroidal anti-inflammatory agent with analgesic properties used in the therapy of rheumatism and arthritis. [NIH] Ichthyosis: Any of several generalized skin disorders characterized by dryness, roughness, and scaliness, due to hypertrophy of the stratum corneum epidermis. Most are genetic, but some are acquired, developing in association with other systemic disease or genetic syndrome. [NIH]
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Idarubicin: An orally administered anthracycline antibiotic. The compound has shown activity against breast cancer, lymphomas and leukemias, together with potential for reduced cardiac toxicity. [NIH] Idiopathic: Describes a disease of unknown cause. [NIH] Idiotype: The unique antigenic determinant in the variable region. [NIH] Ifosfamide: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [NIH] Ileum: The lower end of the small intestine. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]
Immune Sera: Serum that contains antibodies. It is obtained from an animal that has been immunized either by antigen injection or infection with microorganisms containing the antigen. [NIH] Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]
effects
of
foreign
Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunoassay: Immunochemical assay or detection of a substance by serologic or immunologic methods. Usually the substance being studied serves as antigen both in antibody production and in measurement of antibody by the test substance. [NIH] Immunocompromised: Having a weakened immune system caused by certain diseases or treatments. [NIH] Immunocompromised Host: A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] 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] Immunomodulator: New type of drugs mainly using biotechnological methods. Treatment of cancer. [NIH] Immunophenotyping: Process of classifying cells of the immune system based on structural and functional differences. The process is commonly used to analyze and sort Tlymphocytes into subsets based on CD antigens by the technique of flow cytometry. [NIH]
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Immunophilin: A drug for the treatment of Parkinson's disease. [NIH] Immunosuppressant: An agent capable of suppressing immune responses. [EU] Immunosuppression: Deliberate prevention or diminution of the host's immune response. It may be nonspecific as in the administration of immunosuppressive agents (drugs or radiation) or by lymphocyte depletion or may be specific as in desensitization or the simultaneous administration of antigen and immunosuppressive drugs. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of suppressor T-cell populations or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. [NIH] Immunosuppressive therapy: Therapy used to decrease the body's immune response, such as drugs given to prevent transplant rejection. [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] Immunotoxin: An antibody linked to a toxic substance. Some immmunotoxins can bind to cancer cells and kill them. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implant radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indinavir: A potent and specific HIV protease inhibitor that appears to have good oral bioavailability. [NIH] 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] Induction therapy: Treatment designed to be used as a first step toward shrinking the cancer and in evaluating response to drugs and other agents. Induction therapy is followed by additional therapy to eliminate whatever cancer remains. [NIH]
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Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infant, Newborn: An infant during the first month after birth. [NIH] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]
Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Infiltration: The diffusion or accumulation in a tissue or cells of substances not normal to it or in amounts of the normal. Also, the material so accumulated. [EU] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Inflammatory bowel disease: A general term that refers to the inflammation of the colon and rectum. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. [NIH]
Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Inhalation: The drawing of air or other substances into the lungs. [EU] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Initiator: A chemically reactive substance which may cause cell changes if ingested, inhaled or absorbed into the body; the substance may thus initiate a carcinogenic process. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inosine Monophosphate: Inosine 5'-Monophosphate. A purine nucleotide which has hypoxanthine as the base and one phosphate group esterified to the sugar moiety. [NIH] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inotropic: Affecting the force or energy of muscular contractions. [EU] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH]
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Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Intercellular Adhesion Molecule-1: A cell-surface ligand with a role in leukocyte adhesion and inflammation. Its production is induced by gamma-interferon and it is required for neutrophil migration into inflamed tissue. [NIH] Interferon: A biological response modifier (a substance that can improve the body's natural response to disease). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and gamma. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases. [NIH] Interferon-alpha: One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-10: Factor that is a coregulator of mast cell growth. It is produced by T-cells and B-cells and shows extensive homology with the Epstein-Barr virus BCRFI gene. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukins: Soluble factors which stimulate growth-related activities of leukocytes as well as other cell types. They enhance cell proliferation and differentiation, DNA synthesis, secretion of other biologically active molecules and responses to immune and inflammatory stimuli. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal radiation: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near the tumor. Also called brachytherapy, implant radiation, or interstitial radiation therapy. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intoxication: Poisoning, the state of being poisoned. [EU] Intracellular: Inside a cell. [NIH] Intrahepatic: Within the liver. [NIH]
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Intramuscular: IM. Within or into muscle. [NIH] Intraocular: Within the eye. [EU] Intraocular pressure: Pressure of the fluid inside the eye; normal IOP varies among individuals. [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] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]
Involuntary: Reaction occurring without intention or volition. [NIH] Ionizing: Radiation comprising charged particles, e. g. electrons, protons, alpha-particles, etc., having sufficient kinetic energy to produce ionization by collision. [NIH] Ionomycin: A divalent calcium ionophore that is widely used as a tool to investigate the role of intracellular calcium in cellular processes. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irinotecan: An anticancer drug that belongs to a family of anticancer drugs called topoisomerase inhibitors. It is a camptothecin analogue. Also called CPT 11. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Irradiation: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Irradiation is also called radiation therapy, radiotherapy, and x-ray therapy. [NIH] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Isoleucine: An essential branched-chain amino acid found in many proteins. It is an isomer of LEUCINE. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. [NIH] Isomerases: A class of enzymes that catalyze geometric or structural changes within a molecule to form a single product. The reactions do not involve a net change in the
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concentrations of compounds other than the substrate and the product.(from Dorland, 28th ed) EC 5. [NIH] Isozymes: The multiple forms of a single enzyme. [NIH] Itraconazole: An antifungal agent that has been used in the treatment of histoplasmosis, blastomycosis, cryptococcal meningitis, and aspergillosis. [NIH] Jejunoileal Bypass: A surgical procedure consisting of the anastomosis of the proximal part of the jejunum to the distal portion of the ileum, so as to bypass the nutrient-absorptive segment of the small intestine, to treat morbid obesity. [NIH] Jejunum: That portion of the small intestine which extends from the duodenum to the ileum; called also intestinum jejunum. [EU] 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] Keratoconjunctivitis: Simultaneous inflammation of the cornea and conjunctiva. [NIH] Ketoacidosis: Acidosis accompanied by the accumulation of ketone bodies (ketosis) in the body tissues and fluids, as in diabetic acidosis. [EU] Ketoconazole: Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. [NIH] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketorolac: A drug that belongs to a family of drugs called nonsteroidal anti-inflammatory agents. It is being studied in cancer prevention. [NIH] Ketorolac Tromethamine: A pyrrolizine carboxylic acid derivative structurally related to indomethacin. It is a non-steroidal anti-inflammatory agent used for analgesia for postoperative pain and inhibits cyclooxygenase activity. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH]
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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] Kidney Transplantation: The transference of a kidney from one human or animal to another. [NIH] Kinetics: The study of rate dynamics in chemical or physical systems. [NIH] Labile: 1. Gliding; moving from point to point over the surface; unstable; fluctuating. 2. Chemically unstable. [EU] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Leflunomide: An anticancer drug that works by inhibiting a cancer cell growth factor. Also called SU101. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucine: An essential branched-chain amino acid important for hemoglobin formation. [NIH] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]
Leukaemia: An acute or chronic disease of unknown cause in man and other warm-blooded animals that involves the blood-forming organs, is characterized by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood, and is classified according of the type leucocyte most prominently involved. [EU] Leukemia: Cancer of blood-forming tissue. [NIH] Leukoencephalopathy: A condition with spongy holes in the brain's white matter. [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] Levo: It is an experimental treatment for heroin addiction that was developed by German scientists around 1948 as an analgesic. Like methadone, it binds with opioid receptors, but it is longer acting. [NIH] Levodopa: The naturally occurring form of dopa and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonism and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. [NIH]
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Levorphanol: A narcotic analgesic that may be habit-forming. It is nearly as effective orally as by injection. [NIH] Lichen Planus: An inflammatory, pruritic disease of the skin and mucous membranes, which can be either generalized or localized. It is characterized by distinctive purplish, flattopped papules having a predilection for the trunk and flexor surfaces. The lesions may be discrete or coalesce to form plaques. Histologically, there is a "saw-tooth" pattern of epidermal hyperplasia and vacuolar alteration of the basal layer of the epidermis along with an intense upper dermal inflammatory infiltrate composed predominantly of T-cells. Etiology is unknown. [NIH] Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Ligation: Application of a ligature to tie a vessel or strangulate a part. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. [NIH] Lipoid: The most common nephrotic syndrome disease of childhood. [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] Lipoxygenase Inhibitors: Compounds or agents that combine with lipoxygenase and thereby prevent its substrate-enzyme combination with arachidonic acid and the formation of the eicosanoid products hydroxyeicosatetraenoic acid and various leukotrienes. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver cancer: A disease in which malignant (cancer) cells are found in the tissues of the liver. [NIH]
Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another. [NIH] Living Donors: Non-cadaveric providers of organs for transplant to related or non-related recipients. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH]
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Localized: Cancer which has not metastasized yet. [NIH] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lorazepam: An anti-anxiety agent with few side effects. It also has hypnotic, anticonvulsant, and considerable sedative properties and has been proposed as a preanesthetic agent. [NIH] Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. [NIH] 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] Lubricants: Oily or slippery substances. [NIH] Lung Transplantation: The transference of either one or both of the lungs from one human or animal to another. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lupus Nephritis: Glomerulonephritis associated with systemic lupus erythematosus. It is classified into four histologic types: mesangial, focal, diffuse, and membranous. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]
Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphoblastic: One of the most aggressive types of non-Hodgkin lymphoma. [NIH] Lymphoblasts: Interferon produced predominantly by leucocyte cells. [NIH] Lymphocyte Depletion: Immunosuppression by reduction of circulating lymphocytes or by T-cell depletion of bone marrow. The former may be accomplished in vivo by thoracic duct drainage or administration of antilymphocyte serum. The latter is performed ex vivo on bone marrow before its transplantation. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called null cells. [NIH]
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Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphokine: A soluble protein produced by some types of white blood cell that stimulates other white blood cells to kill foreign invaders. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lymphopenia: Reduction in the number of lymphocytes. [NIH] Lymphoproliferative: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Lymphoproliferative Disorders: Disorders characterized by proliferation of lymphoid tissue, general or unspecified. [NIH] Macrolides: A group of organic compounds that contain a macrocyclic lactone ring linked glycosidically to one or more sugar moieties. [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] Macrophage Activation: The process of altering the morphology and functional activity of macrophages so that they become avidly phagocytic. It is initiated by lymphokines, such as the macrophage activation factor (MAF) and the macrophage migration-inhibitory factor (MMIF), immune complexes, C3b, and various peptides, polysaccharides, and immunologic adjuvants. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Maintenance therapy: Treatment that is given to help a primary (original) treatment keep working. Maintenance therapy is often given to help keep cancer in remission. [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malabsorption syndrome: A group of symptoms such as gas, bloating, abdominal pain, and diarrhea resulting from the body's inability to properly absorb nutrients. [NIH] Malaria: A protozoan disease caused in humans by four species of the genus Plasmodium (P. falciparum (malaria, falciparum), P. vivax (malaria, vivax), P. ovale, and P. malariae) and transmitted by the bite of an infected female mosquito of the genus Anopheles. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Malaria in animals is caused by other species of plasmodia. [NIH] Malaria, Falciparum: Malaria caused by Plasmodium falciparum. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations. [NIH] Malaria, Vivax: Malaria caused by Plasmodium vivax. This form of malaria is less severe
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than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant tumor: A tumor capable of metastasizing. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]
Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Mannans: Polysaccharides consisting of mannose units. [NIH] Mastectomy: Surgery to remove the breast (or as much of the breast tissue as possible). [NIH] Mastitis: Inflammatory disease of the breast, or mammary gland. [NIH] Maximum Tolerated Dose: The highest dose level eliciting signs of toxicity without having major effects on survival relative to the test in which it is used. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] 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] Megaloblastic: A large abnormal red blood cell appearing in the blood in pernicious anaemia. [EU] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melphalan: An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - melphalan, the racemic mixture - merphalan, and the dextro isomer medphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. [NIH] Membrane: A very thin layer of tissue that covers a surface. [NIH]
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Membrane Lipids: Lipids, predominantly phospholipids, cholesterol and small amounts of glycolipids found in membranes including cellular and intracellular membranes. These lipids may be arranged in bilayers in the membranes with integral proteins between the layers and peripheral proteins attached to the outside. Membrane lipids are required for active transport, several enzymatic activities and membrane formation. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Membranoproliferative: A disease that occurs primarily in children and young adults. Over time, inflammation leads to scarring in the glomeruli, causing proteinuria, hematuria, and sometimes chronic renal failure or end-stage renal disease. [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] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mercaptopurine: An anticancer drug that belongs to the family of drugs called antimetabolites. [NIH] Mercury: A silver metallic element that exists as a liquid at room temperature. It has the atomic symbol Hg (from hydrargyrum, liquid silver), atomic number 80, and atomic weight 200.59. Mercury is used in many industrial applications and its salts have been employed therapeutically as purgatives, antisyphilitics, disinfectants, and astringents. It can be absorbed through the skin and mucous membranes which leads to mercury poisoning. Because of its toxicity, the clinical use of mercury and mercurials is diminishing. [NIH] Mesencephalic: Ipsilateral oculomotor paralysis and contralateral tremor, spasm. or choreic movements of the face and limbs. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Metastatic: Having to do with metastasis, which is the spread of cancer from one part of the body to another. [NIH] Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of dihydrofolate reductase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [NIH] Methylprednisolone: (6 alpha,11 beta)-11,17,21-Trihydroxy-6-methylpregna-1,4-diene-3,2dione. A prednisolone derivative which has pharmacological actions similar to prednisolone. [NIH]
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Metronidazole: Antiprotozoal used in amebiasis, trichomoniasis, giardiasis, and as treponemacide in livestock. It has also been proposed as a radiation sensitizer for hypoxic cells. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985, p133), this substance may reasonably be anticipated to be a carcinogen (Merck, 11th ed). [NIH] Miconazole: An imidazole antifungal agent that is used topically and by intravenous infusion. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microdialysis: A technique for measuring extracellular concentrations of substances in tissues, usually in vivo, by means of a small probe equipped with a semipermeable membrane. Substances may also be introduced into the extracellular space through the membrane. [NIH] Microgram: A unit of mass (weight) of the metric system, being one-millionth of a gram (106 gm.) or one one-thousandth of a milligram (10-3 mg.). [EU] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microscopy: The application of microscope magnification to the study of materials that cannot be properly seen by the unaided eye. [NIH] Microspheres: Small uniformly-sized spherical particles frequently radioisotopes or various reagents acting as tags or markers. [NIH]
labeled
with
Microtubules: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin. [NIH] Midazolam: A short-acting compound, water-soluble at pH less than 4 and lipid-soluble at physiological pH. It is a hypnotic-sedative drug with anxiolytic and amnestic properties. It is used for sedation in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. Because of its short duration and cardiorespiratory stability, it is particularly useful in poor-risk, elderly, and cardiac patients. [NIH]
Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Milligram: A measure of weight. A milligram is approximately 450,000-times smaller than a pound and 28,000-times smaller than an ounce. [NIH] Milliliter: A measure of volume for a liquid. A milliliter is approximately 950-times smaller than a quart and 30-times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same. [NIH] Minor Histocompatibility Antigens: Allelic alloantigens often responsible for weak graft rejection in cases when (major) histocompatibility has been established by standard tests. In the mouse they are coded by more than 500 genes at up to 30 minor histocompatibility loci. The most well-known minor histocompatibility antigen in mammals is the H-Y antigen. [NIH]
Minor Histocompatibility Loci: Genetic loci responsible for the encoding of histocompatibility antigens other than those encoded by the major histocompatibility complex. The antigens encoded by these genes are often responsible for graft rejection in
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cases where histocompatibility has been established by standard tests. The location of some of these loci on the X and Y chromosomes explains why grafts from males to females may be rejected while grafts from females to males are accepted. In the mouse roughly 30 minor histocompatibility loci have been recognized, comprising more than 500 genes. [NIH] Miosis: Pupillary constriction. This may result from congenital absence of the dilatator pupillary muscle, defective sympathetic innervation, or irritation of the conjunctiva or cornea. [NIH] Miotic: 1. Pertaining to, characterized by, or producing miosis : contraction of the pupil. 2. An agent that causes the pupil to contract. 3. Meiotic: characterized by cell division. [EU] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mitotic: Cell resulting from mitosis. [NIH] Mitotic inhibitors: Drugs that kill cancer cells by interfering with cell division (mitostis). [NIH]
Mitoxantrone: An anthracenedione-derived antineoplastic agent. [NIH] Mobility: Capability of movement, of being moved, or of flowing freely. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]
Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Conformation: The characteristic three-dimensional shape of a molecule. [NIH] Molecular mass: The sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. For example, the molecular mass of water, which has two atoms of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16). [NIH] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monensin: An antiprotozoal agent produced by Streptomyces cinnamonensis. It exerts its effect during the development of first-generation trophozoites into first-generation schizonts within the intestinal epithelial cells. It does not interfere with hosts' development of acquired immunity to the majority of coccidial species. Monensin is a sodium and proton selective ionophore and is widely used as such in biochemical studies. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration,
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pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoamine: Enzyme that breaks down dopamine in the astrocytes and microglia. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monoclonal antibodies: Laboratory-produced substances that can locate and bind to cancer cells wherever they are in the body. Many monoclonal antibodies are used in cancer detection or therapy; each one recognizes a different protein on certain cancer cells. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to a tumor. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Morphological: Relating to the configuration or the structure of live organs. [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] Mucinous: Containing or resembling mucin, the main compound in mucus. [NIH] Mucins: A secretion containing mucopolysaccharides and protein that is the chief constituent of mucus. [NIH] Mucolytic: Destroying or dissolving mucin; an agent that so acts : a mucopolysaccharide or glycoprotein, the chief constituent of mucus. [EU] Mucosa: A mucous membrane, or tunica mucosa. [EU] Mucositis: A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth. [NIH] Mucus: The viscous secretion of mucous membranes. It contains mucin, white blood cells, water, inorganic salts, and exfoliated cells. [NIH] Multicenter Studies: Controlled studies which are planned and carried out by several cooperating institutions to assess certain variables and outcomes in specific patient populations, for example, a multicenter study of congenital anomalies in children. [NIH] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]
Multidrug resistance: Adaptation of tumor cells to anticancer drugs in ways that make the drugs less effective. [NIH] Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Multivariate Analysis: A set of techniques used when variation in several variables has to be studied simultaneously. In statistics, multivariate analysis is interpreted as any analytic method that allows simultaneous study of two or more dependent variables. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic
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unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Diseases: Acquired, familial, and congenital disorders of skeletal muscle and smooth muscle. [NIH] Mutagenic: Inducing genetic mutation. [EU] Myasthenia: Muscular debility; any constitutional anomaly of muscle. [EU] Mycophenolate mofetil: A drug that is being studied for its effectiveness in preventing graft-versus-host disease and autoimmune disorders. [NIH] Myelin: The fatty substance that covers and protects nerves. [NIH] Myelodysplastic Syndromes: Conditions in which the bone marrow shows qualitative and quantitative changes suggestive of a preleukemic process, but having a chronic course that does not necessarily terminate as acute leukemia. [NIH] Myelogenous: Produced by, or originating in, the bone marrow. [NIH] Myeloid Cells: Cells which include the monocytes and the granulocytes. [NIH] Myeloproliferative Disorders: Disorders in which one or more stimuli cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. [NIH] Myelosuppression: A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. [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 Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH] Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]
Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myopathy: Any disease of a muscle. [EU] 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] Naphthoquinones: Naphthalene rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups. [NIH]
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Naproxen: An anti-inflammatory agent with analgesic and antipyretic properties. Both the acid and its sodium salt are used in the treatment of rheumatoid arthritis and other rheumatic or musculoskeletal disorders, dysmenorrhea, and acute gout. [NIH] Narcolepsy: A condition of unknown cause characterized by a periodic uncontrollable tendency to fall asleep. [NIH] Narcotic: 1. Pertaining to or producing narcosis. 2. An agent that produces insensibility or stupor, applied especially to the opioids, i.e. to any natural or synthetic drug that has morphine-like actions. [EU] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrolysis: Separation or exfoliation of tissue due to necrosis. [EU] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplasm: A new growth of benign or malignant tissue. [NIH] Neoral: Drug that prevents transplant rejections. [NIH] Neostriatum: The phylogenetically newer part of the corpus striatum consisting of the caudate nucleus and putamen. It is often called simply the striatum. [NIH] Nephrectomy: Surgery to remove a kidney. Radical nephrectomy removes the kidney, the adrenal gland, nearby lymph nodes, and other surrounding tissue. Simple nephrectomy removes only the kidney. Partial nephrectomy removes the tumor but not the entire kidney. [NIH]
Nephritis: Inflammation of the kidney; a focal or diffuse proliferative or destructive process which may involve the glomerulus, tubule, or interstitial renal tissue. [EU] Nephrologist: A doctor who treats patients with kidney problems or hypertension. [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] Nephrotoxic: Toxic or destructive to kidney cells. [EU] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH]
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Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroblastoma: Cancer that arises in immature nerve cells and affects mostly infants and children. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of 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] Neurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system. [NIH] Neurotoxic: Poisonous or destructive to nerve tissue. [EU] Neurotoxicity: The tendency of some treatments to cause damage to the nervous system. [NIH]
Neurotoxin: A substance that is poisonous to nerve tissue. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Neutrons: Electrically neutral elementary particles found in all atomic nuclei except light hydrogen; the mass is equal to that of the proton and electron combined and they are unstable when isolated from the nucleus, undergoing beta decay. Slow, thermal, epithermal, and fast neutrons refer to the energy levels with which the neutrons are ejected from heavier nuclei during their decay. [NIH] Neutropenia: An abnormal decrease in the number of neutrophils, a type of white blood cell. [NIH] Neutrophil: A type of white blood cell. [NIH] Neutrophil Activation: The process in which the neutrophil is stimulated by diverse substances, resulting in degranulation and/or generation of reactive oxygen products, and culminating in the destruction of invading pathogens. The stimulatory substances, including opsonized particles, immune complexes, and chemotactic factors, bind to specific cellsurface receptors on the neutrophil. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] 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] Nisoldipine: 1,4-Dihydro-2,6-dimethyl-4 (2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester. Nisoldipine is a dihydropyridine calcium channel antagonist that acts as a potent arterial vasodilator and antihypertensive agent. It is also effective in
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patients with cardiac failure and angina. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]
Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [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] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Nystatin: Macrolide antifungal antibiotic complex produced by Streptomyces noursei, S. aureus, and other Streptomyces species. The biologically active components of the complex are nystatin A1, A2, and A3. [NIH] Obsession: A recurrent, persistent thought, image, or impulse that is unwanted and distressing (ego-dystonic) and comes involuntarily to mind despite attempts to ignore or suppress it. Common obsessions involve thoughts of violence, contamination, and selfdoubt. [EU] Obsessive-Compulsive Disorder: An anxiety disorder characterized by recurrent, persistent obsessions or compulsions. Obsessions are the intrusive ideas, thoughts, or images that are experienced as senseless or repugnant. Compulsions are repetitive and seemingly purposeful behavior which the individual generally recognizes as senseless and from which the individual does not derive pleasure although it may provide a release from tension. [NIH] Octreotide: A potent, long-acting somatostatin octapeptide analog which has a wide range
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of physiological actions. It inhibits growth hormone secretion, is effective in the treatment of hormone-secreting tumors from various organs, and has beneficial effects in the management of many pathological states including diabetes mellitus, orthostatic hypertension, hyperinsulinism, hypergastrinemia, and small bowel fistula. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oculomotor: Cranial nerve III. It originate from the lower ventral surface of the midbrain and is classified as a motor nerve. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligopeptides: Peptides composed of between two and twelve amino acids. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Omeprazole: A highly effective inhibitor of gastric acid secretion used in the therapy of gastric ulcers and Zollinger-Ellison syndrome. The drug inhibits the H(+)-K(+)-ATPase (H(+)-K(+)-exchanging ATPase) in a pH-dependent manner. This ATPase is considered the proton pump in the secretory membrane of the parietal cell. [NIH] Oncologist: A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation. [NIH] Oncology: The study of cancer. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmic: Pertaining to the eye. [EU] Opportunistic Infections: An infection caused by an organism which becomes pathogenic under certain conditions, e.g., during immunosuppression. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]
Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Oral Health: The optimal state of the mouth and normal functioning of the organs of the mouth without evidence of disease. [NIH] Oral Hygiene: The practice of personal hygiene of the mouth. It includes the maintenance of oral cleanliness, tissue tone, and general preservation of oral health. [NIH]
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Organ Transplantation: Transference of an organ between individuals of the same species or between individuals of different species. [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] Orlistat: A lipase inhibitor used for weight loss. Lipase is an enzyme found in the bowel that assists in lipid absorption by the body. Orlistat blocks this enzyme, reducing the amount of fat the body absorbs by about 30 percent. It is known colloquially as a "fat blocker." Because more oily fat is left in the bowel to be excreted, Orlistat can cause an oily anal leakage and fecal incontinence. Orlistat may not be suitable for people with bowel conditions such as irritable bowel syndrome or Crohn's disease. [NIH] Ornithine: An amino acid produced in the urea cycle by the splitting off of urea from arginine. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Overall survival: The percentage of subjects in a study who have survived for a defined period of time. Usually reported as time since diagnosis or treatment. Often called the survival rate. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Oxidants: Oxidizing agents or electron-accepting molecules in chemical reactions in which electrons are transferred from one molecule to another (oxidation-reduction). In vivo, it appears that phagocyte-generated oxidants function as tumor promoters or cocarcinogens rather than as complete carcinogens perhaps because of the high levels of endogenous antioxidant defenses. It is also thought that oxidative damage in joints may trigger the autoimmune response that characterizes the persistence of the rheumatoid disease process. [NIH]
Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]
Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). [NIH] Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH]
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Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [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] Oxycodone: Semisynthetic derivative of codeine that acts as a narcotic analgesic more potent and addicting than codeine. [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Oxygenase: Enzyme which breaks down heme, the iron-containing oxygen-carrying constituent of the red blood cells. [NIH] P53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer. [NIH] Pachymeningitis: Inflammation of the dura mater of the brain, the spinal cord or the optic nerve. [NIH] Paclitaxel: Antineoplastic agent isolated from the bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel stabilizes microtubules in their polymerized form and thus mimics the action of the proto-oncogene proteins c-mos. [NIH] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] 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] Pancreas Transplant: A surgical procedure that involves replacing the pancreas of a person who has diabetes with a healthy pancreas that can make insulin. The healthy pancreas comes from a donor who has just died or from a living relative. A person can donate half a pancreas and still live normally. [NIH] Pancreas Transplantation: The transference of a pancreas from one human or animal to another. [NIH] Pancreatectomy: Surgery to remove the pancreas. In a total pancreatectomy, a portion of the stomach, the duodenum, common bile duct, gallbladder, spleen, and nearby lymph nodes also are removed. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancytopenia: Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. [NIH] Panic: A state of extreme acute, intense anxiety and unreasoning fear accompanied by disorganization of personality function. [NIH] Panic Disorder: A type of anxiety disorder characterized by unexpected panic attacks that last minutes or, rarely, hours. Panic attacks begin with intense apprehension, fear or terror and, often, a feeling of impending doom. Symptoms experienced during a panic attack include dyspnea or sensations of being smothered; dizziness, loss of balance or faintness; choking sensations; palpitations or accelerated heart rate; shakiness; sweating; nausea or other form of abdominal distress; depersonalization or derealization; paresthesias; hot
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flashes or chills; chest discomfort or pain; fear of dying and fear of not being in control of oneself or going crazy. Agoraphobia may also develop. Similar to other anxiety disorders, it may be inherited as an autosomal dominant trait. [NIH] Panniculitis: General term for inflammation of adipose tissue, usually of the skin, characterized by reddened subcutaneous nodules. [NIH] Papillomavirus: A genus of Papovaviridae causing proliferation of the epithelium, which may lead to malignancy. A wide range of animals are infected including humans, chimpanzees, cattle, rabbits, dogs, and horses. [NIH] Paralysis: Loss of ability to move all or part of the body. [NIH] Parasite: An animal or a plant that lives on or in an organism of another species and gets at least some of its nutrition from that other organism. [NIH] Parasitic: Having to do with or being a parasite. A parasite is an animal or a plant that lives on or in an organism of another species and gets at least some of its nutrients from it. [NIH] Parenchyma: The essential elements of an organ; used in anatomical nomenclature as a general term to designate the functional elements of an organ, as distinguished from its framework, or stroma. [EU] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paresis: A general term referring to a mild to moderate degree of muscular weakness, occasionally used as a synonym for paralysis (severe or complete loss of motor function). In the older literature, paresis often referred specifically to paretic neurosyphilis. "General paresis" and "general paralysis" may still carry that connotation. Bilateral lower extremity paresis is referred to as paraparesis. [NIH] Parkinsonism: A group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. [EU] Parotid: The space that contains the parotid gland, the facial nerve, the external carotid artery, and the retromandibular vein. [NIH] Paroxetine: A serotonin uptake inhibitor that is effective in the treatment of depression. [NIH]
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] Particle: A tiny mass of material. [EU] Pathogen: Any disease-producing microorganism. [EU] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]
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Pelvic: Pertaining to the pelvis. [EU] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] 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] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]
Perillyl alcohol: A drug used in cancer prevention that belongs to the family of plant drugs called monoterpenes. [NIH] Periodontitis: Inflammation of the periodontal membrane; also called periodontitis simplex. [NIH]
Peripheral blood: Blood circulating throughout the body. [NIH] Peripheral Neuropathy: Nerve damage, usually affecting the feet and legs; causing pain, numbness, or a tingling feeling. Also called "somatic neuropathy" or "distal sensory polyneuropathy." [NIH] Peripheral stem cell transplantation: A method of replacing blood-forming cells destroyed by cancer treatment. Immature blood cells (stem cells) in the circulating blood that are similar to those in the bone marrow are given after treatment to help the bone marrow recover and continue producing healthy blood cells. Transplantation may be autologous (an individual's own blood cells saved earlier), allogeneic (blood cells donated by someone else), or syngeneic (blood cells donated by an identical twin). Also called peripheral stem cell support. [NIH] Peripheral stem cells: Immature cells found circulating in the bloodstream. New blood cells develop from peripheral stem cells. [NIH] Peroral: Performed through or administered through the mouth. [EU] Petrolatum: A colloidal system of semisolid hydrocarbons obtained from petroleum. It is used as an ointment base, topical protectant, and lubricant. [NIH] Petroleum: Naturally occurring complex liquid hydrocarbons which, after distillation, yield combustible fuels, petrochemicals, and lubricants. [NIH] P-Glycoprotein: A 170 kD transmembrane glycoprotein from the superfamily of ABC transporters. It serves as an ATP-dependent efflux pump for a variety of chemicals, including many antineoplastic agents. Overexpression of this glycoprotein is associated with multidrug resistance. [NIH] Phagocyte: An immune system cell that can surround and kill microorganisms and remove dead cells. Phagocytes include macrophages. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by
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phagocytic cells. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacist: A person trained to prepare and distribute medicines and to give information about them. [NIH] Pharmacodynamic: Is concerned with the response of living tissues to chemical stimuli, that is, the action of drugs on the living organism in the absence of disease. [NIH] Pharmacokinetic: The mathematical analysis of the time courses of absorption, distribution, and elimination of drugs. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phorbol Esters: Tumor-promoting compounds obtained from croton oil (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] 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] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of
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skin, eyes, and hair. [NIH] Pilocarpine: A slowly hydrolyzed muscarinic agonist with no nicotinic effects. Pilocarpine is used as a miotic and in the treatment of glaucoma. [NIH] Pilot Projects: Small-scale tests of methods and procedures to be used on a larger scale if the pilot study demonstrates that these methods and procedures can work. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] 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] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Ploidy: The number of sets of chromosomes in a cell or an organism. For example, haploid means one set and diploid means two sets. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Pneumonitis: A disease caused by inhaling a wide variety of substances such as dusts and molds. Also called "farmer's disease". [NIH] Podophyllotoxin: The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polyesters: Polymers of organic acids and alcohols, with ester linkages--usually polyethylene terephthalate; can be cured into hard plastic, films or tapes, or fibers which can
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be woven into fabrics, meshes or velours. [NIH] Polyethylene: A vinyl polymer made from ethylene. It can be branched or linear. Branched or low-density polyethylene is tough and pliable but not to the same degree as linear polyethylene. Linear or high-density polyethylene has a greater hardness and tensile strength. Polyethylene is used in a variety of products, including implants and prostheses. [NIH]
Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymers: Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., polypeptides, proteins, plastics). [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Pons: The part of the central nervous system lying between the medulla oblongata and the mesencephalon, ventral to the cerebellum, and consisting of a pars dorsalis and a pars ventralis. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postoperative: After surgery. [NIH] 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] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiating: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] 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]
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Precipitation: The act or process of precipitating. [EU] Preclinical: Before a disease becomes clinically recognizable. [EU] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predictive factor: A situation or condition that may increase a person's risk of developing a certain disease or disorder. [NIH] Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states. [NIH] Prednisone: A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. [NIH] 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 Sclerosing Cholangitis: Irritation, scarring, and narrowing of the bile ducts inside and outside the liver. Bile builds up in the liver and may damage its cells. Many people with this condition also have ulcerative colitis. [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] Progeny: The offspring produced in any generation. [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH] Prolactin: Pituitary lactogenic hormone. A polypeptide hormone with a molecular weight of about 23,000. It is essential in the induction of lactation in mammals at parturition and is synergistic with estrogen. The hormone also brings about the release of progesterone from lutein cells, which renders the uterine mucosa suited for the embedding of the ovum should fertilization occur. [NIH] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Promotor: In an operon, a nucleotide sequence located at the operator end which contains all the signals for the correct initiation of genetic transcription by the RNA polymerase holoenzyme and determines the maximal rate of RNA synthesis. [NIH] Prophase: The first phase of cell division, in which the chromosomes become visible, the nucleus starts to lose its identity, the spindle appears, and the centrioles migrate toward
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opposite poles. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] 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] Propylene Glycol: A clear, colorless, viscous organic solvent and diluent used in pharmaceutical preparations. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Prosthesis: An artificial replacement of a part of the body. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific proteinbinding measures are often used as assays in diagnostic assessments. [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein Folding: A rapid biochemical reaction involved in the formation of proteins. It begins even before a protein has been completely synthesized and proceeds through discrete intermediates (primary, secondary, and tertiary structures) before the final structure (quaternary structure) is developed. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] 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] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or
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vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Proton Pump: Integral membrane proteins that transport protons across a membrane against a concentration gradient. This transport is driven by hydrolysis of ATP by H(+)transporting ATP synthase. [NIH] Proton Pump Inhibitors: Medicines that stop the stomach's acid pump. Examples are omeprazole (oh-MEH-prah-zol) (Prilosec) and lansoprazole (lan-SOH-prah-zol) (Prevacid). [NIH]
Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Proto-Oncogene Proteins: Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. [NIH] Proto-Oncogene Proteins c-mos: Cellular proteins encoded by the c-mos genes. They function in the cell cycle to maintain maturation promoting factor in the active state and have protein-serine/threonine kinase activity. Oncogenic transformation can take place when c-mos proteins are expressed at the wrong time. [NIH] Protozoa: A subkingdom consisting of unicellular organisms that are the simplest in the animal kingdom. Most are free living. They range in size from submicroscopic to macroscopic. Protozoa are divided into seven phyla: Sarcomastigophora, Labyrinthomorpha, Apicomplexa, Microspora, Ascetospora, Myxozoa, and Ciliophora. [NIH] Protozoal: Having to do with the simplest organisms in the animal kingdom. Protozoa are single-cell organisms, such as ameba, and are different from bacteria, which are not members of the animal kingdom. Some protozoa can be seen without a microscope. [NIH] Protozoan: 1. Any individual of the protozoa; protozoon. 2. Of or pertaining to the protozoa; protozoal. [EU] Proximal: Nearest; closer to any point of reference; opposed to distal. [EU] Pruritic: Pertaining to or characterized by pruritus. [EU] Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychoactive: Those drugs which alter sensation, mood, consciousness or other psychological or behavioral functions. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]
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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 Fibrosis: Chronic inflammation and progressive fibrosis of the pulmonary alveolar walls, with steadily progressive dyspnea, resulting finally in death from oxygen lack or right heart failure. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]
Pupil: The aperture in the iris through which light passes. [NIH] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Purpura: Purplish or brownish red discoloration, easily visible through the epidermis, caused by hemorrhage into the tissues. [NIH] Purulent: Consisting of or containing pus; associated with the formation of or caused by pus. [EU] Putamen: The largest and most lateral of the basal ganglia lying between the lateral medullary lamina of the globus pallidus and the external capsule. It is part of the neostriatum and forms part of the lentiform nucleus along with the globus pallidus. [NIH] Pyoderma: Any purulent skin disease (Dorland, 27th ed). [NIH] Pyoderma Gangrenosum: An idiopathic, rapidly evolving, and severely debilitating disease occurring most commonly in association with chronic ulcerative colitis. It is characterized by the presence of boggy, purplish ulcers with undermined borders, appearing mostly on the legs. The majority of cases are in people between 40 and 60 years old. Its etiology is unknown. [NIH] Pyrazinamide: A pyrazine that is used therapeutically as an antitubercular agent. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Pyrogenic: Inducing fever. [EU] Quality of Health Care: The levels of excellence which characterize the health service or health care provided based on accepted standards of quality. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Quiescent: Marked by a state of inactivity or repose. [EU] Quinoxaline: AMPA/Kainate antagonist. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not
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sufficiently so as to achieve the status of a taxon. [NIH] Racemic: Optically inactive but resolvable in the way of all racemic compounds. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation oncologist: A doctor who specializes in using radiation to treat cancer. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radioimmunoassay: Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Nonimmunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. [NIH] Radioimmunotherapy: Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (immunotoxins) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (radiotherapy). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiolabeled: Any compound that has been joined with a radioactive substance. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Radiosensitization: The use of a drug that makes tumor cells more sensitive to radiation therapy. [NIH] Radiotherapy: The use of ionizing radiation to treat malignant neoplasms and other benign conditions. The most common forms of ionizing radiation used as therapy are x-rays, gamma rays, and electrons. A special form of radiotherapy, targeted radiotherapy, links a cytotoxic radionuclide to a molecule that targets the tumor. When this molecule is an antibody or other immunologic molecule, the technique is called radioimmunotherapy. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH] Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be
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in a randomized trial. [NIH] Reactivation: The restoration of activity to something that has been inactivated. [EU] Reactive Oxygen Species: Reactive intermediate oxygen species including both radicals and non-radicals. These substances are constantly formed in the human body and have been shown to kill bacteria and inactivate proteins, and have been implicated in a number of diseases. Scientific data exist that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. [NIH] Reagent: A substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances. [EU] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Recurrence: The return of a sign, symptom, or disease after a remission. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Rehabilitative: Instruction of incapacitated individuals or of those affected with some mental disorder, so that some or all of their lost ability may be regained. [NIH] Relapse: The return of signs and symptoms of cancer after a period of improvement. [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 cell carcinoma: A type of kidney cancer. [NIH] Renal failure: Progressive renal insufficiency and uremia, due to irreversible and progressive renal glomerular tubular or interstitial disease. [NIH] Renal Osteodystrophy: Decalcification of bone due to hyperparathyroidism secondary to chronic kidney disease. [NIH] Renal pelvis: The area at the center of the kidney. Urine collects here and is funneled into
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the ureter, the tube that connects the kidney to the bladder. [NIH] Renal tubular: A defect in the kidneys that hinders their normal excretion of acids. Failure to excrete acids can lead to weak bones, kidney stones, and poor growth in children. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] 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] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Research Personnel: Those individuals engaged in research. [NIH] Residual disease: Cancer cells that remain after attempts have been made to remove the cancer. [NIH] Resorption: The loss of substance through physiologic or pathologic means, such as loss of dentin and cementum of a tooth, or of the alveolar process of the mandible or maxilla. [EU] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Respiratory failure: Inability of the lungs to conduct gas exchange. [NIH] Response Elements: Nucleotide sequences, usually upstream, which are recognized by specific regulatory transcription factors, thereby causing gene response to various regulatory agents. These elements may be found in both promotor and enhancer regions. [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
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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 Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] Retinoids: Derivatives of vitamin A. Used clinically in the treatment of severe cystic acne, psoriasis, and other disorders of keratinization. Their possible use in the prophylaxis and treatment of cancer is being actively explored. [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] Retraction: 1. The act of drawing back; the condition of being drawn back. 2. Distal movement of teeth, usually accomplished with an orthodontic appliance. [EU] Retreatment: The therapy of the same disease in a patient, with the same agent or procedure repeated after initial treatment, or with an additional or alternate measure or follow-up. It does not include therapy which requires more than one administration of a therapeutic agent or regimen. Retreatment is often used with reference to a different modality when the original one was inadequate, harmful, or unsuccessful. [NIH] Retrospective: Looking back at events that have already taken place. [NIH] Retrospective study: A study that looks backward in time, usually using medical records and interviews with patients who already have or had a disease. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Reversion: A return to the original condition, e. g. the reappearance of the normal or wild type in previously mutated cells, tissues, or organisms. [NIH] Rhabdomyolysis: Necrosis or disintegration of skeletal muscle often followed by myoglobinuria. [NIH] Rhabdomyosarcoma: A malignant tumor of muscle tissue. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Rhinitis: Inflammation of the mucous membrane of the nose. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rigidity: Stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. [EU] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of
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developing a disease. [NIH] Ritonavir: An HIV protease inhibitor that works by interfering with the reproductive cycle of HIV. [NIH] Rods: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide side vision and the ability to see objects in dim light (night vision). [NIH] Saccule: The smaller of the 2 sacs within the vestibule of the ear. [NIH] Saccule and Utricle: Two membranous sacs within the vestibule of the inner ear. The smaller, the saccule, lies near the opening of the scala vestibuli. The larger, the utricle, is in the superoposterior part of the vestibule. Both receive filaments from the vestibulocochlear nerve. [NIH] Saliva: The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptylin. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Salvage Therapy: A therapeutic approach, involving chemotherapy, radiation therapy, or surgery, after initial regimens have failed to lead to improvement in a patient's condition. Salvage therapy is most often used for neoplastic diseases. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcoidosis: An idiopathic systemic inflammatory granulomatous disorder comprised of epithelioid and multinucleated giant cells with little necrosis. It usually invades the lungs with fibrosis and may also involve lymph nodes, skin, liver, spleen, eyes, phalangeal bones, and parotid glands. [NIH] Sarcoma: A connective tissue neoplasm formed by proliferation of mesodermal cells; it is usually highly malignant. [NIH] Sarcomere: The repeating structural unit of a striated muscle fiber. [NIH] Schizoid: Having qualities resembling those found in greater degree in schizophrenics; a person of schizoid personality. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Schizotypal Personality Disorder: A personality disorder in which there are oddities of thought (magical thinking, paranoid ideation, suspiciousness), perception (illusions, depersonalization), speech (digressive, vague, overelaborate), and behavior (inappropriate affect in social interactions, frequently social isolation) that are not severe enough to characterize schizophrenia. [NIH] Sclera: The tough white outer coat of the eyeball, covering approximately the posterior fivesixths of its surface, and continuous anteriorly with the cornea and posteriorly with the external sheath of the optic nerve. [EU] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a
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gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedative: 1. Allaying activity and excitement. 2. An agent that allays excitement. [EU] Sedimentation: The act of causing the deposit of sediment, especially by the use of a centrifugal machine. [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] Segregation: The separation in meiotic cell division of homologous chromosome pairs and their contained allelomorphic gene pairs. [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Selegiline: A selective, irreversible inhibitor of Type B monoamine oxidase. It is used in newly diagnosed patients with Parkinson's disease. It may slow progression of the clinical disease and delay the requirement for levodopa therapy. It also may be given with levodopa upon onset of disability. (From AMA Drug Evaluations Annual, 1994, p385) The compound without isomeric designation is Deprenyl. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Semisynthetic: Produced by chemical manipulation of naturally occurring substances. [EU] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septicaemia: A term originally used to denote a putrefactive process in the body, but now usually referring to infection with pyogenic micro-organisms; a genus of Diptera; the severe type of infection in which the blood stream is invaded by large numbers of the causal. [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] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serologic: Analysis of a person's serum, especially specific immune or lytic serums. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serotypes: A cause of haemorrhagic septicaemia (in cattle, sheep and pigs), fowl cholera of birds, pasteurellosis of rabbits, and gangrenous mastitis of ewes. It is also commonly found in atrophic rhinitis of pigs. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Sertraline: A selective serotonin uptake inhibitor that is used in the treatment of depression.
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[NIH]
Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Serum Albumin: A major plasma protein that serves in maintaining the plasma colloidal osmotic pressure and transporting large organic anions. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] 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 ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH] Silicon: A trace element that constitutes about 27.6% of the earth's crust in the form of silicon dioxide. It does not occur free in nature. Silicon has the atomic symbol Si, atomic number 14, and atomic weight 28.09. [NIH] Silicon Dioxide: Silica. Transparent, tasteless crystals found in nature as agate, amethyst, chalcedony, cristobalite, flint, sand, quartz, and tridymite. The compound is insoluble in water or acids except hydrofluoric acid. [NIH] Simvastatin: A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3methylglutaryl coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic LDL receptors, it increases breakdown of LDL-cholesterol (lipoproteins, LDL cholesterol). [NIH] Sirolimus: A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects
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many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skin graft: Skin that is moved from one part of the body to another. [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]
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] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Soft tissue sarcoma: A sarcoma that begins in the muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solid tumor: Cancer of body tissues other than blood, bone marrow, or the lymphatic system. [NIH] 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] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spasm: An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectroscopic: The recognition of elements through their emission spectra. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH]
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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] Stabilization: The creation of a stable state. [EU] Standard therapy: A currently accepted and widely used treatment for a certain type of cancer, based on the results of past research. [NIH] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steady state: Dynamic equilibrium. [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] Stent: A device placed in a body structure (such as a blood vessel or the gastrointestinal tract) to provide support and keep the structure open. [NIH] Stereotactic: Radiotherapy that treats brain tumors by using a special frame affixed directly to the patient's cranium. By aiming the X-ray source with respect to the rigid frame, technicians can position the beam extremely precisely during each treatment. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Steroid therapy: Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]
Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stomach Ulcer: An open sore in the lining of the stomach. Also called gastric ulcer. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Striatum: A higher brain's domain thus called because of its stripes. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroke Volume: The amount of blood pumped out of the heart per beat not to be confused
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with cardiac output (volume/time). [NIH] Stroma: The middle, thickest layer of tissue in the cornea. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] 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] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Supplementation: Adding nutrients to the diet. [NIH] Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Suppressive: Tending to suppress : effecting suppression; specifically : serving to suppress activity, function, symptoms. [EU] Surfactant: A fat-containing protein in the respiratory passages which reduces the surface tension of pulmonary fluids and contributes to the elastic properties of pulmonary tissue. [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] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Sympathomimetic: 1. Mimicking the effects of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. 2. An agent that produces effects similar to those of impulses conveyed by adrenergic postganglionic fibres of the sympathetic nervous system. Called also adrenergic. [EU] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Symptomatic treatment: Therapy that eases symptoms without addressing the cause of
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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] Synapsis: The pairing between homologous chromosomes of maternal and paternal origin during the prophase of meiosis, leading to the formation of gametes. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Synovial: Of pertaining to, or secreting synovia. [EU] Systemic: Affecting the entire body. [NIH] Systemic disease: Disease that affects the whole body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Systolic blood pressure: The maximum pressure in the artery produced as the heart contracts and blood begins to flow. [NIH] Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. [NIH] Tamoxifen: A first generation selective estrogen receptor modulator (SERM). It acts as an agonist for bone tissue and cholesterol metabolism but is an estrogen antagonist in mammary and uterine. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Taxanes: Anticancer drugs that inhibit cancer cell growth by stopping cell division. Also called antimitotic or antimicrotubule agents or mitotic inhibitors. [NIH] Technetium: The first artificially produced element and a radioactive fission product of uranium. The stablest isotope has a mass number 99 and is used diagnostically as a radioactive imaging agent. Technetium has the atomic symbol Tc, atomic number 43, and atomic weight 98.91. [NIH] Telencephalon: Paired anteriolateral evaginations of the prosencephalon plus the lamina terminalis. The cerebral hemispheres are derived from it. Many authors consider cerebrum a synonymous term to telencephalon, though a minority include diencephalon as part of the cerebrum (Anthoney, 1994). [NIH] Tendon: A discrete band of connective tissue mainly composed of parallel bundles of collagenous fibers by which muscles are attached, or two muscles bellies joined. [NIH] Teniposide: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by
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topoisomerase II binding. Accumulated breaks in DNA prevent cells from entering into the mitotic phase of the cell cycle, and lead to cell death. Teniposide acts primarily in the G2 and S phases of the cycle. [NIH] Teratogenic: Tending to produce anomalies of formation, or teratism (= anomaly of formation or development : condition of a monster). [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Theophylline: Alkaloid obtained from Thea sinensis (tea) and others. It stimulates the heart and central nervous system, dilates bronchi and blood vessels, and causes diuresis. The drug is used mainly in bronchial asthma and for myocardial stimulation. Among its more prominent cellular effects are inhibition of cyclic nucleotide phosphodiesterases and antagonism of adenosine receptors. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases, palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thermography: Measurement of the regional temperature of the body or an organ by infrared sensing devices, based on self-emanating infrared radiation. [NIH] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombocytopenia: A decrease in the number of blood platelets. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]
Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thrush: A disease due to infection with species of fungi of the genus Candida. [NIH] Thymidine: A chemical compound found in DNA. Also used as treatment for mucositis. [NIH]
Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. [NIH] Thymus: An organ that is part of the lymphatic system, in which T lymphocytes grow and multiply. The thymus is in the chest behind the breastbone. [NIH] 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
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metabolism. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] 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] Topical: On the surface of the body. [NIH] Topoisomerase inhibitors: A family of anticancer drugs. The topoisomerase enzymes are responsible for the arrangement and rearrangement of DNA in the cell and for cell growth and replication. Inhibiting these enzymes may kill cancer cells or stop their growth. [NIH] Topotecan: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerase. [NIH] Total pancreatectomy: Surgery to remove the entire pancreas. [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] Toxoplasmosis: The acquired form of infection by Toxoplasma gondii in animals and man. [NIH]
Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH] Transfer Factor: Factor derived from leukocyte lysates of immune donors which can transfer both local and systemic cellular immunity to nonimmune recipients. [NIH] Transfusion: The infusion of components of blood or whole blood into the bloodstream. The
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blood may be donated from another person, or it may have been taken from the person earlier and stored until needed. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocate: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Transplantation Immunology: A general term for the complex phenomena involved in alloand xenograft rejection by a host and graft vs host reaction. Although the reactions involved in transplantation immunology are primarily thymus-dependent phenomena of cellular immunity, humoral factors also play a part in late rejection. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Treatment Failure: A measure of the quality of health care by assessment of unsuccessful results of management and procedures used in combating disease, in individual cases or series. [NIH] Tremor: Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of Parkinson disease. [NIH] Trichomoniasis: An infection with the protozoan parasite Trichomonas vaginalis. [NIH] Tricyclic: Containing three fused rings or closed chains in the molecular structure. [EU] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Trimethoprim-sulfamethoxazole: An antibiotic drug used to treat infection and prevent pneumocystis carinii pneumonia. [NIH] Tropism: Directed movements and orientations found in plants, such as the turning of the sunflower to face the sun. [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] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tubulin: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from sperm flagella, cilia, and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to colchicine, vincristine, and vinblastine. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other
Dictionary 307
body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor suppressor gene: Genes in the body that can suppress or block the development of cancer. [NIH] Tumour: 1. Swelling, one of the cardinal signs of inflammations; morbid enlargement. 2. A new growth of tissue in which the multiplication of cells is uncontrolled and progressive; called also neoplasm. [EU] Tunica: A rather vague term to denote the lining coat of hollow organs, tubes, or cavities. [NIH]
Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ulcer: A localized necrotic lesion of the skin or a mucous surface. [NIH] Ulcerative colitis: Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel. [NIH] Uranium: A radioactive element of the actinide series of metals. It has an atomic symbol U, atomic number 92, and atomic weight 238.03. U-235 is used as the fissionable fuel in nuclear weapons and as fuel in nuclear power reactors. [NIH] Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Urease: An enzyme that catalyzes the conversion of urea and water to carbon dioxide and ammonia. EC 3.5.1.5. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Ureters: Tubes that carry urine from the kidneys to the bladder. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]
Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary tract: The organs of the body that produce and discharge urine. These include the kidneys, ureters, bladder, and urethra. [NIH] Urinary tract infection: An illness caused by harmful bacteria growing in the urinary tract. [NIH]
Urinate: To release urine from the bladder to the outside. [NIH] Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Urticaria: A vascular reaction of the skin characterized by erythema and wheal formation due to localized increase of vascular permeability. The causative mechanism may be allergy, infection, or stress. [NIH] Uvea: The middle coat of the eyeball, consisting of the choroid in the back of the eye and the
308
Cyclosporine
ciliary body and iris in the front of the eye. [NIH] Uveitis: An inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (the sclera and cornea, and the retina). [EU] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vagina: The muscular canal extending from the uterus to the exterior of the body. Also called the birth canal. [NIH] Vaginitis: Inflammation of the vagina characterized by pain and a purulent discharge. [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] Vascular endothelial growth factor: VEGF. A substance made by cells that stimulates new blood vessel formation. [NIH] Vasculitis: Inflammation of a blood vessel. [NIH] Vasoconstriction: Narrowing of the blood vessels without anatomic change, for which constriction, pathologic is used. [NIH] Vasodilator: An agent that widens blood vessels. [NIH] 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] Venom: That produced by the poison glands of the mouth and injected by the fangs of poisonous snakes. [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] 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] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Vestibulocochlear Nerve: The 8th cranial nerve. The vestibulocochlear nerve has a cochlear part (cochlear nerve) which is concerned with hearing and a vestibular part (vestibular nerve) which mediates the sense of balance and head position. The fibers of the cochlear nerve originate from neurons of the spiral ganglion and project to the cochlear nuclei (cochlear nucleus). The fibers of the vestibular nerve arise from neurons of Scarpa's ganglion and project to the vestibular nuclei. [NIH]
Dictionary 309
Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Vinblastine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. It is a mitotic inhibitor. [NIH] Vinca Alkaloids: A class of alkaloids from the genus of apocyanaceous woody herbs including periwinkles. They are some of the most useful antineoplastic agents. [NIH] Vincristine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [NIH] Vinorelbine: An anticancer drug that belongs to the family of plant drugs called vinca alkaloids. [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] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Viscosity: A physical property of fluids that determines the internal resistance to shear forces. [EU] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Void: To urinate, empty the bladder. [NIH] Warts: Benign epidermal proliferations or tumors; some are viral in origin. [NIH] Wetting Agents: A surfactant that renders a surface wettable by water or enhances the spreading of water over the surface; used in foods and cosmetics; important in contrast media; also with contact lenses, dentures, and some prostheses. Synonyms: humectants; hydrating agents. [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]
Withdrawal: 1. A pathological retreat from interpersonal contact and social involvement, as may occur in schizophrenia, depression, or schizoid avoidant and schizotypal personality disorders. 2. (DSM III-R) A substance-specific organic brain syndrome that follows the cessation of use or reduction in intake of a psychoactive substance that had been regularly used to induce a state of intoxication. [EU] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] 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]
310
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X-ray therapy: The use of high-energy radiation from x-rays to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials called radioisotopes. Radioisotopes produce radiation and can be placed in or near the tumor or in the area near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation, interstitial radiation, or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. X-ray therapy is also called radiation therapy, radiotherapy, and irradiation. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]
311
INDEX 6 6-Mercaptopurine, 13, 184, 188, 219 A Abdominal, 168, 205, 219, 266, 271, 283, 307 Abdominal fat, 168, 219 Abdominal Pain, 205, 219, 266, 271, 307 Ablation, 41, 219 Abscess, 108, 219 Acceptor, 20, 219, 269, 282, 304 Acetone, 175, 219, 267 Acetylcholine, 219, 236, 279, 280 Acetylcysteine, 163, 219 Acidosis, 79, 219, 267 Acne, 205, 208, 219, 296 Actin, 60, 219, 277 Acute leukemia, 51, 94, 219, 277 Acute lymphoblastic leukemia, 50, 51, 69, 219 Acute lymphocytic leukemia, 219 Acute myelogenous leukemia, 25, 49, 92, 107, 219, 220 Acute myeloid leukemia, 17, 35, 76, 92, 130, 136, 137, 220 Acute nonlymphocytic leukemia, 220 Acute renal, 7, 101, 162, 182, 220, 258 Acute tubular, 120, 182, 220 Acyclovir, 206, 220, 254 Acyl, 220, 250 Adaptability, 220, 234, 235 Adaptation, 220, 276, 287 Adenine, 37, 168, 220, 292 Adenosine, 220, 232, 261, 286, 304 Adipose Tissue, 219, 220, 284 Adjuvant, 130, 150, 171, 220 Adolescence, 52, 220 Adoptive Transfer, 60, 220 Adrenal Glands, 220, 223 Adrenal Medulla, 220, 234, 249, 280 Adrenergic, 20, 220, 245, 246, 249, 290, 302 Adrenoleukodystrophy, 114, 221 Adverse Effect, 221, 247, 299 Aerobic, 167, 221, 275, 282 Afferent, 71, 221 Affinity, 29, 37, 65, 153, 221, 244, 269, 300 Agar, 221, 241, 287 Age Groups, 107, 221 Aged, 80 and Over, 221
Agonist, 22, 221, 232, 245, 249, 287, 303 Airways, 31, 221 Alanine, 162, 221 Albumin, 221, 246 Algorithms, 34, 221, 230 Alimentary, 221, 284 Alkaline, 219, 221, 223, 232, 286 Alkaloid, 149, 221, 232, 233, 237, 304 Alkylating Agents, 52, 222, 232, 236 Allergen, 31, 222, 244 Allergic Rhinitis, 178, 222, 232, 257 Allo, 222, 306 Allogeneic, 32, 33, 38, 41, 60, 64, 84, 109, 111, 115, 163, 171, 222, 256, 258, 285 Allogeneic bone marrow transplantation, 64, 84, 111, 222 Allylamine, 222, 223 Alopecia, 159, 222, 242 Alpha Cell, 46, 222 Alpha Particles, 222, 293 Alpha-1, 222, 242, 246 Alternative medicine, 187, 222 Aluminum, 164, 222 Ambulatory Care, 222 Amebiasis, 222, 274 Amenorrhea, 222, 232 Amine, 165, 222, 259 Amino Acid Sequence, 65, 156, 223, 225, 254 Amino Acid Substitution, 29, 223 Ammonia, 222, 223, 307 Amnestic, 223, 253, 274 Amplification, 148, 223 Ampulla, 223, 236, 248 Amyloidosis, 102, 223 Anaemia, 95, 223, 226, 272 Anaerobic, 167, 223 Anaesthesia, 223, 263 Anal, 223, 276, 282 Analgesic, 26, 223, 237, 261, 268, 269, 278, 283 Analog, 64, 71, 96, 138, 220, 223, 244, 252, 253, 254, 280 Analogous, 223, 246, 305 Anaphylatoxins, 223, 238 Anaphylaxis, 130, 224 Anaplasia, 224 Anastomosis, 224, 267
312
Cyclosporine
Anatomical, 224, 239, 263, 284, 297 Anemia, 7, 68, 114, 115, 177, 208, 224, 253, 258, 271 Anergic, 23, 224 Anergy, 23, 29, 224 Anesthesia, 224, 248, 274 Anesthetics, 224, 250 Angina, 224, 280, 290 Angina Pectoris, 224, 290 Anginal, 224, 279 Angioplasty, 161, 177, 224, 277 Angiotensinogen, 224, 295 Animal model, 19, 20, 43, 62, 64, 67, 160, 174, 224 Anionic, 171, 224 Anisotropy, 224, 252 Anomalies, 225, 276, 304 Antagonism, 19, 225, 232, 245, 304 Antecedent, 18, 225 Anthracycline, 225, 243, 262 Antibacterial, 225, 247, 300 Antibiotic, 43, 225, 228, 231, 242, 243, 246, 247, 250, 262, 280, 285, 300, 306 Antibiotics, Antifungal, 163, 225 Antibodies, 19, 148, 151, 154, 155, 166, 169, 170, 225, 228, 257, 262, 276, 287, 293 Antibody therapy, 182, 225 Anticoagulant, 225, 290 Anticonvulsant, 225, 270 Antidepressant, 26, 225, 237, 253 Antifungal, 18, 43, 45, 161, 173, 225, 242, 252, 267, 274, 280, 299 Antifungal Agents, 43, 225 Antigen, 23, 27, 29, 30, 31, 42, 59, 63, 65, 160, 179, 221, 224, 225, 238, 243, 252, 260, 261, 262, 263, 264, 272, 274, 293 Antigen-Antibody Complex, 225, 238 Antigen-presenting cell, 225, 243 Antihypertensive, 225, 279 Anti-infective, 225, 260 Anti-Inflammatory Agents, 154, 163, 226, 227, 241, 267 Antimetabolite, 184, 219, 220, 226, 253, 273 Antimicrobial, 226, 236 Antimitotic, 226, 303 Antimycotic, 226, 237 Antineoplastic Agents, 52, 222, 226, 285, 309 Antioxidant, 128, 226, 282, 283 Antiproliferative, 65, 123, 137, 226 Antipyretic, 226, 278 Antiseptic, 219, 226
Antithrombotic, 226, 259 Antithymocyte globulin, 30, 74, 98, 105, 226 Antitussive, 226, 244 Antiviral, 24, 67, 176, 219, 220, 226, 253, 265, 285 Anuria, 226, 267 Anus, 223, 226, 238 Anxiety, 226, 253, 270, 280, 283, 290 Anxiolytic, 226, 274 Aorta, 158, 226, 308 Aplasia, 117, 226 Aplastic anaemia, 95, 104, 226 Aplastic anemia, 30, 94, 105, 162, 186, 226 Apolipoproteins, 226, 269 Aponeurosis, 226, 254 Apoptosis, 17, 22, 27, 28, 29, 32, 34, 36, 39, 45, 47, 67, 122, 130, 134, 135, 227, 234 Applicability, 46, 56, 227 Aqueous, 154, 174, 177, 227, 228, 243, 248, 260, 268 Arachidonic Acid, 227, 268, 269 Arginine, 47, 65, 128, 137, 138, 152, 153, 223, 227, 259, 280, 282 Arterial, 75, 222, 227, 236, 240, 261, 279, 290, 303 Arteries, 161, 226, 227, 230, 231, 240, 241, 270, 277 Arteriolar, 227, 231, 295 Arterioles, 227, 231, 233 Arteriosclerosis, 123, 227, 261 Arteriosus, 227, 292 Artery, 46, 224, 227, 248, 277, 284, 292, 295, 303 Aspartate, 227, 244 Aspergillosis, 227, 267 Aspiration, 182, 227 Aspirin, 204, 227 Assay, 28, 60, 67, 68, 96, 150, 155, 168, 227, 252, 262, 293 Asthenia, 224, 227 Atopic, 22, 102, 227 Atrophy, 37, 227 Attenuated, 60, 228, 245 Auditory, 228, 257 Autacoids, 41, 228, 263 Autoantibodies, 154, 228 Autoantigens, 65, 228 Autoimmune disease, 5, 12, 14, 47, 65, 67, 118, 151, 159, 164, 166, 177, 184, 205, 228, 276 Autoimmunity, 23, 207, 228
313
Autologous, 30, 49, 52, 130, 168, 228, 258, 285 Autologous bone marrow transplantation, 52, 228, 258 Autoradiography, 27, 228 Avian, 28, 228 Axons, 228, 281, 296 Azithromycin, 73, 86, 100, 117, 133, 228 B Bacteria, 220, 225, 228, 229, 239, 249, 252, 257, 274, 291, 294, 298, 300, 305, 307, 308 Bactericidal, 228, 250 Bacteriostatic, 228, 250 Bacterium, 228, 239, 258 Basal Ganglia, 68, 228, 254, 261, 292 Base, 49, 52, 220, 228, 243, 254, 264, 267, 285, 286 Basement Membrane, 228, 251 Basophil, 21, 31, 228 Benign, 228, 254, 278, 293, 309 Bile, 149, 161, 168, 229, 253, 260, 269, 289, 301 Bile Acids, 229, 301 Bile Acids and Salts, 229 Bile duct, 161, 229, 289 Biliary, 78, 149, 154, 162, 173, 229, 233, 236, 238 Binding agent, 160, 229 Binding Sites, 65, 229 Bioassay, 229 Bioavailability, 15, 24, 34, 88, 98, 122, 129, 133, 137, 138, 139, 154, 161, 164, 168, 171, 174, 175, 229, 263 Bioavailable, 174, 229 Biochemical, 16, 22, 43, 53, 61, 62, 96, 136, 226, 229, 252, 267, 275, 290, 298 Bioequivalent, 162, 229 Biological Assay, 21, 229 Biological response modifier, 52, 229, 265 Biological therapy, 229, 257 Biological Transport, 229, 244 Biomarkers, 59, 229 Biomolecular, 34, 229 Biopsy, 4, 7, 8, 13, 21, 25, 113, 182, 230, 285 Biopsy specimen, 8, 230 Biosynthesis, 227, 230, 237, 245, 270, 290, 298, 299 Biotechnology, 70, 72, 122, 183, 187, 199, 229, 230 Biotransformation, 168, 230 Bladder, 112, 230, 239, 242, 263, 276, 290, 295, 307, 309
Blast Crisis, 230 Blast phase, 82, 230 Blastomycosis, 230, 267 Blasts, 30, 230 Blister, 164, 230 Blister pack, 164, 230 Bloating, 230, 266, 271 Blood Coagulation, 230, 233, 304 Blood Glucose, 230, 258, 261, 265 Blood Platelets, 230, 298, 304 Blood Preservation, 230, 244 Blood pressure, 4, 9, 11, 72, 76, 83, 84, 188, 205, 206, 208, 220, 225, 230, 261, 276, 279, 300 Blood transfusion, 104, 231 Blood-Brain Barrier, 75, 231, 268 Blot, 18, 231 Body Fluids, 156, 229, 231, 232, 247, 300, 307 Body Mass Index, 231, 282 Bolus, 83, 231 Bolus infusion, 231 Bone Marrow, 30, 54, 55, 56, 59, 72, 90, 94, 107, 114, 122, 130, 134, 150, 151, 161, 163, 164, 171, 175, 176, 177, 219, 220, 226, 228, 230, 231, 236, 254, 257, 258, 262, 270, 272, 276, 277, 285, 300 Bone Marrow Transplantation, 54, 55, 56, 90, 94, 114, 130, 134, 161, 175, 231 Bone Remodeling, 66, 231 Bone Resorption, 231 Boron, 231, 241 Bowel, 5, 12, 13, 100, 141, 184, 187, 223, 231, 264, 265, 281, 282, 301, 307 Brachytherapy, 231, 265, 266, 293, 310 Bradykinin, 231, 280 Breast reconstruction, 168, 231 Broad-spectrum, 18, 44, 231 Bromocriptine, 206, 232 Bronchi, 232, 250, 304 Bronchial, 232, 259, 304 Bronchioles, 232 Bronchiolitis, 179, 232 Bronchiolitis Obliterans, 179, 232 Bronchitis, 178, 232 Buccal, 232, 259, 270 Budesonide, 187, 232 Bullous, 154, 232 Busulfan, 52, 232 Bypass, 232, 267, 277 C Caffeine, 192, 232, 292
314
Cyclosporine
Calcification, 161, 227, 232 Calcineurin, 7, 19, 20, 32, 38, 40, 41, 43, 65, 71, 93, 101, 119, 148, 153, 232 Calcinosis, 21, 232 Calculi, 233, 256 Calibration, 150, 233 Calmodulin, 232, 233 Camptothecin, 149, 233, 266 Candidiasis, 43, 44, 71, 233 Candidosis, 233 Capillary, 231, 233, 234, 255, 308 Capillary Fragility, 233, 234 Capsules, 175, 182, 233, 246, 255 Carbohydrate, 233, 241, 255, 256, 288 Carbon Dioxide, 145, 233, 243, 254, 295, 307 Carboplatin, 127, 162, 233 Carcinogen, 233, 272, 274 Carcinogenic, 222, 233, 264, 289, 301 Carcinoma, 102, 105, 136, 174, 233 Cardiac Output, 20, 233, 302 Cardiac Surgical Procedures, 46, 234 Cardiomyopathy, 35, 234 Cardiorespiratory, 234, 274 Cardioselective, 234, 290 Cardiovascular, 10, 41, 79, 99, 100, 132, 234, 268, 298 Carotene, 234, 295 Carrier Proteins, 234, 293 Case report, 7, 77, 97, 108, 234 Caspase, 39, 234 Castor Oil, 157, 163, 234 Cataracts, 205, 208, 234 Catechin, 128, 234 Catecholamine, 234, 245 Catheter, 161, 234, 248 Catheterization, 224, 234, 277 Caudal, 234, 261, 288 Causal, 9, 234, 298 Cause of Death, 38, 234 Cell Cycle, 174, 234, 237, 242, 251, 291, 304 Cell Death, 28, 36, 39, 45, 227, 234, 251, 278, 304 Cell Differentiation, 234, 299 Cell Division, 27, 228, 234, 235, 242, 251, 257, 272, 275, 287, 289, 298, 303 Cell membrane, 43, 229, 234, 235, 237, 244, 286 Cell proliferation, 28, 129, 227, 235, 265, 299 Cell Respiration, 235, 275, 282, 295 Cell Size, 235, 252
Cell Survival, 18, 36, 235, 257 Cell Transplantation, 24, 42, 59, 68, 102, 109, 123, 235, 258 Centrifugation, 174, 235 Ceramide, 138, 235 Cerebral, 114, 228, 231, 235, 250, 251, 271, 303, 304 Cerebral Cortex, 235, 251 Cerebrospinal, 18, 22, 235 Cerebrospinal fluid, 18, 22, 235 Cerebrum, 235, 303 Chemokines, 19, 235 Chemotactic Factors, 235, 238, 279 Chemotherapeutic agent, 235, 245 Chemotherapy, 35, 43, 49, 50, 51, 52, 107, 115, 127, 128, 129, 130, 132, 133, 177, 235, 297 Chlorambucil, 13, 236 Chlorophyll, 236, 253 Cholera, 236, 298 Cholestasis, 133, 236 Cholesterol Esters, 236, 269 Choline, 164, 165, 236 Chromatin, 65, 227, 236, 249, 270 Chromosomal, 49, 223, 236, 259 Chromosome, 221, 236, 239, 257, 269, 298, 306 Chronic Disease, 236, 268 Chronic granulocytic leukemia, 236 Chronic myelogenous leukemia, 49, 84, 230, 236 Chronic renal, 11, 66, 236, 273 Chylomicrons, 236, 269 Ciprofloxacin, 72, 236 Cirrhosis, 154, 162, 236 CIS, 153, 172, 236, 242, 296 Cisplatin, 69, 162, 236 Citalopram, 102, 237 Clinical Medicine, 237, 289 Clinical Protocols, 57, 58, 237 Clinical trial, 15, 18, 22, 27, 29, 33, 34, 38, 49, 52, 53, 55, 56, 58, 59, 70, 149, 199, 237, 240, 246, 276, 290, 293 Cloning, 230, 237 Clotrimazole, 206, 237 Cochlea, 28, 237, 264 Coculture, 45, 237 Codeine, 237, 244, 283 Coenzyme, 237, 252, 270, 299 Cofactor, 237, 290, 304 Colchicine, 106, 237, 306 Colitis, 12, 44, 141, 187, 188, 204, 237, 266
315
Collagen, 136, 178, 228, 234, 237, 252, 287, 289 Collapse, 36, 224, 237 Colon, 174, 237, 238, 264, 266, 268, 307 Colorectal, 45, 103, 238 Colorectal Cancer, 45, 238 Combination Therapy, 32, 115, 134, 135, 183, 238 Combinatorial, 21, 238 Common Bile Duct, 238, 283 Communis, 234, 238 Complement, 63, 65, 68, 223, 238, 271 Complementary and alternative medicine, 127, 143, 238 Complementary medicine, 127, 238 Complete remission, 4, 25, 238, 294 Complete response, 239 Compliance, 54, 57, 74, 239 Compulsions, 61, 239, 280 Computational Biology, 199, 239 Concomitant, 85, 239 Cones, 239, 296 Conjugated, 150, 229, 239, 242, 280 Conjugation, 15, 230, 239 Conjunctiva, 93, 158, 239, 267, 275 Connective Tissue, 9, 45, 231, 237, 239, 252, 254, 257, 270, 297, 303 Connective Tissue Cells, 239 Consciousness, 223, 239, 243, 245, 291 Constitutional, 239, 277 Constriction, 239, 266, 275, 308 Constriction, Pathologic, 239, 308 Continuous infusion, 69, 123, 134, 239 Contracture, 167, 239 Contraindications, ii, 240 Contralateral, 240, 273, 281 Contrast Media, 240, 309 Control group, 9, 240 Controlled study, 74, 132, 240 Contusion, 22, 240 Conus, 240, 292 Convulsion, 229, 240 Cooperative group, 47, 51, 53, 69, 240 Coordination, 6, 50, 55, 58, 240, 276 Cor, 240 Corn Oil, 130, 163, 240 Cornea, 82, 117, 177, 240, 267, 275, 297, 302, 308 Corneum, 240, 249, 261 Coronary, 46, 161, 169, 224, 240, 253, 259, 277 Coronary Arteriosclerosis, 169, 240
Coronary heart disease, 240, 259 Cortex, 241, 289, 295 Cortical, 16, 22, 241, 258 Corticosteroid, 241, 289, 301 Cortisone, 241, 244, 289 Cranial, 241, 281, 308 Creatinine, 6, 11, 12, 162, 241, 267 Crossing-over, 241, 294 Croton Oil, 241, 286 Cryptococcosis, 18, 43, 241 Cryptosporidiosis, 228, 241 Culture Media, 156, 221, 241 Curative, 59, 164, 241, 279, 304 Curcumin, 37, 129, 133, 241 Cutaneous, 76, 230, 233, 241, 270 Cyclic, 72, 150, 151, 156, 158, 161, 163, 164, 165, 166, 171, 173, 175, 176, 177, 232, 233, 241, 242, 257, 280, 304 Cyclin, 174, 242 Cyclin-Dependent Kinases, 174, 242 Cyclodextrins, 39, 242 Cyclophilins, 43, 242 Cyclophosphamide, 13, 52, 68, 122, 133, 170, 242, 262 Cycloserine, 69, 242 Cyclosporins, 39, 165, 172, 173, 175, 176, 242 Cysteine, 219, 235, 242 Cystitis, 149, 242 Cytarabine, 25, 92, 107, 136, 242 Cytochrome, 26, 35, 36, 39, 63, 242, 283 Cytogenetics, 57, 242 Cytokine, 19, 21, 28, 31, 33, 45, 59, 242, 299 Cytomegalovirus, 71, 72, 78, 182, 183, 242, 254 Cytomegalovirus Infections, 78, 242, 254 Cytopenia, 30, 243 Cytoplasm, 20, 148, 227, 235, 243, 249, 270, 276, 296 Cytosine, 243, 252, 292 Cytostatic, 162, 243 Cytotoxic, 13, 14, 17, 24, 34, 64, 112, 118, 134, 152, 184, 243, 263, 293, 299 Cytotoxicity, 222, 236, 243 Cytotoxins, 35, 243 D Daclizumab, 110, 243 Daunorubicin, 243, 246 De novo, 18, 25, 38, 77, 83, 88, 120, 243 Decarboxylation, 243, 259 Defense Mechanisms, 44, 152, 153, 243 Degenerative, 240, 243, 259
316
Cyclosporine
Deletion, 29, 227, 243 Delivery of Health Care, 243, 258 Dementia, 29, 243 Demethylation, 26, 243 Dendrites, 243, 279 Dendritic, 32, 243, 272, 296 Dendritic cell, 32, 243 Dentures, 243, 309 Depolarization, 244, 299 Dermatitis, 102, 244, 247 Dermatology, 73, 76, 77, 78, 88, 89, 95, 102, 113, 115, 140, 159, 244 Desensitization, 97, 244, 263 Detoxification, 26, 244 Deuterium, 173, 244, 260 Dexamethasone, 28, 244 Dexterity, 4, 244 Dextromethorphan, 63, 244 Diabetes Mellitus, 10, 64, 153, 161, 206, 244, 255, 256, 258, 281 Diagnostic procedure, 147, 187, 244 Dialyzer, 244, 258 Diarrhea, 13, 84, 174, 222, 241, 244, 266, 271 Diastolic, 244, 261 Diathesis, 31, 244 Dietitian, 206, 244 Diffusion, 112, 229, 244, 245, 264 Digestion, 221, 229, 231, 244, 265, 269, 301 Digestive tract, 154, 174, 244, 300 Dihydroxy, 24, 244, 250 Dihydroxyacetone, 167, 244, 245 Dihydroxyacetone Phosphate, 244, 245 Dilated cardiomyopathy, 35, 245 Diltiazem, 90, 245 Dilution, 163, 245 Dimethyl, 139, 150, 245, 279 Dipeptides, 34, 245 Diploid, 43, 245, 287 Dipyridamole, 127, 245 Direct, iii, 22, 28, 29, 65, 174, 191, 237, 245, 255, 294, 303 Discrete, 231, 245, 269, 290, 303 Disease-Free Survival, 48, 53, 245 Disinfectant, 245, 250 Disposition, 26, 34, 92, 157, 245 Dissociation, 221, 245 Distal, 245, 267, 285, 291, 296 Diuresis, 162, 232, 245, 304 Docetaxel, 129, 133, 245 Dopamine, 27, 232, 245, 268, 276, 279, 286 Dorsal, 245, 288
Dorsum, 245, 246, 254 Dosage Forms, 171, 175, 176, 246 Dose-limiting, 149, 174, 246 Double-blind, 12, 38, 61, 70, 74, 85, 113, 246 Doxazosin, 85, 246 Doxorubicin, 34, 246 Drive, ii, vi, 4, 36, 41, 121, 205, 246 Drug Carriers, 15, 246 Drug Combinations, 13, 149, 173, 246 Drug Design, 34, 246 Drug Interactions, 35, 43, 63, 192, 207, 246 Drug Monitoring, 12, 61, 78, 81, 85, 96, 106, 148, 246 Drug Resistance, 18, 25, 35, 56, 76, 132, 246 Drug Tolerance, 246, 305 Drug Toxicity, 41, 149, 247 Dry Eye Syndrome, 93, 247 Duct, 66, 223, 234, 238, 247, 251, 270, 297 Duodenum, 229, 247, 248, 267, 283, 301 Dura mater, 247, 273, 283 Dyskinesia, 237, 247 Dyslipidemia, 10, 85, 247 Dysmenorrhea, 247, 278 Dyspnea, 247, 283, 292 E Echinomycin, 158, 247 Eczema, 159, 247 Edema, 247, 277, 278 Effector, 41, 42, 44, 64, 156, 219, 238, 247 Effector cell, 44, 156, 247 Efferent, 71, 247 Elastic, 167, 247, 302 Elasticity, 227, 240, 247 Elastin, 237, 247 Elective, 9, 83, 247 Electrolyte, 241, 247, 267, 288, 300 Electrons, 226, 228, 247, 266, 282, 293 Elementary Particles, 247, 248, 279, 291 Embryo, 235, 248, 263 Emollient, 248, 256, 281 Emulsion, 78, 164, 177, 228, 248 Enalapril, 49, 85, 248 Encapsulated, 164, 248 Encephalitis, 248 Encephalomyelitis, 150, 171, 248 Endarterectomy, 224, 248 Endemic, 236, 248, 271 Endocarditis, 233, 248 Endogenous, 20, 151, 166, 228, 245, 247, 248, 282, 290, 305 Endoscopic, 248, 274
317
Endothelial cell, 19, 41, 75, 81, 91, 231, 248, 304 Endothelins, 138, 248 Endothelium, 81, 249, 280 Endothelium, Lymphatic, 249 Endothelium, Vascular, 249 Endothelium-derived, 249, 280 Endotoxic, 44, 249, 269 Endotoxin, 249 End-stage renal, 8, 236, 249, 273 Enhancer, 26, 65, 249, 295 Environmental Health, 198, 200, 249 Enzymatic, 153, 233, 234, 238, 242, 249, 250, 259, 273, 295 Eosinophils, 31, 249, 257 Ephedrine, 39, 249 Epidermal, 85, 88, 159, 249, 269, 272, 309 Epidermis, 230, 240, 249, 261, 269, 292 Epigastric, 249, 283 Epinephrine, 47, 220, 245, 249, 279, 280, 307 Epithelial, 21, 28, 45, 93, 229, 250, 275 Epithelial Cells, 45, 250, 275 Epithelium, 28, 228, 249, 250, 266, 284 Epitope, 32, 250 Ergot, 232, 250 Erythrocyte Deformability, 130, 250 Erythrocytes, 223, 224, 231, 244, 246, 250, 283, 294 Erythromycin, 35, 228, 250 Esophagus, 244, 250, 301 Esterification, 164, 250 Estrogen, 250, 289, 298, 303 Ethanol, 163, 164, 165, 175, 177, 237, 250 Ethanolamine, 164, 250 Ether, 163, 250 Ethylene Glycol, 137, 250 Etoposide, 35, 69, 127, 132, 134, 136, 137, 176, 250 Evaluable patients, 51, 251 Evoke, 251, 301 Excipient, 39, 251 Excitation, 251, 252, 279 Excrete, 226, 251, 267, 295 Exfoliation, 251, 278 Exhaustion, 225, 251, 271 Exocrine, 251, 283 Exogenous, 230, 247, 248, 251, 290 Expiration, 251, 295 Extensor, 251, 291 External-beam radiation, 251, 266, 293, 310
Extracellular, 21, 239, 251, 252, 274, 300 Extracellular Matrix, 21, 239, 251, 252 Extracellular Space, 251, 274 Extraction, 145, 251 Extrapyramidal, 245, 251 Exudate, 232, 251 F Facial, 82, 251, 284 Facial Paralysis, 82, 251 Family Planning, 199, 251 Fat, 219, 220, 227, 229, 231, 234, 235, 240, 241, 251, 267, 269, 276, 282, 288, 300, 302, 306 Fatigue, 251, 258 Fatty acids, 129, 131, 152, 164, 175, 188, 221, 252, 256 Feces, 168, 252, 301 Femoral, 77, 252 Femur, 252 Fentanyl, 26, 252 Fibroblasts, 9, 82, 239, 252 Fibrosis, 123, 161, 178, 222, 240, 252, 292, 297 Filtration, 60, 174, 252, 267 Fistula, 184, 252, 281 Flavopiridol, 173, 174, 252 Flexor, 251, 252, 269 Flow Cytometry, 22, 57, 91, 252, 262 Flucytosine, 43, 252 Fludarabine, 92, 107, 252 Fluorescence, 22, 81, 155, 252, 253 Fluorescence Polarization, 81, 155, 252 Fluorescence Polarization Immunoassay, 81, 155, 252 Fluorescent Dyes, 252 Fluorouracil, 245, 253 Fluoxetine, 61, 253 Fluvoxamine, 61, 253 Folate, 253 Fold, 44, 149, 253 Folic Acid, 140, 253 Forearm, 91, 230, 253 Free Radicals, 226, 245, 253, 277 Fructose, 166, 167, 253, 266 Fungicides, Industrial, 225, 253 Fungus, 18, 145, 150, 184, 233, 241, 250, 253 G Gallbladder, 219, 229, 253, 283 Gallopamil, 74, 253 Gamma Rays, 253, 293 Gamma-interferon, 149, 253, 265
318
Cyclosporine
Ganciclovir, 24, 206, 254 Ganglia, 219, 254, 278, 302 Ganglion, 39, 254, 296, 308 Gangrenous, 254, 298 Gas, 223, 233, 244, 250, 254, 260, 266, 271, 280, 295, 302 Gas exchange, 254, 295 Gastrectomy, 3, 254 Gastric, 115, 128, 246, 254, 259, 260, 281, 301 Gastrin, 254, 260 Gastrointestinal, 3, 6, 149, 169, 231, 236, 250, 254, 268, 271, 298, 301, 302, 307 Gastrointestinal tract, 3, 6, 169, 250, 254, 268, 298, 301, 307 Gene Expression, 25, 33, 41, 42, 43, 106, 254 Gene Expression Profiling, 25, 254 Gene Therapy, 16, 54, 254 Genetic Code, 254, 280 Genetic Markers, 27, 254 Genetics, 35, 43, 57, 239, 242, 254 Genital, 236, 255 Genomics, 20, 32, 255 Genotype, 25, 255, 286 Germ Cells, 255, 272, 300, 304 Giardiasis, 255, 274 Gingival Hyperplasia, 4, 9, 86, 100, 208, 255 Gingivitis, 4, 255 Gland, 220, 241, 255, 259, 261, 270, 272, 278, 283, 284, 290, 298, 301, 304 Globus Pallidus, 255, 292 Glomerular, 11, 21, 60, 71, 93, 109, 183, 184, 255, 266, 267, 294 Glomerular Filtration Rate, 11, 109, 255, 267 Glomeruli, 21, 60, 255, 273 Glomerulonephritis, 184, 255, 270 Glomerulosclerosis, 4, 184, 255 Glomerulus, 66, 255, 278 Glucans, 242, 255 Glucocorticoid, 232, 244, 255, 289 Gluconeogenesis, 255 Glucose, 39, 47, 60, 83, 93, 222, 230, 242, 244, 255, 256, 258, 264, 265, 297 Glucose Intolerance, 244, 255 Glucuronic Acid, 256, 259 Glutamate, 244, 256 Glutamic Acid, 253, 256, 279, 289 Glycerol, 177, 256, 286 Glycerophospholipids, 256, 286
Glycine, 69, 162, 229, 256, 279, 298 Glycogen, 256 Glycolysis, 167, 245, 256 Glycoprotein, 17, 26, 34, 82, 88, 96, 119, 132, 133, 136, 256, 276, 285, 304 Glycosidic, 256 Gonadal, 256, 301 Gout, 8, 204, 237, 256, 278 Governing Board, 256, 288 Gp120, 256, 285 Graft, 5, 8, 9, 10, 11, 15, 24, 27, 29, 33, 38, 41, 42, 46, 64, 68, 75, 82, 94, 98, 103, 109, 110, 119, 130, 132, 134, 150, 152, 154, 157, 159, 169, 170, 171, 176, 178, 226, 242, 256, 257, 263, 274, 277, 306 Graft Rejection, 24, 42, 154, 170, 178, 242, 256, 263, 274 Graft Survival, 5, 10, 11, 15, 29, 64, 103, 109, 152, 157, 160, 256 Graft vs Host Reaction, 256, 306 Grafting, 33, 41, 168, 257, 263 Graft-versus-host disease, 33, 64, 109, 130, 134, 159, 176, 226, 257, 277 Gram-negative, 249, 257 Granulation Tissue, 232, 257 Granulocyte, 30, 45, 94, 257 Granulocytopenia, 226, 257 Grasses, 253, 257 Gravis, 162, 257 Growth factors, 21, 41, 178, 257 Guanine, 257, 292 Guanylate Cyclase, 257, 280 H Haematological, 96, 257 Haematology, 95, 96, 129, 134, 139, 257 Hair Cells, 28, 257 Half-Life, 169, 257 Haploid, 257, 287 Haplotypes, 105, 257 Haptens, 221, 257, 293 Hay Fever, 222, 257 Health Care Costs, 37, 257, 258 Health Expenditures, 258 Heart failure, 20, 35, 249, 258, 292 Heart Transplantation, 44, 76, 86, 88, 99, 103, 108, 111, 118, 135, 139, 258 Hematologic malignancies, 68, 258 Hematopoiesis, 31, 52, 258 Hematopoietic growth factors, 58, 258 Hematopoietic Stem Cell Transplantation, 24, 38, 42, 258 Hematopoietic Stem Cells, 24, 258
319
Hematuria, 258, 273 Hemodialysis, 206, 244, 258, 267 Hemodynamics, 71, 83, 84, 258 Hemoglobin, 224, 250, 258, 266, 268 Hemoglobinopathies, 254, 258 Hemolytic, 7, 83, 95, 110, 115, 258 Hemolytic-Uremic Syndrome, 110, 258 Hemorrhage, 258, 277, 292, 301 Hemostasis, 117, 259, 298 Heparin, 160, 167, 259 Hepatic, 24, 26, 63, 86, 122, 131, 174, 221, 238, 259, 299 Hepatitis, 139, 183, 259 Hepatocyte, 236, 259 Hepatotoxicity, 163, 171, 259 Heredity, 254, 259 Herpes, 24, 220, 259 Herpes Zoster, 259 Heterogeneity, 221, 259 High-density lipoproteins, 130, 259 Hirsutism, 4, 259, 261 Hirudin, 160, 259 Histamine, 31, 223, 259 Histidine, 259 Histocompatibility, 63, 182, 259, 274 Histones, 232, 236, 259 Homeostasis, 36, 41, 231, 259 Homogeneous, 106, 153, 260, 286 Homologous, 65, 241, 242, 254, 260, 298, 303, 306 Hormonal, 24, 46, 66, 227, 229, 241, 260 Hormone, 66, 222, 229, 241, 249, 254, 260, 265, 273, 281, 289, 296, 299, 304 Human papillomavirus, 13, 260 Humoral, 150, 171, 256, 260, 306 Humour, 260 Hybrid, 20, 43, 61, 260 Hydrochloric Acid, 176, 260 Hydrogen, 34, 44, 219, 222, 228, 233, 244, 260, 269, 275, 279, 282, 291 Hydrogen Bonding, 34, 260 Hydrogen Peroxide, 44, 260, 269 Hydrolysis, 230, 236, 260, 286, 288, 290, 291 Hydrophilic, 154, 164, 171, 260 Hydrophobic, 161, 163, 164, 168, 173, 174, 256, 260, 269 Hydroxylysine, 237, 260 Hydroxyproline, 237, 260 Hypercholesterolemia, 10, 97, 133, 247, 260 Hyperlipidemia, 97, 247, 260
Hyperlipoproteinemia, 260, 261 Hyperplasia, 5, 9, 178, 261, 269 Hypersensitivity, 65, 97, 150, 159, 171, 176, 222, 224, 244, 261, 268, 296 Hyperthermia, 60, 261 Hyperthyroidism, 261, 290 Hypertrichosis, 259, 261 Hypertriglyceridemia, 10, 247, 261 Hypertrophic cardiomyopathy, 35, 261 Hypertrophy, 20, 35, 240, 261 Hyperuricemia, 8, 112, 149, 256, 261 Hypnotic, 261, 270, 274 Hypoglycemia, 46, 261 Hypoglycemic, 47, 261 Hypokinesia, 261, 284 Hypothalamus, 130, 261, 304 Hypoxanthine, 261, 264 Hypoxia, 19, 261 Hypoxic, 261, 274 I Ibuprofen, 39, 160, 167, 261 Ichthyosis, 154, 261 Idarubicin, 52, 262 Idiopathic, 14, 80, 177, 178, 184, 262, 292, 297 Idiotype, 72, 262 Ifosfamide, 69, 122, 133, 262 Ileum, 262, 267 Imaging procedures, 262, 305 Imidazole, 237, 259, 262, 274 Immune Sera, 262 Immunity, 5, 32, 64, 150, 171, 182, 221, 243, 262, 275, 305, 306 Immunization, 148, 220, 262, 263 Immunoassay, 96, 106, 155, 262 Immunocompromised, 18, 44, 262 Immunocompromised Host, 45, 262 Immunodeficiency, 71, 152, 262 Immunogenic, 262, 269, 293 Immunohistochemistry, 27, 262 Immunologic, 53, 159, 220, 235, 262, 271, 293 Immunology, 30, 51, 63, 67, 69, 98, 130, 155, 220, 221, 253, 262, 306 Immunomodulator, 184, 262 Immunophenotyping, 51, 262 Immunophilin, 29, 148, 156, 160, 232, 263 Immunosuppressive Agents, 18, 28, 31, 32, 41, 145, 162, 169, 170, 179, 182, 184, 263 Immunosuppressive therapy, 6, 13, 59, 94, 98, 153, 169, 171, 263
320
Cyclosporine
Immunotherapy, 23, 31, 164, 220, 229, 244, 263 Immunotoxin, 71, 263 Impairment, 162, 236, 247, 263 Implant radiation, 263, 265, 266, 293, 310 Implantation, 161, 167, 178, 263 In situ, 38, 57, 263 Incision, 263, 266 Incontinence, 249, 263, 282 Indinavir, 26, 63, 263 Indomethacin, 263, 267 Induction therapy, 74, 82, 83, 263 Infancy, 52, 264 Infant, Newborn, 221, 264 Infarction, 264, 295 Infertility, 232, 264 Infiltration, 9, 160, 255, 264 Inflammatory bowel disease, 5, 12, 13, 95, 118, 154, 161, 184, 187, 264 Informed Consent, 47, 50, 54, 264 Infusion, 26, 84, 113, 134, 162, 264, 274, 277, 305 Ingestion, 135, 264, 287 Inhalation, 232, 264, 287 Initiation, 45, 264, 289, 305 Initiator, 229, 264 Inner ear, 264, 297 Inorganic, 236, 264, 276 Inosine Monophosphate, 38, 264 Inositol, 164, 264 Inotropic, 245, 264 Insight, 23, 30, 33, 264 Insulator, 265, 276 Insulin, 10, 12, 46, 59, 99, 229, 265, 267, 283 Insulin-dependent diabetes mellitus, 10, 12, 265 Intercellular Adhesion Molecule-1, 59, 265 Interferon, 84, 163, 253, 265, 270 Interferon-alpha, 84, 265 Interleukin-1, 28, 45, 88, 265 Interleukin-10, 28, 265 Interleukin-2, 64, 91, 163, 265 Interleukins, 263, 265 Intermittent, 186, 247, 265 Internal radiation, 265, 266, 293, 310 Interstitial, 21, 118, 231, 251, 265, 266, 278, 294, 310 Intestinal, 5, 24, 26, 35, 81, 234, 241, 265, 271, 275 Intestine, 90, 168, 171, 229, 231, 238, 265, 268 Intoxication, 265, 309
Intracellular, 20, 21, 28, 29, 46, 65, 232, 264, 265, 266, 273, 280, 288, 294, 299 Intrahepatic, 46, 265 Intramuscular, 266, 284 Intraocular, 39, 266 Intraocular pressure, 39, 266 Intravascular, 177, 178, 266 Intravenous, 12, 26, 71, 95, 98, 100, 103, 113, 163, 165, 178, 205, 206, 264, 266, 274, 284 Intrinsic, 25, 221, 228, 266 Inulin, 255, 266 Invasive, 43, 44, 160, 262, 266, 271 Involuntary, 240, 266, 277, 300 Ionizing, 222, 266, 293 Ionomycin, 21, 266 Ions, 228, 233, 245, 247, 260, 266, 275 Irinotecan, 149, 266 Iris, 227, 240, 266, 292, 308 Irradiation, 24, 37, 41, 266, 310 Irritable Bowel Syndrome, 266, 282 Ischemia, 19, 32, 44, 46, 66, 224, 227, 266, 277, 295 Isoleucine, 162, 266 Isomerases, 242, 266 Isozymes, 22, 63, 267 Itraconazole, 101, 176, 267 J Jejunoileal Bypass, 85, 267 Jejunum, 267 K Kb, 198, 267 Keratoconjunctivitis, 117, 267 Ketoacidosis, 219, 267 Ketoconazole, 73, 81, 101, 137, 267 Ketone Bodies, 219, 267 Ketorolac, 117, 267 Ketorolac Tromethamine, 117, 267 Kidney Disease, 4, 16, 60, 66, 80, 90, 112, 131, 135, 188, 198, 205, 208, 267, 294 Kidney Failure, 59, 66, 249, 255, 267 Kidney Failure, Acute, 267 Kidney Failure, Chronic, 267 Kidney stone, 205, 268, 295, 307 Kidney Transplantation, 4, 6, 7, 15, 73, 83, 84, 87, 89, 104, 109, 116, 120, 182, 188, 204, 267, 268 Kinetics, 22, 26, 28, 33, 268 L Labile, 238, 268 Labyrinth, 237, 264, 268, 308 Large Intestine, 238, 244, 265, 268, 294, 300
321
Latent, 18, 268 Leflunomide, 169, 268 Lens, 234, 268 Lesion, 16, 230, 268, 269, 303, 307 Lethal, 64, 228, 268 Leucine, 162, 268 Leucocyte, 222, 268, 270 Leukaemia, 129, 268 Leukoencephalopathy, 111, 113, 114, 268 Leukotrienes, 31, 133, 138, 227, 268, 269 Levo, 268, 272 Levodopa, 268, 298 Levorphanol, 244, 269 Lichen Planus, 207, 269 Ligament, 269, 290 Ligands, 29, 269 Ligation, 66, 269 Linkage, 149, 254, 269 Lipase, 269, 282 Lipid A, 269, 282 Lipid Peroxidation, 269, 283 Lipoid, 14, 269 Lipophilic, 154, 165, 171, 177, 269 Lipoprotein, 11, 86, 106, 116, 247, 257, 269, 270 Lipoxygenase Inhibitors, 154, 269 Liver cancer, 100, 269 Liver Transplantation, 73, 76, 78, 79, 82, 84, 85, 88, 91, 94, 96, 97, 105, 108, 116, 204, 269 Living Donors, 46, 76, 269 Localization, 46, 70, 262, 269 Localized, 71, 159, 160, 161, 219, 223, 248, 259, 261, 264, 269, 270, 287, 307 Longitudinal Studies, 46, 270 Loop, 64, 270 Lorazepam, 158, 270 Lovastatin, 270, 299 Low-density lipoprotein, 11, 75, 90, 106, 247, 269, 270 Lubricants, 163, 270, 285 Lung Transplantation, 65, 76, 77, 78, 86, 88, 98, 99, 103, 111, 135, 139, 178, 270 Lupus, 14, 65, 84, 91, 141, 153, 184, 204, 270, 303 Lupus Nephritis, 14, 91, 184, 270 Lymph, 248, 249, 260, 270, 278, 283, 297 Lymph node, 270, 278, 283, 297 Lymphatic, 249, 264, 270, 300, 301, 304 Lymphatic system, 270, 300, 301, 304 Lymphoblastic, 25, 270 Lymphoblasts, 50, 58, 219, 270
Lymphocyte Depletion, 263, 270 Lymphoid, 32, 41, 49, 50, 55, 62, 69, 225, 257, 268, 270, 271 Lymphokine, 156, 160, 163, 271 Lymphoma, 51, 55, 69, 114, 115, 134, 258, 270, 271 Lymphopenia, 42, 271 Lymphoproliferative, 53, 59, 67, 96, 271 Lymphoproliferative Disorders, 96, 271 M Macrolides, 117, 176, 271 Macrophage, 28, 30, 45, 85, 100, 265, 271 Macrophage Activation, 85, 271 Magnetic Resonance Imaging, 182, 271 Maintenance therapy, 49, 103, 271 Major Histocompatibility Complex, 24, 160, 257, 271, 274 Malabsorption, 177, 271 Malabsorption syndrome, 177, 271 Malaria, 62, 177, 271 Malaria, Falciparum, 271, 272 Malaria, Vivax, 271 Malignancy, 38, 48, 272, 284 Malignant, 47, 48, 53, 95, 162, 226, 269, 272, 278, 282, 293, 296, 297 Malignant tumor, 162, 272, 282, 296 Malnutrition, 221, 227, 272 Mammary, 168, 272, 303 Mammogram, 232, 272, 274 Mannans, 253, 272 Mastectomy, 231, 272 Mastitis, 272, 298 Maximum Tolerated Dose, 47, 247, 272 Mediate, 29, 33, 178, 245, 272 Mediator, 19, 22, 36, 265, 272, 298 Medical Records, 272, 296 Medicament, 165, 272 MEDLINE, 199, 272 Medullary, 244, 272, 292 Megaloblastic, 253, 272 Meiosis, 272, 303 Melanin, 18, 266, 272, 286, 307 Melanocytes, 272 Melanoma, 149, 272 Melphalan, 52, 272 Membrane Lipids, 273, 286 Membrane Proteins, 273, 291 Membranoproliferative, 184, 273 Memory, 243, 273 Meninges, 235, 247, 273 Meningitis, 43, 71, 267, 273 Menopause, 273, 290
322
Cyclosporine
Mental, iv, 14, 198, 200, 235, 243, 245, 251, 261, 273, 291, 294, 297, 307 Mental Processes, 245, 273, 291 Mercaptopurine, 13, 273 Mercury, 252, 273 Mesencephalic, 27, 273 Metabolic disorder, 256, 273 Metabolite, 27, 148, 149, 150, 158, 160, 163, 167, 169, 177, 230, 245, 270, 273, 289 Metastasis, 273 Metastatic, 102, 136, 273 Methotrexate, 13, 50, 52, 55, 68, 73, 80, 105, 186, 188, 273 Methylprednisolone, 68, 94, 273 Metronidazole, 117, 274 Miconazole, 158, 274 Microbe, 274, 305 Microcalcifications, 232, 274 Microdialysis, 136, 274 Microgram, 44, 176, 274 Microorganism, 45, 237, 274, 284, 309 Microscopy, 131, 228, 274 Microspheres, 246, 274 Microtubules, 274, 283 Midazolam, 25, 26, 274 Migration, 27, 265, 271, 274 Milligram, 274 Milliliter, 176, 274 Minor Histocompatibility Antigens, 24, 64, 274 Minor Histocompatibility Loci, 274 Miosis, 275 Miotic, 26, 275, 287 Mitochondria, 36, 132, 275, 277, 282 Mitochondrial Swelling, 275, 278 Mitosis, 226, 227, 275 Mitotic, 245, 250, 275, 303, 304, 309 Mitotic inhibitors, 245, 275, 303 Mitoxantrone, 15, 34, 136, 137, 275 Mobility, 37, 275 Modeling, 26, 34, 59, 246, 275 Modification, 37, 275, 292 Modulator, 138, 275 Molecular Conformation, 39, 275 Molecular mass, 36, 156, 275 Molecular Structure, 39, 173, 275, 306 Monensin, 22, 275 Monitor, 9, 30, 241, 275, 280 Monoamine, 276, 298 Monoclonal, 7, 32, 42, 68, 148, 155, 160, 166, 167, 243, 266, 276, 293, 310
Monoclonal antibodies, 68, 148, 155, 160, 167, 243, 276 Monocytes, 32, 265, 276, 277 Mononuclear, 95, 160, 276 Monotherapy, 78, 89, 94, 96, 276 Morphological, 68, 248, 253, 272, 276 Morphology, 35, 135, 257, 271, 276 Motility, 263, 276, 298 Mucinous, 254, 276 Mucins, 276, 297 Mucolytic, 163, 219, 276 Mucosa, 45, 207, 270, 276, 289 Mucositis, 276, 304 Mucus, 276, 307 Multicenter Studies, 12, 276 Multicenter study, 109, 110, 118, 120, 276 Multidrug resistance, 17, 34, 49, 138, 276, 285 Multiple sclerosis, 4, 154, 276 Multivariate Analysis, 114, 276 Muscle Fibers, 276, 277 Muscular Diseases, 251, 277 Mutagenic, 222, 277 Myasthenia, 162, 277 Myelin, 276, 277 Myelodysplastic Syndromes, 18, 92, 94, 277 Myelogenous, 277 Myeloid Cells, 32, 277 Myeloproliferative Disorders, 53, 277 Myelosuppression, 149, 277 Myocardial infarction, 277, 290 Myocardial Reperfusion, 277, 295 Myocardial Reperfusion Injury, 277, 295 Myocardium, 20, 224, 277 Myopathy, 128, 277 Myosin, 35, 232, 277 N Naphthoquinones, 244, 277 Naproxen, 39, 278 Narcolepsy, 249, 278 Narcotic, 252, 269, 278, 283 Nausea, 246, 278, 283, 307 NCI, 1, 197, 236, 278 Necrolysis, 85, 278 Necrosis, 77, 120, 182, 227, 258, 264, 277, 278, 295, 296, 297 Neonatal, 27, 33, 278 Neoplasia, 57, 278 Neoplasm, 278, 297, 307 Neoral, 3, 6, 8, 9, 12, 77, 78, 91, 97, 98, 107, 109, 141, 182, 192, 207, 278
323
Neostriatum, 278, 292 Nephrectomy, 67, 278 Nephritis, 66, 81, 278 Nephrologist, 188, 278 Nephron, 104, 133, 255, 278 Nephropathy, 8, 11, 14, 21, 65, 67, 77, 103, 106, 119, 184, 267, 278 Nephrosis, 14, 60, 278 Nephrotic, 4, 10, 12, 60, 90, 93, 98, 100, 107, 112, 184, 269, 278 Nephrotic Syndrome, 4, 10, 12, 90, 93, 98, 100, 112, 184, 269, 278 Nephrotoxic, 21, 162, 278 Nervous System, 9, 18, 22, 27, 54, 154, 219, 221, 232, 235, 247, 249, 254, 256, 257, 268, 272, 276, 278, 279, 281, 288, 298, 302, 304 Neural, 22, 27, 221, 260, 279 Neuroblastoma, 49, 51, 52, 53, 55, 58, 279 Neurology, 45, 58, 69, 87, 279 Neuronal, 16, 22, 30, 68, 237, 279 Neurons, 27, 29, 68, 243, 254, 268, 279, 302, 303, 308 Neuropathy, 87, 279, 285 Neurosurgery, 56, 58, 69, 279 Neurotoxic, 30, 279 Neurotoxicity, 30, 90, 111, 112, 244, 279 Neurotoxin, 27, 279 Neurotransmitter, 219, 220, 231, 245, 256, 259, 279, 280, 299, 302 Neutrons, 222, 266, 279, 293 Neutropenia, 44, 68, 279 Neutrophil, 44, 265, 279 Neutrophil Activation, 45, 279 Niacin, 204, 279, 306 Nifedipine, 133, 279 Nisoldipine, 99, 279 Nitric Oxide, 44, 86, 280 Nitrogen, 222, 242, 267, 272, 275, 280, 306 Norepinephrine, 220, 245, 249, 279, 280 Nuclear, 19, 20, 33, 41, 46, 65, 133, 139, 228, 233, 239, 248, 253, 254, 278, 280, 296, 307 Nuclear Proteins, 65, 280 Nuclei, 222, 239, 248, 251, 254, 259, 271, 275, 279, 280, 281, 291, 308 Nucleic acid, 13, 14, 219, 243, 254, 261, 280, 292 Nucleoproteins, 280 Nurse Practitioners, 54, 280 Nystatin, 206, 280
O Obsession, 239, 280 Obsessive-Compulsive Disorder, 253, 280 Octreotide, 206, 280 Ocular, 158, 163, 281 Oculomotor, 273, 281 Ointments, 246, 281 Oligopeptides, 34, 165, 173, 176, 177, 281 Oliguria, 267, 281 Omeprazole, 281, 291 Oncologist, 281 Opacity, 234, 281 Operon, 281, 289, 295 Ophthalmic, 158, 163, 192, 281 Opportunistic Infections, 62, 152, 179, 184, 281 Opsin, 281, 296 Optic Chiasm, 261, 281 Optic Nerve, 39, 281, 283, 295, 296, 297 Oral Health, 281 Oral Hygiene, 4, 281 Organelles, 235, 243, 272, 276, 282 Orlistat, 108, 282 Ornithine, 153, 282 Orthostatic, 281, 282 Osteogenic sarcoma, 282 Osteoporosis, 231, 282 Osteosarcoma, 45, 51, 282 Outpatient, 282 Overall survival, 42, 282 Overweight, 124, 204, 282 Oxidants, 44, 282 Oxidation, 219, 226, 230, 242, 269, 282, 283 Oxidation-Reduction, 230, 282 Oxidative metabolism, 268, 282 Oxidative Phosphorylation, 45, 283 Oxidative Stress, 30, 46, 105, 123, 138, 283 Oxycodone, 26, 283 Oxygen Consumption, 283, 295 Oxygenase, 16, 283 P P53 gene, 50, 283 Pachymeningitis, 273, 283 Paclitaxel, 34, 122, 123, 133, 136, 137, 138, 175, 176, 186, 283 Paediatric, 101, 283 Palliative, 26, 152, 283, 304 Pancreas, 6, 21, 46, 87, 110, 116, 119, 150, 163, 171, 177, 219, 222, 229, 265, 269, 283, 305, 307 Pancreas Transplant, 6, 46, 119, 283 Pancreas Transplantation, 46, 119, 283
324
Cyclosporine
Pancreatectomy, 46, 283 Pancreatic, 10, 46, 283 Pancytopenia, 30, 283 Panic, 253, 283 Panic Disorder, 253, 283 Panniculitis, 89, 284 Papillomavirus, 13, 284 Paralysis, 251, 273, 284 Parasite, 62, 284, 306 Parasitic, 62, 176, 241, 284 Parenchyma, 14, 284 Parenteral, 12, 153, 163, 284 Paresis, 251, 284 Parkinsonism, 27, 268, 284 Parotid, 284, 297 Paroxetine, 61, 284 Partial remission, 4, 284, 294 Partial response, 61, 149, 284 Particle, 39, 150, 161, 171, 284, 305 Pathogen, 43, 71, 284 Pathologic, 21, 86, 219, 227, 230, 232, 233, 240, 261, 284, 291, 295 Pathologic Processes, 227, 284 Pathophysiology, 11, 33, 284 Patient Compliance, 182, 284 Patient Education, 13, 204, 212, 214, 217, 284 Pelvic, 285, 290 Pelvis, 219, 285 Penicillin, 225, 285, 308 Peptide, 29, 34, 63, 150, 153, 163, 164, 285, 288, 290 Peptide T, 150, 285 Percutaneous, 161, 285 Perfusion, 261, 285 Pericardium, 285, 303 Perillyl alcohol, 170, 285 Periodontitis, 255, 285 Peripheral blood, 30, 42, 52, 59, 71, 95, 106, 107, 109, 226, 258, 265, 285 Peripheral Neuropathy, 30, 285 Peripheral stem cell transplantation, 115, 285 Peripheral stem cells, 257, 285 Peroral, 176, 285 Petrolatum, 248, 285 Petroleum, 163, 285 P-Glycoprotein, 149, 285 Phagocyte, 282, 285 Phagocytosis, 45, 285 Pharmaceutical Preparations, 250, 286, 290
Pharmaceutical Solutions, 246, 286 Pharmacist, 207, 286 Pharmacodynamic, 22, 26, 44, 59, 286 Pharmacokinetic, 12, 22, 26, 35, 59, 63, 77, 84, 101, 110, 137, 157, 286 Pharmacologic, 20, 31, 53, 55, 123, 137, 224, 228, 241, 257, 286, 305 Phenolphthalein, 248, 286 Phenotype, 17, 20, 24, 31, 36, 286 Phenyl, 27, 286 Phenylalanine, 28, 286, 307 Phorbol, 22, 286 Phorbol Esters, 22, 286 Phospholipases, 286, 299 Phospholipids, 171, 251, 264, 269, 273, 286 Phosphorus, 206, 233, 286 Phosphorylated, 237, 244, 286 Phosphorylation, 40, 60, 62, 64, 242, 286 Physiologic, 41, 63, 221, 230, 257, 261, 266, 286, 294, 295, 306 Physiology, 167, 220, 286 Pigment, 272, 286 Pilocarpine, 163, 287 Pilot Projects, 55, 287 Pilot study, 13, 23, 111, 136, 184, 287 Plants, 221, 233, 234, 236, 243, 255, 266, 276, 280, 287, 288, 297, 305, 306 Plaque, 4, 105, 161, 224, 287 Plasma cells, 225, 257, 287 Plasmapheresis, 6, 287 Plasticity, 68, 287 Platelet Activation, 287, 299 Platelet Aggregation, 223, 280, 287 Platelets, 277, 280, 283, 287 Ploidy, 57, 287 Pneumonia, 118, 232, 240, 287, 306 Pneumonitis, 65, 97, 287 Podophyllotoxin, 250, 287, 303 Poisoning, 247, 250, 265, 273, 278, 287 Polyesters, 167, 287 Polyethylene, 167, 175, 287, 288 Polymerase, 288, 289, 295 Polymers, 160, 246, 287, 288, 290 Polymorphic, 29, 32, 288 Polypeptide, 150, 176, 223, 237, 247, 288, 289, 290, 310 Polyposis, 238, 288 Polysaccharide, 225, 288 Polyunsaturated fat, 132, 153, 288 Pons, 79, 251, 288 Posterior, 111, 113, 114, 223, 227, 245, 246, 266, 283, 288, 297
325
Postnatal, 288, 301 Postoperative, 4, 7, 169, 267, 288 Postsynaptic, 288, 299 Potassium, 125, 131, 206, 288 Potentiates, 97, 265, 288 Potentiating, 229, 288 Potentiation, 47, 288, 299 Practice Guidelines, 200, 288 Precipitation, 154, 289 Preclinical, 35, 64, 65, 174, 289 Precursor, 37, 224, 227, 236, 242, 245, 247, 249, 268, 280, 286, 289, 306, 307, 308 Predictive factor, 75, 289 Prednisolone, 78, 90, 92, 207, 273, 289 Prednisone, 8, 9, 27, 38, 75, 76, 103, 115, 120, 170, 205, 207, 208, 289 Prevalence, 8, 61, 289 Primary Sclerosing Cholangitis, 5, 289 Probe, 21, 26, 38, 63, 274, 289 Prodrug, 38, 289 Progeny, 239, 289 Progesterone, 289, 301 Progression, 8, 10, 73, 85, 86, 174, 224, 242, 289, 298 Progressive, 8, 11, 30, 115, 117, 118, 169, 179, 188, 234, 236, 243, 246, 267, 278, 287, 289, 292, 294, 307 Projection, 243, 280, 281, 289 Prolactin, 232, 289 Proline, 64, 150, 153, 162, 237, 260, 289 Promoter, 23, 47, 289 Promotor, 289, 295 Prophase, 289, 303 Prophylaxis, 33, 94, 109, 290, 296 Propranolol, 39, 290 Propylene Glycol, 175, 290 Prospective study, 6, 116, 290 Prostate, 174, 229, 290, 307 Prosthesis, 167, 290 Protease, 34, 96, 154, 238, 263, 290, 297 Protease Inhibitors, 154, 290 Protein Binding, 156, 290 Protein C, 148, 150, 221, 223, 226, 269, 290, 307 Protein Conformation, 223, 290 Protein Folding, 34, 290 Protein S, 13, 14, 22, 34, 183, 230, 250, 254, 290, 296 Proteinuria, 81, 255, 273, 278, 290 Proteolytic, 222, 238, 290 Protocol, 8, 10, 18, 27, 35, 40, 47, 49, 50, 51, 52, 54, 55, 56, 57, 74, 103, 290
Proton Pump, 36, 43, 281, 291 Proton Pump Inhibitors, 43, 291 Protons, 36, 222, 260, 266, 291, 293 Proto-Oncogene Proteins, 283, 291 Proto-Oncogene Proteins c-mos, 283, 291 Protozoa, 239, 274, 291 Protozoal, 158, 177, 291 Protozoan, 241, 255, 271, 291, 306 Proximal, 66, 171, 245, 267, 291 Pruritic, 247, 269, 291 Psoriasis, 73, 77, 78, 105, 139, 141, 154, 159, 161, 166, 171, 186, 204, 291, 296 Psychiatric, 63, 291 Psychiatry, 26, 69, 291 Psychoactive, 291, 309 Psychology, 58, 239, 245, 291 Public Policy, 199, 291 Publishing, 70, 291 Pulmonary, 19, 86, 101, 178, 230, 240, 267, 268, 292, 302, 308 Pulmonary Artery, 19, 230, 292, 308 Pulmonary Edema, 267, 292 Pulmonary Fibrosis, 178, 292 Pulse, 276, 292 Pupil, 240, 275, 292 Purifying, 166, 292 Purines, 204, 292, 298 Purpura, 5, 6, 7, 81, 89, 139, 140, 292 Purulent, 292, 308 Putamen, 68, 278, 292 Pyoderma, 12, 95, 113, 115, 292 Pyoderma Gangrenosum, 12, 113, 115, 292 Pyrazinamide, 128, 292 Pyrimidines, 292, 298 Pyrogenic, 167, 292 Q Quality of Health Care, 292, 306 Quality of Life, 13, 37, 38, 69, 182, 292, 302 Quaternary, 290, 292 Quiescent, 71, 292 Quinoxaline, 247, 292 R Race, 272, 274, 292, 293 Racemic, 272, 293 Radiation oncologist, 47, 281, 293 Radiation therapy, 50, 58, 153, 251, 265, 266, 293, 297, 310 Radioactive, 155, 228, 257, 260, 263, 265, 266, 276, 280, 293, 303, 307, 310 Radioimmunoassay, 81, 155, 293 Radioimmunotherapy, 293 Radioisotope, 293, 305
326
Cyclosporine
Radiolabeled, 266, 293, 310 Radiological, 285, 293 Radiology, 58, 293 Radiosensitization, 136, 138, 293 Radiotherapy, 49, 55, 231, 266, 293, 301, 310 Randomized clinical trial, 31, 56, 95, 293 Reactivation, 18, 294 Reactive Oxygen Species, 45, 294 Reagent, 21, 250, 260, 294 Receptor, 12, 22, 23, 24, 31, 32, 40, 60, 63, 64, 65, 72, 100, 157, 220, 225, 244, 245, 256, 285, 293, 294, 298, 299 Receptors, Serotonin, 294, 298 Recombinant, 15, 22, 30, 41, 156, 294, 308 Recombination, 65, 239, 254, 294 Rectum, 226, 238, 244, 254, 263, 264, 268, 290, 294 Recurrence, 15, 21, 294 Red blood cells, 250, 258, 277, 283, 294, 297 Reductase, 270, 273, 294, 299 Refer, 1, 158, 164, 232, 238, 259, 269, 279, 293, 294, 305, 308 Refraction, 224, 294, 300 Refractory, 5, 38, 52, 80, 95, 103, 114, 129, 136, 139, 161, 178, 184, 294 Regeneration, 28, 294 Rehabilitative, 38, 294 Relapse, 6, 7, 14, 25, 47, 50, 55, 69, 80, 84, 94, 184, 294 Remission, 4, 6, 25, 80, 107, 114, 184, 219, 271, 294 Renal cell carcinoma, 136, 294 Renal failure, 21, 162, 294 Renal Osteodystrophy, 67, 294 Renal pelvis, 268, 294 Renal tubular, 66, 295 Renin, 135, 224, 295 Renin-Angiotensin System, 135, 295 Reperfusion, 19, 44, 46, 66, 277, 295 Reperfusion Injury, 19, 46, 66, 295 Repressor, 23, 281, 295 Research Personnel, 54, 295 Residual disease, 58, 84, 295 Resorption, 231, 295 Respiration, 36, 233, 275, 282, 295 Respiratory failure, 179, 295 Response Elements, 64, 72, 295 Response rate, 4, 295 Retina, 239, 240, 268, 281, 295, 296, 297, 308
Retinal, 39, 281, 295, 296 Retinal Ganglion Cells, 39, 281, 296 Retinoids, 296, 309 Retinol, 117, 295, 296 Retraction, 60, 296 Retreatment, 72, 296 Retrospective, 8, 10, 11, 296 Retrospective study, 10, 296 Retroviral vector, 254, 296 Reversion, 9, 296 Rhabdomyolysis, 98, 101, 296 Rhabdomyosarcoma, 56, 69, 296 Rheumatoid, 82, 141, 153, 161, 166, 171, 177, 205, 278, 282, 296 Rheumatoid arthritis, 153, 161, 166, 171, 205, 278, 296 Rhinitis, 249, 296, 298 Rhodopsin, 281, 296 Ribosome, 296, 306 Rigidity, 284, 287, 296 Risk factor, 10, 44, 85, 99, 114, 179, 204, 290, 296 Ritonavir, 96, 154, 297 Rods, 296, 297 S Saccule, 28, 297, 308 Saccule and Utricle, 28, 297 Saliva, 4, 297 Salivary, 242, 297 Salivary glands, 242, 243, 297 Salvage Therapy, 99, 297 Saponins, 297, 301 Sarcoidosis, 65, 118, 154, 297 Sarcoma, 48, 51, 69, 128, 297, 300 Sarcomere, 35, 297 Schizoid, 297, 309 Schizophrenia, 69, 297, 309 Schizotypal Personality Disorder, 297, 309 Sclera, 239, 240, 297, 308 Sclerosis, 4, 32, 40, 227, 276, 297 Screening, 63, 152, 166, 237, 297 Secretion, 22, 45, 47, 68, 99, 149, 232, 241, 259, 260, 265, 276, 281, 297, 298 Secretory, 46, 281, 298 Sedative, 237, 270, 274, 298 Sedimentation, 235, 298, 306 Segmental, 4, 184, 255, 298 Segmentation, 298 Segregation, 294, 298 Selective estrogen receptor modulator, 298, 303 Selegiline, 206, 298
327
Semen, 290, 298 Semisynthetic, 158, 174, 232, 233, 250, 283, 298, 303 Sepsis, 7, 298 Septicaemia, 298 Sequence Homology, 285, 298 Serine, 64, 162, 164, 165, 166, 291, 298 Serologic, 262, 298 Serotonin, 61, 237, 253, 279, 284, 294, 298, 306 Serotypes, 15, 298 Serous, 249, 298 Sertraline, 61, 298 Serum Albumin, 293, 299 Sex Characteristics, 220, 299 Shock, 44, 60, 95, 224, 299, 306 Signal Transduction, 43, 232, 264, 299 Signs and Symptoms, 294, 299 Silicon, 122, 299 Silicon Dioxide, 299 Simvastatin, 101, 299 Skeletal, 37, 70, 277, 296, 299, 300 Skeleton, 66, 219, 231, 252, 299 Skin graft, 115, 300 Small intestine, 24, 150, 163, 171, 236, 247, 255, 260, 262, 265, 267, 300 Smooth muscle, 16, 41, 123, 137, 178, 222, 223, 228, 232, 239, 259, 277, 295, 300, 302 Social Environment, 292, 300 Sodium, 71, 85, 149, 168, 170, 206, 256, 275, 278, 300 Soft tissue, 69, 205, 231, 299, 300 Soft tissue sarcoma, 69, 300 Solid tumor, 50, 52, 54, 57, 69, 246, 300 Solvent, 157, 175, 219, 250, 256, 286, 290, 300 Soma, 300 Somatic, 45, 220, 260, 272, 275, 285, 300 Soybean Oil, 288, 300 Spasm, 273, 300 Specialist, 209, 300 Specificity, 63, 155, 221, 300 Spectroscopic, 39, 300 Spectrum, 18, 41, 177, 237, 241, 267, 300 Sperm, 236, 300, 306 Spinal cord, 235, 236, 247, 248, 254, 273, 278, 279, 283, 301, 302 Spleen, 223, 242, 270, 283, 297, 301 Stabilization, 115, 171, 301 Standard therapy, 38, 301 Statistically significant, 11, 40, 53, 301 Steady state, 165, 301
Stem Cells, 24, 27, 33, 65, 222, 258, 285, 301 Stent, 160, 161, 301 Stereotactic, 49, 50, 301 Sterile, 167, 301 Sterility, 242, 264, 301 Steroid, 6, 11, 12, 14, 27, 38, 43, 79, 95, 98, 103, 106, 111, 118, 187, 229, 241, 297, 299, 301 Steroid therapy, 6, 301 Stimulant, 192, 232, 259, 301, 308 Stimulus, 10, 20, 246, 247, 251, 301, 304 Stomach, 4, 207, 208, 219, 229, 244, 250, 254, 260, 278, 283, 291, 300, 301 Stomach Ulcer, 208, 301 Stool, 238, 263, 266, 268, 301 Stress, 13, 20, 43, 44, 46, 54, 60, 233, 234, 266, 278, 283, 296, 301, 307 Striatum, 68, 255, 278, 301 Stroke, 198, 233, 301 Stroke Volume, 233, 301 Stroma, 266, 284, 302 Subacute, 27, 40, 264, 302 Subclinical, 123, 264, 302 Subcutaneous, 115, 247, 254, 284, 302 Subspecies, 300, 302 Substance P, 242, 250, 273, 298, 302 Substrate, 34, 150, 167, 267, 269, 302 Suction, 252, 302 Superoxide, 44, 302 Supplementation, 128, 131, 132, 135, 137, 138, 302 Supportive care, 55, 302 Suppression, 64, 67, 128, 159, 177, 241, 302 Suppressive, 97, 152, 177, 302 Surfactant, 154, 164, 175, 250, 302, 309 Survival Rate, 152, 282, 302 Sympathetic Nervous System, 279, 302 Sympathomimetic, 245, 249, 280, 302 Symphysis, 290, 302 Symptomatic, 164, 302 Symptomatic treatment, 164, 302 Synapse, 221, 303, 306 Synapsis, 303 Synaptic, 27, 279, 299, 303 Synergistic, 32, 43, 166, 289, 303 Synovial, 82, 303 Systemic disease, 79, 261, 303 Systemic lupus erythematosus, 177, 205, 270, 303 Systolic, 11, 261, 303 Systolic blood pressure, 11, 303
328
Cyclosporine
T Tamoxifen, 122, 133, 136, 298, 303 Tardive, 237, 303 Taxanes, 34, 158, 303 Technetium, 133, 139, 303 Telencephalon, 228, 235, 303 Tendon, 238, 254, 303 Teniposide, 158, 303 Teratogenic, 222, 245, 304 Testis, 32, 304 Theophylline, 122, 292, 304 Therapeutics, 26, 54, 57, 82, 92, 93, 98, 100, 113, 138, 149, 173, 192, 304 Thermal, 18, 224, 245, 279, 304 Thermography, 118, 304 Thigh, 252, 304 Third Ventricle, 261, 304 Threonine, 162, 285, 291, 298, 304 Threshold, 59, 261, 304 Thrombin, 287, 290, 304 Thrombocytopenia, 7, 226, 258, 304 Thrombomodulin, 290, 304 Thrombosis, 117, 119, 161, 277, 290, 301, 304 Thrush, 233, 304 Thymidine, 24, 304 Thymidine Kinase, 24, 304 Thymus, 62, 262, 270, 304, 306 Thyroid, 261, 304, 307 Thyroxine, 221, 286, 304 Tolerance, 23, 29, 32, 43, 62, 160, 182, 220, 256, 305 Tone, 281, 305 Topical, 77, 117, 154, 159, 160, 163, 184, 186, 250, 260, 285, 305 Topoisomerase inhibitors, 266, 305 Topotecan, 149, 305 Total pancreatectomy, 283, 305 Toxicokinetics, 117, 305 Toxicology, 35, 44, 200, 305 Toxin, 62, 249, 305 Toxoplasmosis, 228, 305 Trace element, 231, 299, 305 Tracer, 155, 305 Transcription Factors, 23, 41, 64, 65, 128, 295, 305 Transduction, 16, 24, 299, 305 Transfection, 230, 254, 305 Transfer Factor, 262, 305 Transfusion, 103, 131, 139, 152, 305 Translation, 65, 250, 306 Translational, 24, 42, 52, 306
Translocate, 39, 306 Translocation, 65, 148, 250, 306 Transmitter, 219, 245, 272, 280, 306 Transplantation Immunology, 66, 306 Trauma, 22, 153, 278, 306 Treatment Failure, 17, 306 Tremor, 273, 284, 306 Trichomoniasis, 274, 306 Tricyclic, 237, 306 Triglyceride, 11, 130, 164, 260, 261, 306 Trimethoprim-sulfamethoxazole, 206, 306 Tropism, 18, 306 Tryptophan, 237, 298, 306 Tuberculosis, 242, 270, 306 Tubulin, 49, 274, 306 Tumor marker, 229, 306 Tumor suppressor gene, 283, 307 Tumour, 254, 307 Tunica, 248, 276, 307 Tyrosine, 21, 27, 64, 245, 307 U Ulcer, 115, 257, 301, 307 Ulcerative colitis, 5, 12, 99, 100, 103, 108, 109, 113, 154, 162, 184, 187, 264, 289, 292, 307 Uranium, 303, 307 Urea, 267, 282, 307 Urease, 18, 307 Uremia, 267, 294, 307 Ureters, 268, 307 Urethra, 161, 290, 307 Uric, 8, 112, 204, 256, 261, 292, 307 Urinary, 117, 233, 236, 242, 249, 263, 281, 307 Urinary tract, 242, 307 Urinary tract infection, 242, 307 Urinate, 307, 309 Urine, 63, 162, 168, 226, 230, 241, 245, 258, 263, 267, 268, 281, 290, 294, 307 Urticaria, 118, 224, 307 Uvea, 307, 308 Uveitis, 12, 104, 151, 154, 161, 166, 308 V Vaccine, 220, 291, 308 Vagina, 233, 308 Vaginitis, 233, 308 Valine, 162, 308 Vascular endothelial growth factor, 82, 308 Vasculitis, 13, 14, 118, 308 Vasoconstriction, 158, 250, 308
329
Vasodilator, 231, 245, 253, 259, 277, 279, 308 Vector, 305, 308 Vein, 158, 266, 280, 284, 308 Venom, 160, 167, 308 Venous, 290, 308 Venter, 308 Ventral, 27, 261, 281, 288, 308 Ventricle, 240, 292, 303, 304, 308 Venules, 231, 233, 249, 308 Verapamil, 74, 253, 308 Vestibular, 28, 257, 308 Vestibule, 237, 264, 297, 308 Vestibulocochlear Nerve, 297, 308 Veterinary Medicine, 122, 199, 309 Vinblastine, 136, 138, 306, 309 Vinca Alkaloids, 309 Vincristine, 52, 140, 306, 309 Vinorelbine, 35, 309 Viral, 7, 15, 67, 179, 219, 248, 305, 309 Virulence, 18, 43, 228, 229, 305, 309 Virus, 24, 29, 70, 71, 114, 152, 249, 256, 260, 265, 287, 296, 305, 309 Viscera, 300, 309 Viscosity, 219, 309 Vitamin A, 264, 296, 309
Vitro, 15, 18, 19, 20, 29, 30, 31, 33, 36, 37, 42, 45, 52, 53, 60, 62, 63, 65, 68, 71, 90, 134, 136, 139, 149, 174, 229, 254, 259, 263, 303, 309 Vivo, 19, 23, 24, 25, 26, 28, 29, 31, 36, 42, 44, 45, 53, 60, 68, 119, 128, 134, 156, 165, 229, 246, 254, 259, 263, 270, 274, 282, 303, 309 Void, 63, 309 W Warts, 260, 287, 309 Wetting Agents, 163, 309 White blood cell, 208, 219, 225, 228, 230, 236, 257, 270, 271, 276, 277, 279, 287, 309 Withdrawal, 9, 11, 12, 27, 83, 91, 104, 106, 107, 111, 114, 118, 120, 186, 309 Wound Healing, 159, 309 X Xenograft, 134, 169, 224, 306, 309 X-ray, 252, 253, 266, 272, 280, 293, 301, 309, 310 X-ray therapy, 266, 310 Y Yeasts, 233, 253, 286, 310 Z Zygote, 239, 310 Zymogen, 290, 310
330
Cyclosporine
331
332
Cyclosporine
